WO2012149329A2 - Methods of predicting the development of complement-mediated disease - Google Patents

Methods of predicting the development of complement-mediated disease Download PDF

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WO2012149329A2
WO2012149329A2 PCT/US2012/035467 US2012035467W WO2012149329A2 WO 2012149329 A2 WO2012149329 A2 WO 2012149329A2 US 2012035467 W US2012035467 W US 2012035467W WO 2012149329 A2 WO2012149329 A2 WO 2012149329A2
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subject
macular degeneration
related macular
age
complement
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English (en)
French (fr)
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WO2012149329A3 (en
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Gregory S. Hageman
Christian Matthew PAPPAS
Eric N. Brown
David HUTCHESON
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University of Utah Research Foundation Inc
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University of Utah Research Foundation Inc
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Priority to CN201280031235.6A priority Critical patent/CN103874526A/zh
Priority to AU2012249521A priority patent/AU2012249521A1/en
Priority to JP2014508602A priority patent/JP2014513958A/ja
Priority to US14/114,751 priority patent/US20140357732A1/en
Priority to DK12776262.3T priority patent/DK2704800T3/en
Priority to EP12776262.3A priority patent/EP2704800B1/en
Priority to CA2834676A priority patent/CA2834676A1/en
Priority to SG2013080502A priority patent/SG194235A1/en
Priority to BR112013027851A priority patent/BR112013027851A2/pt
Priority to KR1020137031638A priority patent/KR20140074258A/ko
Application filed by University of Utah Research Foundation Inc filed Critical University of Utah Research Foundation Inc
Publication of WO2012149329A2 publication Critical patent/WO2012149329A2/en
Publication of WO2012149329A3 publication Critical patent/WO2012149329A3/en
Anticipated expiration legal-status Critical
Priority to US15/634,892 priority patent/US20180155788A1/en
Priority to US16/734,168 priority patent/US20200239958A1/en
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    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease
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    • G01N2800/60—Complex ways of combining multiple protein biomarkers for diagnosis

Definitions

  • the invention relates generally to the diagnosis and treatment of complement- mediated disease in a human subject. Specifically, the invention relates to the prediction or diagnosis of age-related macular degeneration through the detection of a collection of polymorphisms and haplotypes comprised of multiple variations in the CFH-to-F13B locus.
  • Age related macular degeneration a complement-mediated disease
  • AMD Age related macular degeneration
  • C3 Chrl, ChrlO, Chr6 (CFB), and Chrl9 (C3).
  • the RCA gene cluster is located on chromosome lq32 and includes the genes for complement factor
  • CFH Factor H
  • CFHR1, CFHR2, CFHR3, CFHR4 and CFHR5 Factor H-related genes
  • CFHR5 Factor H-related genes
  • CFHR5 Factor H-related genes
  • CFHR5 the gene encoding the beta subunit of coagulation factor XIII.
  • CFH is a significant regulator of complement activity and is thought to be essential to prevent injury to self-tissues by inappropriate C3 activation. Additionally, alterations in CFH activity have been associated with altered binding to membrane bound glycoproteins, other complement inhibitors, and the surface of pathogenic bacteria.
  • Described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes, wherein the one or more haplotypes are H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, HI 1_62_A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates the subject's susceptibility for having or developing a complement-mediated disease.
  • Also described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes, wherein the one or more haplotypes are HI 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9_51_A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates the subject's susceptibility for having or developing a complement-mediated disease.
  • Also described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes, wherein the one or more haplotypes are HI 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9_51_A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates the subject's susceptibility for having or developing a complement-mediated disease.
  • Also described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of at least six SNPs in the CFH-to- F13B locus, wherein the SNPs are: (i) rs35928059, rs800292, rsl061170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage
  • Also described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the subject the identity of one or more SNPs in the CFH-to-F13B locus, wherein the SNPs is: (i) rsl061170, rsl410996, rs2274700, rs3753395, rs403846, or rs3753396 or (ii) a SNP in linkage disequilibrium with the SNPs of (i), and wherein the presence of one or more of the SNPs indicates the subject's susceptibility for having or developing a complement-mediated disease.
  • Also described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the subject the identity of a deletion tagging SNP in the CFH-to-F13B locus, wherein the SNP is: (i) rsl2144939 or (ii) a SNP in linkage disequilibrium with rsl2144939, and wherein the presence of the SNP indicates the subject's susceptibility for having or developing a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes, wherein the one or more haplotypes are H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H11 62 A, H12 62 A, H13 62 A,
  • Also described herein are methods of identifying a Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes, wherein the one or more haplotypes are H1 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51_A, H15 51_A, H16 51_A, H17 51_A, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates whether the subject is in need of treatment for a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes, wherein the one or more haplotypes are H1 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, HI 4 51 A, HI 5 51 A, HI 6 51 A, HI 7 51 A, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates whether the subject is in need of treatment for a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the subject the identity of one or more SNPs in the CFH-to-F13B locus, wherein the
  • SNPs is: (i) rsl061170, rsl410996, rs2274700, rs3753395, rs403846, or rs3753396 or (ii) a SNP in linkage disequilibrium with the SNPs of (i), and wherein the presence of one or more of the SNPs indicates whether the subject is in need of treatment for a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the subject the identity of a deletion tagging SNP in the CFH-to-F13B locus, wherein the SNPs are: (i) rsl2144939 or (ii) a SNP in linkage disequilibrium with rsl2144939, and wherein the presence of one or more of the SNPs indicates whether the subject is in need of treatment for a complement-mediated disease.
  • methods of identifying a Caucasian subject in need of a prophylactic treatment for a complement-mediated disease comprising
  • the identity of one or more haplotypes wherein the one or more haplotypes are H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, HI 1_62_A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates whether the subject is in need of prophylactic treatment for a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for a complement-mediated disease comprising
  • the identity of one or more haplotypes wherein the one or more haplotypes are HI 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates whether the subject is in need of prophylactic treatment for a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for a complement-mediated disease comprising
  • the identity of one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B,
  • Also described herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19_51_B, H20 5 I B, H21 5 I B, H22 5 I B, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates whether the subject is in need of prophylactic treatment for a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for a complement-mediated disease comprising determining in the subject the identity of one or more SNPs in the CFH-to-F13B locus, wherein the SNPs is: (i) rsl061170, rsl410996, rs2274700, rs3753395, rs403846, or rs3753396 or (ii) a SNP in linkage disequilibrium with the SNPs of (i), and wherein the presence of one or more of the SNPs indicates whether the subject is in need of prophylactic treatment for a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for a complement-mediated disease comprising determining in the subject the identity of a deletion tagging SNP in the CFH-to-F13B locus, wherein the SNPs are: (i) rsl2144939 or (ii) a SNP in linkage disequilibrium with rsl2144939, and wherein the presence of one or more of the SNPs indicates whether the subject is in need of prophylactic treatment for a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject appropriate for an a complement-mediated disease clinical trial comprising determining in the Caucasian subject the identity of one or more haplotypes, wherein the one or more haplotypes are H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, HI 1_62_A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates whether the subject is appropriate for the clinical trial.
  • the identity of one or more haplotypes wherein the one or more haplotypes are HI 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, or a complement thereof, and wherein the presence of one or more of the haplotypes indicates whether the subject is appropriate for the clinical trial.
  • the identity of one or more haplotypes wherein the one or more haplotypes are H1 5 I B, H2 5 I B, H3 5 I B, H4 5 I B, H5 5 I B,
  • the identity of one or more SNPs in the CFH-to-F13B locus wherein the SNPs is: (i) rsl061170, rsl410996, rs2274700, rs3753395, rs403846, or rs3753396 or (ii) a SNP in linkage disequilibrium with the SNPs of (i), and wherein the presence of one or more of the SNPs indicates whether the subject is appropriate for the clinical trial.
  • Also described herein are methods of of identifying a Caucasian subject appropriate for an a complement-mediated disease clinical trial comprising determining in the subject the identity of a deletion tagging SNP in the CFH-to-F13B locus, wherein the SNPs are: (i) rsl2144939 or (ii) a SNP in linkage disequilibrium with rsl2144939, and wherein the presence of one or more of the SNPs indicates whether the subject is appropriate for the clinical trial.
  • kits kit comprising an assay for detecting one or more haplotypes in a nucleic acid sample of a subject, wherein the one or more haplotypes are H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H11 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H11 51 A, H12 51 A,
  • H10 51 B HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof.
  • Also descibed herein are methods for determining a Caucasian subject's susceptibility to having or developing age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 5 I B, H4 5 I B, H5 5 I B, H6 5 I B, H7 5 I B, H8 5 I B, H9 5 I B,
  • H10 51 B HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, and wherein the presence of one or more of the diplotypes indicates the subject's susceptibility for having or developing age-related macular degeneration.
  • Also descibed herein are methods of identifying a Caucasian subject in need of treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19_51_B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, and wherein the presence of one or more of the diplotypes indicates whether the subject is in need of treatment for age-related macular degeneration.
  • Also descibed herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B,
  • H10 51 B HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, and wherein the presence of one or more of the diplotypes indicates whether the subject is in need of prophylactic treatment for age-related macular degeneration.
  • Also descibed herein are methods of identifying a Caucasian subject appropriate for an age-related macular degeneration clinical trial comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B,
  • H10 51 B HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, and wherein the presence of one or more of the diplotypes indicates whether the subject is appropriate for the clinical trial.
  • Figure 1 shows major haplotypes H1 61 A through H15 62 A.
  • Figure 2 shows the 63 SNPs utilized in the preliminary haplotype studies.
  • Figure 3 shows minor haplotypes H16 62 A through H163 62 A.
  • Figure 4 shows the verification of halotypes derived from the GSH - 1073 cohort and the GSH - 927 cohort.
  • Figure 5 shows the single SNP association data for the 62 SNP panel in the GSH cohort.
  • Figure 6 shows disease associations that were analyzed for the entire extended haplotypes using Haploview 4.2.
  • Figure 7 shows the haplotype tagging SNPs for 62 SNP haplotypes.
  • Figure 8 shows the 51_A haplotype tagging SNPS (51_A htSNPs).
  • Figure 9 shows the 51_B haplotype tagging SNPS (51_A htSNPs).
  • Figure 10 shows the effect of generating haplotypes using fewer and fewer SNPs has on association values for haplotypes.
  • Figure 11 shows the qPCR assay for R3-1 deletion, regular PCR assay for homozygous deletion or non-deletion.
  • Figure 12 shows the asessment of 51 SNP haplotypes in the Sib-pair cohort.
  • Figure 13 shows the 62 single marker (SNPs) and haplotypes association with gender in the GSH case-control cohort the male and female gender association in the '927 cohort.
  • Figure 14 shows the haplotype boundaries extended beyond that covered by 63 SNPs. Provided in the figure is a list of all Hapmap SNPs.
  • Figure 15 shows the CFH locus and the haplotypes in the 5 I B cohort.
  • Figure 16 shows a comparison of 51_A and 62 A haplotypes.
  • Figure 17 shows shows the frequences of the 62 A haplotypes.
  • Figure 18 shows the 62 A SNP haplotype schema regrouped with P values.
  • Figure 19 shows a comparison of the 51 SNP haplotypes in the 1073 cohort and combined cohorts.
  • Figure 20 shows the '927 cohort and the 62 A to 51 A conversion.
  • Figure 21 shows a haplotype tree for the 62 A cohort.
  • Figure 21(A) shows the hierarchical relationships between the 163 62_A SNP-based haplotypes.
  • Figure 22 shows the association of haplotypes in the '927 cohort using a 51 SNP-based haplotype.
  • Figure 23 shows the gender associations of the 62 A haplotypes.
  • Figure 24 shows the gender associations of the 5 I B haplotypes.
  • Figure 25 shows haplotype disease association.
  • Figure 26 shows haplotype disease association based on gender.
  • Figure 27 shows the SNPs used in a haplotype reconstruction.
  • Figure 28 shows Taqman qPCR copy number variation data.
  • Figure 29 shows the frequency of subjects with varying number of SNPs screened.
  • Figure 30 shows a deletion decision tree made to predict deletion status from three SNPs.
  • Figure 31 shows the results of the real-time quantitative PCR (qPCR) used to determine the copy number state of the CFHR3 and CFHR1 genes.
  • Figure 32 shows the HI -HI 9 haplotypes based on 1073 cohort screened for 63 SNPs.
  • Figure 33 shows haplotype frequencies calculated on 136 unrelated UGRP individuals, who were mostly first generation grandparents, using Haploview program's phased haplotype input mode, Haps format.
  • Figure 34 shows association of 63 SNP-based CFH-to-F13B Haplotypes with AMD.
  • Figure 35 shows the diplotype analysis of the overall 5 I B cohort.
  • Figure 36 shows diplotype analysis for males in the 5 I B cohort.
  • Figure 37 shows diplotype analysis for females in the 5 I B cohort.
  • Figure 38 shows the combined cohort with all haplotypes, Ovslb-4, highlighted to match major HapMap haplotypes.
  • Figure 39 shows the major CFH-to-F13B HapMap haplotypes with >0.5% frequencies for CEU.
  • Figure 40 shows the marker-rs number IDs shown in Figure 39.
  • Figure 41 shows a comparison of the 51_B-based haplotypes to HapMap haplotypes >0.05% frequencies.
  • Figure 42 shows single marker associations; Controls (0) vs all AMD in the 5 I B cohort.
  • Figure 43 shows single marker associations; Controls (0) vs ealy AMD (lb-3) in the 5 I B cohort.
  • Figure 44 shows single marker associations; Controls (0) vs geographic atrophy (4 A) in the 5 IB cohort.
  • Figure 45 shows the single marker associations; Controls (0) vs CNV (4B) in the 5 I B cohort.
  • Figure 46 shows the haplotype associations; Controls (0) vs all AMD, early AMD (1B-3), GA only (4A) & CNV only (4B) in the 5 I B cohort.
  • Figure 47 shows the diplotype associations; Controls (0) vs early AMD (1B-3) in the 5 I B cohort.
  • Figure 48 shows the diplotype associations; Controls (0) vs CNV (4B) in the 5 I B cohort.
  • each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values described herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10" is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10" as well as “greater than or equal to 10" is also disclosed.
  • data are provided in a number of different formats, and that these data, represent endpoints, starting points, and ranges for any combination of the data points. For example, if a particular data point "10" and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
  • Complement-Mediated Disease refers to a disease caused by or resulting from abnormal complement activation or function of its four major pathways. The complement pathway consists of three stages: recognition, enzymatic activation and membrane attack leading to cell death. "Complement-Mediated Disease” as used herein also refers to a disease caused by or resulting from alterations of the classical, exogenous, mannan-binding lectin (MBL) or alternative pathways.
  • MBL mannan-binding lectin
  • Complement-Mediated Disease examples include, but are not limited to, atypical haemolytic uraemic syndrome (aHUS), membranoproliferative glomerulonephritis type II (MPGN II; also known as dense deposit disease), systemic lupus
  • SLE erythematosus
  • SLE erythematosus
  • PNH paroxysmal nocturnal haemoglobinuria
  • APD age-related macular degeneration
  • rheumatois arthritis myocarditis, multiple sclerosis, IgA nephropathy, Henoch-Schoenlein purpura, glaucoma, poststreptococcal disease, anti-phospholipid antibody syndrome, recurrent pregnancy loss, asthma, antibody-mediated cutaneous disease and anti-nuclear cytoplasmic antigen- associated pauci-immune vasculitis.
  • Haplotype refers to a DNA sequence or a combination of DNA sequences present at various loci on a chromosome that are transmitted together; a haplotype may be one locus, several loci, or an entire chromosome depending on the number of recombination events that have occurred between a given set of loci.
  • Risk Haplotype refers to a haplotype of a subject wherein the presence of the haplotype indicates the subject's increased risk of developing a complement-mediated disease (e.g. AMD) when compared to a subject without said risk haplotype.
  • a “Risk Haplotype” also refers to a haplotype that occurs more often in subjects with Complement-Mediated Disease (e.g. AMD) (cases) than in subjects without Complement-Mediated Disease (e.g. AMD) (controls) in a given cohort. In other words, the case versus control percentage is different in cases than in controls as illustrated in the tables herein (see FIG. 15).
  • H2 62 A, H2 51 A, and H2 51 B are examples of "Risk Haplotypes" as they relate to AMD.
  • Protective Haplotype refers to a haplotype of a subject wherein the presence of the haplotype indicates the subject's decreased risk of developing Complement-Mediated Disease (e.g. AMD) when compared to a subject without said protective haplotype.
  • a “Protective Haplotype” also refers to a haplotype that occurs less often in subjects with Complement-Mediated Disease (e.g. AMD) (cases) than in subjects without Complement-Mediated Disease (e.g. AMD) (controls), in other words, the case versus control percentage is lower in cases than in controls as illustrated in the tables herein (See FIG. 15).
  • the difference between the number of subjects with Complement-Mediated Disease e.g.
  • H5 62 A, H5 51 A, and H5 51 B are examples of "protective haplotypes" as they relate to AMD.
  • Neutral Haplotype refers to a haplotype of a subject wherein the presence of the haplotype does not indicate the subject's increased or decreased risk of developing Complement-Mediated Disease (e.g. AMD).
  • a "Neutral Haplotype” refers to a haplotype of a subject wherein the presence of the haplotype does not indicate the subject's increased or decreased risk of developing Complement-Mediated Disease (e.g. AMD).
  • Haplotype also refers to a haplotype that occurs about equally in subjects with Complement-Mediated Disease (e.g. AMD) (cases) and in subjects without Complement-Mediated Disease (e.g. AMD) (cases) and in subjects without Complement-Mediated Disease (e.g. AMD) (cases) and in subjects without Complement-Mediated Disease (e.g. AMD) (cases) and in subjects without Complement-Mediated Disease (e.g. AMD) (cases) and in subjects without
  • Complement-Mediated Disease e.g. AMD
  • Complement-Mediated Disease e.g. AMD
  • controls in other words, the case versus control percentage is about equal in cases and controls as illustrated in the tables herein (See FIG. 15).
  • the difference between the number of subjects with Complement-Mediated Disease (e.g. AMD) (case) and the number of subjects without Complement-Mediated Disease (e.g. AMD) (control) can be non- statistically significant.
  • H4 62 A, H4 51 A, and H4 51 B are examples of "neutral haplotypes" as they relate to AMD.
  • Haplotypes as described herein can be referred to by the generic
  • Hx Y Z wherein "Hx” indicates the numbering of the specific haplotype as determined by the frequency of the specific haplotype in a given population or cohort. For example, H2 indicates a specific haplotype that occurs with the second highest frequency in the given data set, population or cohort.
  • Y in the context of this nomenclature, specifies the SNP panel from which the overall haplotype was determined. For example, Hx_62_Z would refer to the 62 SNP Panel as described herein, whereas Hx_51_Z refers to the 51 SNP Panel as described herein.
  • Z in the context of this nomenclature, refers to the specific cohort used in ascertaining the specific haplotype. For example, Hx Y A would refer to the '927 cohort' as described herein, whereas Hx Y B refers to the combined cohort as described herein.
  • Haplotype Tagging Haplotype refers to haplotypes that can tag one or more of the haplotypes described herein. Such haplotypes can be referred to as “tagging haplotypes”. Such tagging haplotypes can be identified based on HapMap Analysis as described herein. When such tagging haplotypes are referenced herein, the generic nomenclature: "Hx_Y_Z_t” can be used wherein “t” represents a "tagging haplotype” and Hx, Y, and Z represent the same categories as described above for the generic nomenclature "Hx Y Z”. For example, H2 62 A 1 would represent a first haplotype that tags the H2 62 A haplotype.
  • Major Haplotype refers to a haplotype that occurs in greater than 1% of the population, data set or cohort being examined.
  • Minor Haplotype refers to a haplotype that occurs in 1% or less than 1% of the population, data set or cohort being examined.
  • CH-to-F13B Locus refers to a region of chromosome Iq25-q31 (approximately 196,580,000 to 197,053,000; hgl9) containing the following genes and pseudogenes: complement factor H (CFH) and its truncated isoform (CFHT), the complement factor H related genes 3, 1, 4, 2 and 5 (CFHR3, CFHR1, CFHR4, CFHR2 and CFHR5), a CFHR pseudogene () and factor 13B (F13B).
  • the CFH-to-F13B Locus includes all non-genic DNA, including that extending proximal to CFH and distal to F13B. Blocks of linkage disequilibrium (LD) that initiate within the CFH-to-F13B and extend proximal to CFH and/or distal to F 13b are also included.
  • LD linkage disequilibrium
  • 62 SNP Panel refers to 62 SNPs that were selected based on their significance of association as well as locations selected to provide coverage across the entire CFH-to-F13B Locus and its LD blocks.
  • the 62 SNP Panel consists of the SNPs shown in FIG. 17.
  • 51 SNP Panel refers to 51 SNPs of the 62 SNP Panel described herein.
  • the 51 SNP Panel consists of the SNPs shown in FIG. 15.
  • HapMap refers to a haplotype map of the human genome that is a catalog of common genetic variants that occur in human beings. HapMap describes what these variants are, where they occur in DNA, how they distribute in haplotypes, and their frequencies among people within populations and among populations in different parts of the world. (The International HapMap Consortium. The International HapMap Project. Nature 426, 789-796 (2003)).
  • Haploview Analysis refers to an analysis that can be conducted using Haploview software (Barrett JC, Fry B, Mailer J, Daly MJ.
  • Linkage Disequilibrium refers to the non-random association between two or more alleles at two or more loci (not necessarily on the same chromosome) such that certain combinations of alleles are more likely to occur together on a chromosome than other combinations of alleles than would be expected from a random formation of haplotypes from alleles based on their frequencies.
  • Described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more major or minor haplotypes.
  • the haplotypes can include, but are not limited to H1 62 A, H2 62 A,
  • H9 51 A H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9_51_B, H10 51 B, HI 1 5 I B, H12 51 B,
  • haplotype sequence can be converted to its complement thereof "TACG”. Therefore, by way of example, if "ATGC” represents a haplotype indicative of a subject's susceptibility to having or developing a complement-mediated disease, its complement haplotype sequence, "TACG”, also represents a haplotype indicative of a subject's susceptibility to having or developing a complement-mediated disease.
  • the presence of one or more of the haplotypes disclosed herein can indicate a subject's susceptibility for having or developing a complement-mediated disease.
  • the complement-mediated disease can be age-related macular degeneration (AMD).
  • the complement-mediated disease can include, but is not limited to atypical haemolytic uraemic syndrome (aHUS), membranoproliferative
  • MPGN II glomerulonephritis type II
  • SLE systemic lupus erythematosus
  • PNH paroxysmal nocturnal haemoglobinuria
  • Schoenlein purpura glaucoma, post-streptococcal disease, anti-phospholipid antibody syndrome, recurrent pregnancy loss, asthma, antibody-mediated cutaneous disease, or anti-nuclear cytoplasmic antigen-associated pauci-immune vasculitis.
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject has an increased risk of having or developing a complement-mediated disease.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H2 62 A, H2 51 A, H1 5 I B, H2 5 I B, or a complement thereof.
  • determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a risk haplotype is indicative of the subject's increased risk for having or developing a complement- mediated disease.
  • methods of determining a Caucasian subject's increased risk susceptibility to having or developing comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a risk haplotype is indicative of the subject's increased risk for having or developing a complement- mediated disease.
  • complement-mediated disease wherein the method further comprises administering a therapeutic composition to the subject when an increased risk is determined.
  • methods of determining a Caucasian subject's increased risk susceptibility to having or developing complement-mediated disease wherein the subject has an increased risk of having or developing complement-mediated disease and further comprises administering a therapeutic composition to the subject when an increased risk is determined.
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject has a deacreased risk of having or developing a complement-mediated disease.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be H3 62 A, H5 62 A, H11 62 A, H3 51 A, H5 51 A, H10 51 A, H3 51 B, H5 5 I B, H12 5 I B, H14 5 I B, or a complement thereof.
  • determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a protective haplotype is indicative of the subject's decreased risk for having or developing a complement-mediated disease.
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject does not have an increased risk or a decreased risk of having or developing a complement-mediated disease.
  • Such haplotypes can be neutral haplotypes.
  • a neutral haplotype can be H1 62 A, H4 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 A, H4 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, H4 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H13 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof.
  • determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype does not indicate that the subject has an increased risk or a decreased risk for having or developing a complement-mediated disease.
  • a subject means an individual.
  • a subject is a mammal such as a human.
  • the subject can be a Caucasian subject.
  • a subject can be a non-human primate.
  • Non- human primates include marmosets, monkeys, chimpanzees, gorillas, orangutans, and gibbons, to name a few.
  • subject also includes domesticated animals, such as cats, dogs, etc., livestock (for example, cattle (cows), horses, pigs, sheep, goats, etc.), laboratory animals (for example, ferret, chinchilla, mouse, rabbit, rat, gerbil, guinea pig, etc.) and avian species (for example, chickens, turkeys, ducks, pheasants, pigeons, doves, parrots, cockatoos, geese, etc.).
  • Subjects can also include, but are not limited to fish (for example, zebrafish, goldfish, tilapia, salmon, and trout), amphibians and reptiles.
  • a "subject” is the same as a "patient,” and the terms can be used interchangeably.
  • a haplotype can refer to a set of polymorphisms in a single gene, an intergenic sequence, or in larger sequences including both gene and intergenic sequences, e.g., a collection of genes, or of genes and intergenic sequences.
  • a haplotype can refer to a set of polymorphisms in the CFH-to-F13B locus.
  • the CFH-to-F13B locus comprises the chromosome region of chromosome Iq25-q31 (approximately 196,580,000 to 197,053,000; hgl9) that contains the following genes and pseudogenes: complement factor H (CFH) and its truncated isoform (CFHT), the complement factor H related genes 3, 1, 4, 2, and 5 (CFHR3, CFHR1, CFHR4, CFHR2 and CFHR5), a CFHR pseudogene, and factor 13B (F13B).
  • the locus can also incude all non-genic DNA, including that extending proximal to CFH and distal to F13B.
  • Blocks of linkage disequilibrium (LD) that initiate within the CFH-to-F13B and extend proximal to CFH and/or distal to F 13b are also included in the locus.
  • haplotype can also refer to a set of single nucleotide polymorphisms (SNPs) found to be statistically associated with each other on a single chromosome.
  • SNPs single nucleotide polymorphisms
  • a haplotype can also refer to a combination of polymorphisms (e.g., SNPs) and other genetic markers (e.g., an insertion or a deletion) found to be statistically associated with each other on a single chromosome.
  • polymorphism refers to the occurrence of one or more genetically determined alternative sequences or alleles in a population.
  • polymorphic site is the locus at which sequence divergence occurs. Polymorphic sites have at least one allele. A diallelic polymorphism has two alleles. A triallelic polymorphism has three alleles. Diploid organisms may be homozygous or heterozygous for allelic forms. A polymorphic site can be as small as one base pair. Examples of polymorphic sites include: restriction fragment length polymorphisms (RFLPs), variable number of tandem repeats (VNTRs), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats, and simple sequence repeats. As used herein, reference to a "polymorphism” can encompass a set of polymorphisms (i.e., a haplotype).
  • a "single nucleotide polymorphism (SNP)" can occur at a polymorphic site occupied by a single nucleotide, which is the site of variation between allelic sequences. The site can be preceded by and followed by highly conserved sequences of the allele.
  • a SNP can arise due to substitution of one nucleotide for another at the polymorphic site. Replacement of one purine by another purine or one pyrimidine by another pyrimidine is called a transition. Replacement of a purine by a pyrimidine or vice versa is called a transversion.
  • a synonymous SNP refers to a substitution of one nucleotide for another in the coding region that does not change the amino acid sequence of the encoded polypeptide.
  • a non-synonymous SNP refers to a substitution of one nucleotide for another in the coding region that changes the amino acid sequence of the encoded polypeptide.
  • a SNP may also arise from a deletion or an insertion of a nucleotide or nucleotides relative to a reference allele.
  • a "set" of polymorphisms means one or more polymorphism, e.g., at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or more than 6 polymorphisms known, for example, in the CFH-to-F13B locus.
  • nucleic acid can be a polymeric form of nucleotides of any length, can be DNA or RNA, and can be single- or double-stranded.
  • Nucleic acids can include promoters or other regulatory sequences.
  • Oligonucleotides can be prepared by synthetic means. Nucleic acids include segments of DNA, or their complements spanning or flanking any one of the polymorphic sites known in the CFH-to-F13B locus.
  • the segments can be between 5 and 100 contiguous bases and can range from a lower limit of 5, 10, 15, 20, or 25 nucleotides to an upper limit of 10, 15, 20, 25, 30, 50, or 100 nucleotides (where the upper limit is greater than the lower limit).
  • Nucleic acids between 5-10, 5-20, 10-20, 12-30, 15-30, 10-50, 20-50, or 20-100 bases are common.
  • the polymorphic site can occur within any position of the segment.
  • a reference to the sequence of one strand of a double-stranded nucleic acid defines the complementary sequence and except where otherwise clear from context, a reference to one strand of a nucleic acid also refers to its complement.
  • Nucleotide refers to molecules that, when joined, make up the individual structural units of the nucleic acids RNA and DNA.
  • a nucleotide is composed of a nucleobase (nitrogenous base), a five-carbon sugar (either ribose or 2-deoxyribose), and one phosphate group.
  • Nucleic acids are polymeric macromolecules made from nucleotide monomers.
  • the purine bases are adenine (A) and guanine (G), while the pyrimidines are thymine (T) and cytosine (C).
  • RNA uses uracil (U) in place of thymine (T).
  • S represents short; “L” represents “long, and “D” represents deleted in the context of the SNP analysis.
  • N refers to any specific nucleotide in the posotion identified.
  • Exemplary polymorphic sites in the CFH-to-F13B locus are described herein as examples and are not intended to be limiting. These polymorphic sites, SNPs, or haplotypes can also be used in carrying out methods described herein. Moreover, it will be appreciated that these CFH-to-F13B locus polymorphisms are useful for linkage and association studies, genotyping clinical populations, correlation of genotype information to phenotype information, loss of heterozygosity analysis, identification of the source of a cell sample, and can also be useful to target potential therapeutics to cells.
  • polymorphic sites in the CFH-to-F13B locus may further refine this analysis.
  • a SNP analysis using non-synonymous polymorphisms in the CFH-to-F13B locus can be useful to identify variant polypeptides.
  • Other SNPs associated with risk may encode a protein with the same sequence as a protein encoded by a neutral or protective SNP but contain an allele in a promoter or intron, for example, changes the level or site of gene expression. It will also be appreciated that a polymorphism in the
  • CFH-to-F13B locus may be linked to a variation in a neighboring gene.
  • the variation in the neighboring gene may result in a change in expression or form of an encoded protein and have detrimental or protective effects in the carrier.
  • variant can also refer to a nucleotide sequence in which the sequence differs from the sequence most prevalent in a population, for example by one nucleotide, in the case of the SNPs described herein.
  • some variations or substitutions in the nucleotide sequence of the CFH-to-F13B locus alter a codon so that a different amino acid is encoded resulting in a variant polypeptide.
  • variant can also refer to a polypeptide in which the sequence differs from the sequence most prevalent in a population at a position that does not change the amino acid sequence of the encoded polypeptide (i.e., a conserved change).
  • Variant polypeptides can be encoded by a risk haplotype, encoded by a protective haplotype, or can be encoded by a neutral haplotype. Variant polypeptides can be associated with risk, associated with protection, or can be neutral.
  • the methods and materials described herein can be used to determine whether the nucleic acid of a subject (e.g., human) contains a polymorphism, such as a single nucleotide polymorphism (SNP).
  • SNP single nucleotide polymorphism
  • Any method can be used to detect a polymorphism in the CFH-to-F13B locus.
  • polymorphisms can be detected by sequencing exons, introns, or
  • DPLC allele-specific hybridization
  • allele-specific restriction digests mutation specific polymerase chain reactions
  • mutation specific polymerase chain reactions mutation specific polymerase chain reactions
  • single-stranded conformational polymorphism detection and combinations of such methods.
  • polymorphisms can be detected in a target nucleic acid isolated from a subject.
  • genomic DNA is analyzed.
  • assay of genomic DNA virtually any biological sample containing genomic DNA or RNA, e.g., nucleated cells, is suitable. For example, in the experiments described in the
  • genomic DNA was obtained from peripheral blood leukocytes collected from case and control subjects (QIAamp DNA Blood Maxi kit, Qiagen, Valencia, Calif).
  • suitable samples include, but are not limited to, saliva, cheek scrapings, biopsies of retina, kidney or liver or other organs or tissues; skin biopsies; amniotic fluid or CNS samples; and the like.
  • RNA or cDNA can be assayed.
  • the assay can detect variant proteins encoded by one or more genes present in the CFH-to-F13B. Methods for purification or partial purification of nucleic acids or proteins from patient samples for use in diagnostic or other assays are known in the art.
  • isolated nucleic acid or “purified nucleic acid” is meant DNA that is free of the genes that, in the naturally-occurring genome of the organism from which the DNA of the invention is derived, flank the gene.
  • the term therefore includes, for example, a recombinant DNA which is incorporated into a vector, such as an autonomously replicating plasmid or virus; or incorporated into the genomic DNA of a prokaryote or eukaryote (e.g., a transgene); or which exists as a separate molecule (for example, a cDNA or a genomic or cDNA fragment produced by PCR, restriction endonuclease digestion, or chemical or in vitro synthesis).
  • isolated nucleic acid also refers to RNA, e.g., an mRNA molecule that is encoded by an isolated DNA molecule, or that is chemically synthesized, or that is separated or substantially free from at least some cellular components, for example, other types of RNA molecules or polypeptide molecules.
  • identity of bases occupying the polymorphic sites in CFH-to-F13B locus can be determined in a subject, e.g., in a patient being analyzed, using any of several methods known in the art. For example, and not to be limiting use of allele- specific probes, use of allele-specific primers, direct sequence analysis, denaturing gradient gel electrophoresis (DGGE) analysis, single-strand conformation
  • DGGE denaturing gradient gel electrophoresis
  • DPLC chromatography
  • polymorphisms in DNA include use of: Molecular Beacons technology (see, e.g., Piatek et al, 1998; Nat. Biotechnol. 16:359-63; Tyagi, and Kramer, 1996, Nat.
  • primer refers to a single-stranded oligonucleotide capable of acting as a point of initiation of template-directed DNA synthesis under appropriate conditions, in an appropriate buffer and at a suitable temperature.
  • the appropriate length of a primer depends on the intended use of the primer but typically ranges from 15 to 30 nucleotides.
  • a primer sequence need not be exactly complementary to a template but must be sufficiently complementary to hybridize with a template.
  • primer site refers to the area of the target DNA to which a primer hybridizes.
  • primer pair means a set of primers including a 5' upstream primer, which hybridizes to the 5' end of the DNA sequence to be amplified and a 3' downstream primer, which hybridizes to the complement of the 3' end of the sequence to be amplified.
  • Exemplary hybridization conditions for short probes and primers is about 5 to 12 degrees C, below the calculated Tm.
  • allele-specific probes for analyzing polymorphisms are described by e.g., Saiki et al, 1986; Dattagupta, EP 235,726, Saiki, WO 89/11548. Briefly, allele-specific probes are designed to hybridize to a segment of target DNA from one individual but not to the corresponding segment from another individual, if the two segments represent different polymorphic forms. Hybridization conditions are chosen that are sufficiently stringent so that a given probe essentially hybridizes to only one of two alleles. Typically, allele-specific probes can be designed to hybridize to a segment of target DNA such that the polymorphic site aligns with a central position of the probe.
  • probes are nucleic acids capable of binding in a base- specific manner to a complementary strand of nucleic acid.
  • probes include nucleic acids and peptide nucleic acids (Nielsen et al, 1991). Hybridization may be performed under stringent conditions which are known in the art. For example, see Berger and Kimmel (1987) Methods In Enzymology, Vol. 152: Guide To Molecular Cloning Techniques, San Diego: Academic Press, Inc.; Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual, 2nd Ed., Vols. 1-3, Cold Spring Harbor Laboratory; Sambook (2001) 3rd Edition; Rychlik, W. and Rhoads, R.
  • probe includes primers. Probes and primers are sometimes referred to as "oligonucleotides.”
  • Allele-specific probes can be used in pairs, one member of a pair designed to hybridize to the reference allele of a target sequence and the other member designed to hybridize to the variant allele.
  • Several pairs of probes can be immobilized on the same support for simultaneous analysis of multiple polymorphisms within the same target gene sequence.
  • allele-specific primers for analyzing polymorphisms are described by, e.g., WO 93/22456 and Gibbs, 1989. Briefly, allele-specific primers are designed to hybridize to a site on target DNA overlapping a polymorphism and to prime DNA amplification according to standard PCR protocols only when the primer exhibits perfect complementarity to the particular allelic form. A single-base mismatch prevents DNA amplification and no detectable PCR product is formed. The method works best when the polymorphic site is at the extreme 3 '-end of the primer, because this position is most destabilizing to elongation from the primer.
  • genomic DNA can be used to detect polymorphisms in the CFH-to-F13B locus.
  • Genomic DNA can be extracted from a sample, such as a peripheral blood sample or a tissue sample. Standard methods can be used to extract genomic DNA from a sample, such as phenol extraction. In some cases, genomic
  • DNA can be extracted using a commercially available kit (e.g., from Qiagen, Chatsworth, Calif; Promega, Madison, Wis.; or Gentra Systems, Minneapolis, Minn.).
  • Other methods for detecting polymorphisms can involve amplifying a nucleic acid from a sample obtained from a subject (e.g., amplifying the segments of nucleic acids from the CFH-to-F13B locus using CFH-to-F13B locus-specific primers) and analyzing the amplified nucleic acids. This can be accomplished by standard polymerase chain reaction (PCR, qPCT, & RT-PCR) protocols or other methods known in the art. The amplifying can result in the generation of CFH/F13B allele-specific oligonucleotides, which span the single nucleotide polymorphic sites in the CFH-to-F13B locus.
  • PCR polymerase chain reaction
  • the CFH/F13B specific primer sequences and CFH/F13B allele-specific oligonucleotides can be derived from the coding (exons) or non-coding (promoter, 5' untranslated, introns or 3' untranslated) regions of the CFH-to-F13B locus.
  • Genomic DNA from all subjects can be isolated from peripheral blood leukocytes with QIAamp DNA Blood Maxi kits (Qiagen, Valencia, CA). DNA samples can be screened for SNPs in the genes contained within the CFH-to-F13B locus. Genotyping can be performed byTaqMan assays (Applied Biosystems, Foster City, California) using 10 ng of template DNA in a 5uL reaction.
  • the thermal cycling conditions in the 384-well thermocycler can consist of an initial hold at 95°C for 10 minutes, followed by 40 cycles of a 15-second 95°C denaturation step and a 1 -minute 60°C annealing and extension step. Plates can be read in the 7900HT Fast Real-Time PCR System (Applied Biosystems).
  • DGGE denaturing gradient gel electrophoresis
  • Different alleles can be identified based on sequence-dependent melting properties and electrophoretic migration in solution. See Erlich, ed., PCR Technology, Principles and Applications for DNA Amplification, Chapter 7 (W.H. Freeman and Co, New York, 1992).
  • Alleles of target sequences can be differentiated using single-strand conformation polymorphism (SSCP) analysis. Different alleles can be identified based on sequence- and structure-dependent electrophoretic migration of single stranded PCR products (Orita et al, 1989). Amplified PCR products can be generated according to standard protocols and heated or otherwise denatured to form single stranded products, which may refold or form secondary structures that are partially dependent on base sequence.
  • SSCP single-strand conformation polymorphism
  • Alleles of target sequences can be differentiated using denaturing high performance liquid chromatography (DHPLC) analysis. Different alleles can be identified based on base differences by alteration in chromatographic migration of single stranded PCR products (Frueh and Noyer-Weidner, 2003). Amplified PCR products can be generated according to standard protocols and heated or otherwise denatured to form single stranded products, which may refold or form secondary structures that are partially dependent on the base sequence.
  • DPLC denaturing high performance liquid chromatography
  • the haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H11 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, H20 51 B, or a complement thereof.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject has an increased risk of having or developing a complement-mediated disease.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be
  • H1 62 A, H2 62 A, H1 51 B, H2 51 B, or a complement thereof are methods for determining a female Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the female Caucasian subject the identity of one or more haplotypes described herein, wherein a risk haplotype is indicative of the female subject's increased risk for having or developing a complement-mediated disease.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject has a deacreased risk of having or developing a complement-mediated disease.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be H3 62 A, H5 62 A, H11 62 A, H3 51 B, H5 51 B, H12 51 B, H14 51 B, or a complement thereof.
  • determining a female Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the female Caucasian subject the identity of one or more haplotypes described herein, wherein a protective haplotype is indicative of the female subject's decreased risk for having or developing a complement-mediated disease.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject does not have an increased risk or a decreased risk of having or developing a complement- mediated disease.
  • Such haplotypes can be neutral haplotypes.
  • a neutral haplotype can be H4 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H4 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H13 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19_51_B, H20 51 B, or a complement thereof.
  • determining a female Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the female Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype does not indicate that the female subject has an increased risk or a decreased risk for having or developing a complement-mediated disease.
  • the haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H11 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, or a complement thereof.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject has a increased risk of having or developing a complement-mediated disease.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H2 62 A, H1 5 I B, H2 5 I B, or a complement thereof.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject has a deacreased risk of having or developing a complement-mediated disease.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be HI 1_62_A, H3 51 B, H14 51 B, or a complement thereof.
  • determining a male Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the male Caucasian subject the identity of one or more haplotypes described herein, wherein a protective haplotype is indicative of the male subject's decreased risk for having or developing a complement-mediated disease.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject does not have an increased risk or a decreased risk of having or developing a complement-mediated disease.
  • Such haplotypes can be neutral haplotypes.
  • a neutral haplotype can be H1 62 A, H3 62 A, H4 62 A, H5 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19_51_B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof.
  • determining a male Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the male Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype does not indicate that the male subject has an increased risk or a decreased risk for having or developing a complement-mediated disease.
  • the SNPs, haplotypes, or diplotypes described herein can be determined from a sample obtained from the subject.
  • the subject's SNPs, haplotype, or diplotype can be determined by amplifying or sequencing a nucleic acid sample obtained from the subject.
  • the methods descrined herein can further comprise administering a therapeutic composition to the subject or treating the subject with an effective amount of a therapeutic composition.
  • treating refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
  • a mammal e.g., a human
  • administering and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, sublingual administration, trans-buccal mucosa administration, transdermal administration, administration by inhalation, nasal administration, topical
  • Ophthalmic administration can include topical administration, subconjunctival administration, sub-Tenon's administration, epibulbar administration, retrobulbar administration, intra-orbital administration, and intraocular
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • the term "therapeutically effective amount” refers to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • the methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease described herein can further comprise examining the subject with an ophthalmo logical procedure.
  • Various ophthalmological procedures known to persons of ordinary skill in the art can be performed to examine the subject including, but not limited to, autofluorescent imaging techniques, infrared imaging techniques, optical coherence tomography (OCT), Stratus optical coherence tomography (Stratus OCT), Fourier- domain optical coherence tomography (Fd-OCT), two-photon-excited fluorescence (TPEF) imaging, adaptive optics scanning laser ophthalmoscopy (AOSLO), scanning laser ophthalmoscopy, near-infrared imaging combined with spectral domain optical coherence tomography (SD-OCT), color fundus photography, fundus
  • OCT optical coherence tomography
  • Stratus OCT Stratus optical coherence tomography
  • Fd-OCT Fourier- domain optical coherence tomography
  • TPEF two-photon-excited fluorescence
  • AOSLO adaptive optics scanning laser ophthalmoscopy
  • SD-OCT spectral domain optical coherence tom
  • the complement-mediated disease can be, but is not limited to, age-related macular degeneration.
  • the methods comprise determining in the Caucasian subject the identity of one or more major or minor haplotypes.
  • the haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H11 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject has a increased risk of having or developing late-stage age-related macular degeneration.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H2 62 A, H2 51_A, H1 5 I B, H2 5 I B, or a complement thereof.
  • determining a Caucasian subject's susceptibility to having or developing late-stage age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a risk haplotype is indicative of the subject's increased risk for having or developing late- stage age-related macular degeneration.
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject has a deacreased risk of having or developing late-stage age-related macular degeneration.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be H3 62 A, H5 62 A, H11 62 A, H3 51 A, H5 51 A, H10 51 A, H3 51 B, H5 5 I B, H12 5 I B, H14 5 I B, or a complement thereof.
  • determining a Caucasian subject's susceptibility to having or developing late-stage age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a protective haplotype is indicative of the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject does not have an increased risk or a decreased risk of having or developing late-stage age-related macular degeneration.
  • Such haplotypes can be neutral haplotypes.
  • a neutral haplotype can be H1 62 A, H4 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51_A, H4 51_A, H6 51_A, H7 51_A, H8 51_A, H9 51_A, HI 1 51_A,
  • determining a Caucasian subject's susceptibility to having or developing late-stage age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype does not indicate that the subject has an increased risk or a decreased risk for having or developing late-stage age-related macular degeneration.
  • the haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, HI 1_62_A, H12 62 A, H13 62 A,
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject has a increased risk of having or developing late-stage age-related macular degeneration.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H1 62 A, H2 62 A, H1 51 B, H2 51 B, or a complement thereof.
  • determining a female Caucasian subject's susceptibility to having or developing late-stage age-related macular degeneration comprising determining in the female Caucasian subject the identity of one or more haplotypes described herein, wherein a risk haplotype is indicative of the female subject's increased risk for having or developing late-stage age-related macular degeneration.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject has a deacreased risk of having or developing late-stage age-related macular degeneration.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be H3 62 A, H5 62 A, HI 1_62_A, H3 51 B, H5 51 B, H12 51 B, H14 51 B, or a complement thereof.
  • determining a female Caucasian subject's susceptibility to having or developing late-stage age-related macular degeneration comprising determining in the female Caucasian subject the identity of one or more haplotypes described herein, wherein a protective haplotype is indicative of the female subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject does not have an increased risk or a decreased risk of having or developing late-stage age- related macular degeneration.
  • Such haplotypes can be neutral haplotypes.
  • a neutral haplotype can be H4 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H4 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H13 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19_51_B, H20 51 B, or a complement thereof.
  • described herein are methods for determining a female Caucasian subject's susceptibility to having or developing late- stage age-related macular degeneration comprising determining in the female
  • Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral ha lotype does not indicate that the female subject has an increased risk or a decreased risk for having or developing late-stage age-related macular degeneration.
  • the haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H11 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, or a complement thereof.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject has a increased risk of having or developing late-stage age-related macular degeneration.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H2 62 A, H1 51 B, H2 51 B, or a complement thereof.
  • determining a male Caucasian subject's susceptibility to having or late- stage age-related macular degeneration comprising determining in the male Caucasian subject the identity of one or more haplotypes described herein, wherein a risk haplotype is indicative of the male subject's increased risk for having or developing late-stage age-related macular degeneration.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject has a deacreased risk of having or developing late-stage age-related macular degeneration.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be HI 1 62 A, H3 51 B, H14 51 B, or a complement thereof.
  • determining a male Caucasian subject's susceptibility to having or developing late-stage age-related macular degeneration comprising determining in the male Caucasian subject the identity of one or more haplotypes described herein, wherein a protective haplotype is indicative of the male subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject does not have an increased risk or a decreased risk of having or developing late-stage age-related macular degeneration.
  • Such haplotypes can be neutral haplotypes.
  • a neutral haplotype can be H1 62 A, H3 62 A, H4 62 A, H5 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H15 51 B,
  • methods for determining a male Caucasian subject's susceptibility to having or developing late-stage age-related macular degeneration comprising determining in the male Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype does not indicate that the male subject has an increased risk or a decreased risk for having or developing late-stage age-related macular degeneration.
  • Also described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more diplotypes described herein.
  • Human autosomal chromosomes normally come in pairs, and the combination in one individual of these two haplotypes is referred to herein as a "Diplotype".
  • "based on” when used in the context of a diplotype "based on" a haplotype can refer to identifying the combination in one individual of these two haplotypes.
  • a diplotype can comprise a protective and a risk haplotype, two protective haplotypes, two risk haplotypes, a neutral and a risk haplotype, a neutral and a protective haplotype, or two neutral haplotypes.
  • one haplotype may be dominant or one haplotype may be recessive.
  • a single HI haplotype when combined with another HI haplotype can be an H1_Y_Z:H1_Y_Z diplotype; a single HI haplotype when combined a H2, H8, or H13 haplotype can be an H1_Y_Z:H2_Y_Z diplotype, an H1_Y_Z:H8_Y_Z diplotype, or an H1_Y_Z:H13_Y_Z diplotype.
  • the diplotypes described herein can be associated with increased risk for developing AMD.
  • the diplotypes described herein can be associated with a decreased risk for developing AMD.
  • Described hereis are methods for determining a Caucasian subject's susceptibility to having or developing age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B,
  • the subject's haplotype can be determined from a sample obtained from the subject. In some aspects the subject's haplotype can be determined by amplifying or sequencing a nucleic acid sample obtained from the subject.
  • Described hereis are methods for determining a Caucasian subject's susceptibility to having or developing age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 5 I B, H4 5 I B, H5 5 I B, H6 5 I B, H7 5 I B, H8 5 I B, H9 5 I B,
  • Described hereis are methods for determining a Caucasian subject's susceptibility to having or developing age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 5 I B, H4 5 I B, H5 5 I B, H6 5 I B, H7 5 I B, H8 5 I B, H9 51_B,
  • H10 51 B HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19_51_B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, wherein the diplotype H1 51 B: H1 51 B, H1_51_B:H2_51_B, H1_51_B:H8_51_B, H1_51_B:H13_51_B, H2_51_B:H2_51_B,
  • H2 51_B H10_5 I B
  • H1 5 l_B any minor 5 I B haplotype
  • H2 5 l_B any minor
  • the method can further comprise administering a therapeutic composition to the subject.
  • a therapeutic composition to the subject.
  • Described hereis are methods for determining a Caucasian subject's susceptibility to having or developing age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9_51_B,
  • H10 51 B HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B,
  • H6 5 I B, H6 5 I B: any 5 I B minor haplotype, or a complement thereof, is indicative of the subject's decreased risk for having or developing age-related macular degeneration.
  • the subject can be female. In some aspects wherein the subject is female, one or more of the diplotypes identified in Figure 37 can be used to indicate the subject's risk for having or developing age-related macular degeneration. [00175] In some aspects the subject can be male. In some aspects wherein the subject is male, one or more of the diplotypes identified in Figure 36 can be used to indicate the subject's risk for having or developing age-related macular degeneration.
  • Described herein are methods of identifying a Caucasian subject in need of treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H1951 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, and wherein the presence of one or more of the diplotypes indicates whether the subject is in need of treatment for age-related macular degeneration.
  • the subject's haplotype can be determined from a sample obtained from the subject. In some aspects the subject's haplotype can be determined by amplifying or sequencing a nucleic acid sample obtained from the subject.
  • Described herein are methods of identifying a Caucasian subject in need of treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H1951 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, , wherein diplotype H1 51 B: H1 51 B, H1_51_B:H2_51_B, H1_51_B:H8_51_B, H1_51_B:H13_51_B, H2_51
  • Described herein are methods of identifying a Caucasian subject in need of treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B,
  • H18 51 B H1951 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, , wherein diplotype H1 51 B: H3 51 B, H1_51_B:H5_51_B, H1_51_B:H14_51_B, H3 51 B: H3 51 B, H3 51 B: H4 51 B, H3 51 B: H5 51 B, H3 51 B:
  • H6 51 B: H6 51 B, H6 51 B: any 5 I B minor haplotype, or a complement thereof indicates the subject is not in need of treatment for age-related macular degeneration.
  • Described herein are methods of identifying a Caucasian subject in need of treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B,
  • the subject can be female.
  • one or more of the diplotypes identified in Figure 37 can be used to deterime whether the subject is in need of treatment for age-related macular degeneration.
  • the subject can be male.
  • one or more of the diplotypes identified in Figure 36 can be used to determine whether the subject is in need of treatment for age-related macular degeneration.
  • Described herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B,
  • Described herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H1951 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, wherein diplotype H1 51 B: H1 51 B, H1_51_B:H2_51_B, H1_51_B:H8_51_B, H1_51_B:H13_51_B, H
  • Described herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H1951 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, wherein diplotype H1 51 B: H3 51 B, H1_51_B:H5_51_B, H1_51_B:H14_51_B, H3 51 B: H3 51 B, H3 51 B:
  • H4 51 B H5 51 B
  • H5 51 B H5 51 B
  • H5 51 B any 51 B minor haplotype
  • H6 51 B H6 51 B
  • H6 51 B any 5 I B minor haplotype, or a complement thereof, indicates the subject is not in need of prophylactic treatment for age-related macular degeneration.
  • Described herein are methods of identifying a Caucasian subject in need of a prophylactic treatment for age-related macular degeneration comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B,
  • H18 51 B, H1951 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, wherein the presence of one or more of the diplotypes identified in Figure 36, or a complement thereof, can be used to determine whether, the subject may be in need of prophylactic treatment for age-related macular degeneration.
  • Described herein are methods of identifying a Caucasian subject appropriate for an age-related macular degeneration clinical trial comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 5 I B, H2 5 I B, H3 5 I B,
  • Described herein are methods of identifying a Caucasian subject appropriate for an age-related macular degeneration clinical trial comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B,
  • Described herein are methods of identifying a Caucasian subject appropriate for an age-related macular degeneration clinical trial comprising determining in the Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 5 I B, H2 5 I B, H3 5 I B,
  • H6 51 B, H3 51 B any 51 B minor haplotype
  • H4 51 B H5 51 B
  • H5 51 B any 51 B minor haplotype
  • Described herein are methods of identifying a Caucasian subject appropriate for an age-related macular degeneration clinical trial comprising determining in the
  • Caucasian subject the identity of one or more diplotypes based on one or more haplotypes, wherein the one or more haplotypes are H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H1951 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof, wherein the presence of one or more of the diplotypes identified in Figure 36, or a complement thereof, indicates the subject may be appropriate for the clinical trial.
  • Described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the Caucasian subject the identity of at least six SNPs in the CFH-to- F13B locus.
  • the SNPs can be, but are not limited to: (i) rs35928059, rs800292, rsl061170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs can indicate the subject's susceptibility for having or developing age-related macular degeneration.
  • the SNPs can be haplotype tagging SNPs (htSNPs).
  • haplotype tagging SNP means a SNP or multiple SNPs that can identify or represent a haplotype or multiple haplotypes described herein.
  • a tagging SNP or multiple tagging SNPs can be used to identify or depict a haplotype or multiple haplotypes in a subject, and, therefore, can be used to determine a subject's susceptibility to having or developing a complement-mediated disease.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject's increased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rs 1061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject's increased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject's decreased risk for having or developing age- related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rs 1061170, a G at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject's decreased risk for having or developing age- related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing age- related macular degeneration.
  • Also described herein are methods for determining a female Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the female Caucasian subject the identity of at least six SNPs in the CFH-to-F13B locus.
  • the SNPs can be, but are not limited to: (i) rs35928059, rs800292, rsl061170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs can indicate the subject's susceptibility for having or developing a complement-mediated disease.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an G at rs698859 can indicate the subject's increased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject's increased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject's increased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rs 1061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a T at rs698859 can indicate the subject's increased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject's decreased risk for having or developing age- related macular degeneration.
  • T at rsl0922153, or a C at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, an A at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing age- related macular degeneration.
  • T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • Also described herein are methods for determining a male Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the male Caucasian subject the identity of at least six SNPs in the CFH-to-F13B locus.
  • the SNPs can include, but are not limited to: (i) rs35928059, rs800292, rsl061170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs indicates the subject's susceptibility for having or developing a complement-mediated disease.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject's increased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a T at rs698859 can indicate the subject's increased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject's decreased risk for having or developing age- related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • Also described herein are methods for predicting progression of a complement-mediated disease in a Caucasian subject comprising determining in the
  • the SNPs can be, but are not limited to: (i) rs35928059, rs800292, rs 1061170,
  • the presence of at least six of the SNPs can indicate the subject's risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a T at rs698859 can indicate the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • complement-mediated disease in a female Caucasian subject comprising determining in the female Caucasian subject the identity of at least six SNPs in the CFH-to-F13B locus.
  • the SNPs can be, but are not limited to: (i) rs35928059, rs800292, rsl061 170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs is indicative of the subject's risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an G at rs698859 can indicate the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • Also described herein are methods for predicting progression of a complement-mediated disease in a male Caucasian subject comprising determining in the male Caucasian subject the identity of at least six SNPs in the CFH-to-F13B locus.
  • the SNPs can include, but are not limited to: (i) rs35928059, rs800292, rsl061170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a
  • the presence of at least six of the SNPs can indicate the subject's risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a T at rs698859 can indicate the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • Described herein are a collection of polymorphisms and haplotypes comprised of multiple variations in the CFH-to-F13B locus.
  • One or more of these polymorphisms or haplotypes can be associated with complement-mediated disease.
  • Detection of these and other polymorphisms and sets of polymorphisms can be useful in designing and performing diagnostic assays for complement-mediated disease.
  • Polymorphisms and sets of polymorphisms can be detected by analysis of nucleic acids, by analysis of polypeptides encoded the CFH- to-F13B locus coding sequences (including polypeptides encoded by splice variants), by analysis of the CFH-to-F13B locus non-coding sequences, or by other means known in the art. Analysis of such polymorphisms and haplotypes can also be useful in designing prophylactic and therapeutic regimes for complement-mediated disease.
  • the SNPs can include, but are not limited to: (i) rsl061170, rsl410996, rs2274700, rs3753395, rs403846, or rs3753396 or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of one or more of the SNPs described herein can indicate the subject's susceptibility for having or developing age-related macular degeneration.
  • an A at the rsl061170 SNP can be indicative of the subject's increased risk for having or developing a complement-mediated disease.
  • an A at the rsl410996 SNP, an A at the rs2274700 SNP, a T at the rs3753395 SNP, or a G at the rs403846 SNP can be indicative of the subject's decreased risk for having or developing age-related macular degeneration.
  • a G at the rs3753396 SNP does not indicate that the subject has an increased risk or a decreased risk for having or developing age-related macular degeneration.
  • the SNPs can include, but are not limited to: (i) rsl061 170, rsl410996, rs2274700, rs3753395, rs403846, or rs3753396 or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of one or more of the SNPs described herein can be indicative of the subject's risk for having or developing late-stage age-related macular degeneration.
  • an A at the rs 1061170 SNP can be indicative of the subject's increased risk for having or developing late-stage age-related macular degeneration.
  • an A at the rs 1410996 SNP, an A at the rs2274700 SNP, a T at the rs3753395 SNP, or a G at the rs403846 SNP can be indicative of the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • a G at the rs3753396 SNP does not indicate whether a subject has an increased risk or a decreased risk for having or developing late-stage age- related macular degeneration.
  • LD linkage disequilibrium
  • These methods can involve identifying a polymorphic site in a gene that is in linkage disequilibrium with a polymorphic site in the CFH-to-F13B locus, wherein the polymorphic form of the polymorphic site in the CFH-to-F13B locus is associated with complement-mediated disease, (e.g., increased or decreased risk), and determining haplotypes in a population of individuals to indicate whether the linked polymorphic site has a polymorphic form in linkage disequilibrium with the polymorphic form of the CFH/F13B gene that correlates with the complement-mediated disease phenotype.
  • SNPs in LD with the SNPs described herein include, but are not limited to
  • SNPs in LD with the SNPs described herein can be, but are not limited to rsl0489456, rs70620, rs742855, rsl 1799380, rsl065489, rsl 1582939, rs385390, rs421820, rs426736, rs370953, rs371075.
  • linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is not the same as linkage, which describes the association of two or more loci on a
  • Linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies. Non-random associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium (LD).
  • the level of linkage disequilibrium can be influenced by a number of factors including genetic linkage, the rate of recombination, the rate of mutation, random drift, non-random mating, and population structure.
  • Linkage disequilibrium or “allelic association” thus means the non-random association of a particular allele or genetic marker with another specific allele or genetic marker more frequently than expected by chance for any particular allele frequency in the population.
  • a marker in linkage disequilibrium with an informative marker, such as one of the CFH/F13B SNPs or haplotypes described herein can be useful in detecting susceptibility to complement-mediated disease.
  • a proxy SNP may be in at least 50%, 60%, or 70%> in linkage disequilibrium with risk, protective, or otherwise informative SNP or genetic marker described herein, and in one aspect is at least about 80%, 90%, and in another aspect 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100% in LD with a risk, protective, or otherwise informative SNP, haplotype, or genetic marker described herein.
  • Bioinformatics 21, 263 (2005) may be used to calculate linkage disequilibrium between two SNPs.
  • the frequency of identified alleles in disease versus control populations can be determined using the methods described herein.
  • Statistical analyses can be employed to determine the significance of a non-random association between the two SNPs (e.g., Hardy- Weinberg Equilibrium, Genotype likelihood ratio (genotype p value), Chi Square analysis, Fishers Exact test).
  • a statistically significant non-random association between the two SNPs indicates that they are in linkage disequilibrium and that one SNP can serve as a proxy for the second SNP.
  • polymorphisms in the CFH-to-F13B locus can be used to establish physical linkage between a genetic locus associated with a trait of interest and polymorphic markers that are not associated with the trait, but are in physical proximity with the genetic locus responsible for the trait and co-segregate with it. Mapping a genetic locus associated with a trait of interest facilitates cloning the gene(s) responsible for the trait following procedures that are well-known in the art.
  • "physical linkage" describes the tendency of genes, alleles, loci or genetic markers to be inherited together as a result of their location on the same chromosome.
  • Linkage can be measured by percent recombination between the two genes, alleles, loci or genetic markers. Typically, loci occurring within a 50 centimorgan (cM) distance of each other are linked. Linked markers may occur within the same gene or gene cluster.
  • SNPs that tag the deletion status of the CFHR- 3/CFHR-l genes. Therefore, also described herein are methods for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the subject the identity of a deletion tagging SNP in the CFH-to-F13B locus.
  • the SNP can be, but is not limited to: (i) rsl2144939 or (ii) a SNP in linkage disequilibrium with rs 12144939.
  • the presence of the SNP can indicate the subject's susceptibility for having or developing age-related macular degeneration.
  • a T at the rs 12144939 SNP can indicate the subject's decreased risk for having or developing age-related macular degeneration.
  • methods determining for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the subject the identity of at lease one SNP that tags the deletion tagging SNPs described herein.
  • the tagging SNPs can be, but are not limited to, rs6689009, rs35253683, rs731557, and rs60642321.
  • methods determining for determining a Caucasian subject's susceptibility to having or developing a complement-mediated disease comprising determining in the subject the identity of at lease one SNP in LD with the deletion tagging SNPs described herein.
  • the SNPs can be, but are not limited to, rs6677604, rs 16840522 and rs2019727.
  • methods for predicting progression of a complement-mediated disease in a Caucasian subject comprising determining in the subject the identity of a deletion tagging SNP in the CFH-to-F13B locus.
  • the SNP can include, but is not limited to: (i) rs 12144939 or (ii) a SNP in linkage
  • the presence of the deletion tagging SNP can indicate the subject's risk for having or developing late-stage age-related macular degeneration.
  • a T at the rs 12144939 SNP can indicate the subject's decreased risk for having or developing late-stage age-related macular degeneration.
  • haplotypes described herein can be compared to haplotypes generated using a genetic variation database, for example, HapMap, in order to further refine haplotype association with complement-mediated diseases, such as AMD.
  • HapMap a genetic variation database
  • the International HapMap Project available at
  • genotypes from Caucasian individuals referred to as the CEU population
  • Phased genotype data from the CEU set can then be downloaded, including the most informative SNPs (i.e. those that segregate in the CEU population) in this region of interest.
  • Haploview www.broadinstitute.org
  • haplotypes for the CEU dataset and their frequencies can be calculated.
  • the overlapping SNPs obtiained from that analysis can be used as 'tagging' SNPs to match the case/control haplotypes described herein to their equivalent HapMap CEU haplotypes, thereby allowing the disease associations described herein to be extended to the equivalent HapMap haplotypes.
  • the methods can identify HapMap SNPs that were not included in the 51 SNP-based haplotypes described herein. These newly identified SNPs can further refine the discriminative value of the 51 SNP -based haplotypes described herein, and the association of those haplotypes with complement-mediated disease.
  • the methods can comprise entering the SNP sequence of one or more CFH/F13B haplotypes into a genetic variation database and determining the identity of one or more tagging SNPs or haplotypes.
  • the one or more CFH/F13B haplotypes can be H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H11 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B,
  • H10 51 B HI 1 5 I B, H12 51 B, H13 51 B, H14 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, H20 51 B, H21 51 B, H22 51 B, or a complement thereof.
  • the genetic variation database can be HapMap.
  • the one or more CFH/F13B haplotypes can be risk haplotypes, including, but not limited to, H2 62 A, H2 51 A, H1 51 B, H2 51 B, or a complement thereof.
  • the one or more CFH/F13B haplotypes can be protective haplotypes, including, but not limited to, H3 62 A, H5 62 A, H11 62 A, H3 51 A, H5 51 A, H10 51 A, H3 51 B, H5 51 B, H12 51 B, HI 4 5 I B, or a complement thereof.
  • the haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, HI 1_62_A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, H1 51 B, H2 51 B,
  • the presence of one or more of the haplotypes disclosed herein can indicate whether the subject is in need of treatment for a complement-mediated disease.
  • treatment can also mean prophylactic, or preventative treatment.
  • the complement-mediated disease can be age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject is in need of treatment for a complement-mediated disease.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H2 62 A, H2 51 A, H1 5 I B, H2 5 I B, or a complement thereof.
  • the method of identifying a subject in need of treatment can further comprise administering a therapeutic composition to the subject identified as being in need of treatment.
  • the methods described herein can be used to identify a Caucasian subject in need of more frequent screening for complement-mediated diseases, including, but not limited to, age-related macular degeneration. For example, identifying a subject with a risk haplotype can indicate that the subject needs to be more closely and frequently monitored for the
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject is not in need of treatment for a complement-mediated disease.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be H3 62 A, H5 62 A, H11 62 A, H3 51 A, H5 51 A, H10 51 A, H3 51 B, H5 51 B, H12 51 B,
  • HI 4 5 I B or a complement thereof.
  • methods for identifying a Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a protective haplotype can indicate that the subject is not in need of treatment for a complement-mediated disease.
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject is in need of continued screening for the development of a complement-mediated disease.
  • haplotypes can be neutral haplotypes.
  • a neutral haplotype can be H1 62 A, H4 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A,
  • identifying a Caucasian subject in need of screening for the development of a complement-mediated disease comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype can indicate a subject in need of screening for the development of a complement-mediated disease.
  • identifying a subject with a neutral haplotype can indicate that the subject should be screened for the development of a complement-mediated disease, such as AMD, at an earlier age, and more often than would typically be done in the general population.
  • Also described herein are methods for identifying a female Caucasian subject in need of treatment for complement-mediated disease comprising
  • haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A, H6 62 A, H7 62 A, H8 62 A,
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject is in need of treatment for a complement-mediated disease.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H1 62 A, H2 62 A, H1 51 B, H2 51 B, or a complement thereof.
  • the method of identifying a female subject in need of treatment can further comprise administering a therapeutic composition to the female subject identified as being in need of treatment.
  • the methods described herein can be used to identify a female Caucasian subject in need of more frequent screening for complement-mediated diseases, including, but not limited to, age-related macular degeneration. For example, identifying a female subject with a risk haplotype can indicate that the female subject needs to be more closely and frequently monitored for the development of a complement-mediated disease such as AMD.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject is not in need of treatment for complement-mediated disease.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be H3 62 A, H5 62 A, HI 1_62_A, H3 51 B, H5 51 B, H12 51 B, H14 51 B, or a complement thereof.
  • identifying a female Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the female Caucasian subject the identity of one or more haplotypes described herein, wherein a protective haplotype can indicate that the female subject is not in need of treatment for a complement-mediated disease.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject is in need of continued screening for the development of a complement-mediated disease.
  • Such haplotypes can be neutral haplotypes.
  • a neutral haplotype can be H4 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H4 51 B, H6 51 B, H7 51 B, H8 51 B, H9 51 B, H10 51 B, HI 1 5 I B, H13 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51 B, H20 51 B, or a complement thereof.
  • identifying a female Caucasian subject in need of screening for the development of a complement-mediated disease comprising determining in the female Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype can indicate a female subject in need of screening for the development of a complement-mediated disease.
  • identifying a female subject with a neutral haplotype can indicate that the female subject should be screened for the development of a complement- mediated disease, such as AMD, at an earlier age, and more often than would typically be done in the general population.
  • methods methods identifying a male Caucasian subject in need of treatment for complement-mediated disease comprising
  • haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, HI 1_62_A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 B,
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject is in need of treatment for a complement-mediated disease.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H2 62 A, HI 5 I B, H2 5 I B, or a complement thereof.
  • the method of identifying a male subject in need of treatment can further comprise administering a therapeutic composition to the male subject identified as being in need of treatment.
  • the methods described herein can be used to identify a male Caucasian subject in need of more frequent screening for complement-mediated diseases, including, but not limited to, age-related macular degeneration. For example, identifying a male subject with risk haplotype can indicate that the male subject needs to be more closely and frequently monitored for the development of a complement-mediated disease such as AMD.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject is not in need of treatment for complement-mediated disease.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be HI 1 62 A, H3 5 I B, H14 5 I B, or a complement thereof.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject is in need of continued screening for the development of a complement-mediated disease.
  • Such haplotypes can be neutral haplotypes.
  • a neutral haplotype can be H1 62 A, H3 62 A, H4 62 A, H5 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B, H9_51_B, H10 51 B, HI 1 5 I B, H12 51 B, H13 51 B, H15 51 B, H16 51 B, H17 51 B, H18 51 B, H19 51_B, H20 5 I B, H21 5 I B, H22 5 I B, or a complement thereof.
  • identifying a male Caucasian subject in need of screening for the development of a complement-mediated disease comprising determining in the male Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype can indicate a male subject in need of screening for the development of a complement-mediated disease.
  • identifying a male subject with a neutral haplotype can indicate that the male subject should be screened for the development of a complement-mediated disease, such as AMD, at an earlier age, and more often than would typically be done in the general population.
  • Also described herein are methods of identifying a Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the subject the identity of one or more SNPs in the CFH-to-F13B locus.
  • the SNPs can include, but are not limited to: (i) rsl061 170, rsl410996, rs2274700, rs3753395, rs403846, or rs3753396 or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of one or more of the SNPs can indicate whether the subject is in need of treatment for a complement-mediated disease.
  • an A at the rs 1061170 SNP can indicate the subject is in need of treatment for a complement-mediated disease.
  • an A at the rs 1410996 SNP, an A at the rs2274700 SNP, a T at the rs3753395 SNP, or a G at the rs403846 SNP can indicate the subject is not in need of treatment for a complement-mediated disease.
  • a G at the rs3753396 SNP can indicate the subject may be in need of treatment for a complement-mediated disease.
  • Also described herein are methods of identifying a Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the subject the identity of a deletion tagging SNP in the CFH-to-F13B locus.
  • the SNP can include, but is not limited to: (i) rs 12144939 or (ii) a SNP in linkage
  • the presence of one or more of the SNPs can indicate whether the subject is in need of treatment for age-related macular degeneration.
  • a T at the rs 12144939 SNP can indicate the subject is not in need of treatment for age-related macular degeneration.
  • the SNPs can include, but are not limited to: (i) rs35928059, rs800292, rsl061170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs can indicate whether the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rs 1061170, a G at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • Also described herein are methods of identifying a female Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the female Caucasian subject the identity of at least six SNPs in the CFH-to-F13B locus.
  • the SNPs can be, but are not limited to: (i) rs35928059, rs800292, rsl061 170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs can indicate whether the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an G at rs698859 can indicate the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a T at rs698859 can indicate the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, an A at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • Also described herein are methods of identifying a male Caucasian subject in need of treatment for a complement-mediated disease comprising determining in the male Caucasian subject the identity of at least six SNPs in the CFH-to-F13B locus.
  • the SNPs can be, but are not limited to: (i) rs35928059, rs800292, rsl061 170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs can indicate whether the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a T at rs698859 can indicate the subject is in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not in need of treatment for age-related macular degeneration.
  • haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H662 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H11 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H11 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, H1 51 B, H2 51 B,
  • the presence of one or more of the haplotypes disclosed herein can indicate whether the subject is appropriate for a complement-mediated disease clinical trial.
  • the complement-mediated disease can be age-related macular degeneration (AMD), and the clinical trial can be an age-related macular degeneration clinical trial.
  • AMD age-related macular degeneration
  • the methods described herein can be used to identify a Caucasian subject that is appropriate for an age-related macular degeneration clinical trial.
  • clinical trial means an experimental study conducted to evaluate the effectiveness and safety of a treatment or medical device by monitoring their effects on a subject or group of subjects.
  • the clinical trial can be conducted to evaluate the effectiveness and safety of medications for a complement-mediated disease, for example, AMD.
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject is appropriate for a complement- mediated disease clinical trial.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H2 62 A, H2 51_A, H1 5 I B, H2 51 B, or a complement thereof.
  • described herein are methods for identifying a Caucasian subject that is appropriate for a complement-mediated disease clinical trial comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a risk haplotype can indicate that the subject is appropriate for the clinical trial.
  • the method of identifying a subject for the clinical trial can further comprise administering a therapeutic composition to the subject identified as being appropriate for the clinical trial.
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject is not appropriate for a complement-mediated disease clinical trial.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be H3 62 A, H5 62 A, H11 62 A, H3 51 A, H5 51 A, H10 51 A, H3 51 B, H5 5 I B, H12 5 I B, H14 5 I B, or a complement thereof.
  • a subject identified to have a protective haplotype described herein can be excluded from participation in a clinical trial designed to evaluate a treatment for a complement-mediated disease.
  • determining the identity of a certain haplotype or certain haplotypes in a subject can indicate that the subject may be appropriate for a complement-mediated disease clinical trial.
  • haplotypes can be neutral haplotypes.
  • a neutral haplotype can be
  • identifying a Caucasian subject appropriate for a complement-mediated disease clinical trial comprising determining in the Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype can indicate a subject that may be appropriate for a complement-mediated disease clinical trial.
  • the haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A, H6 62 A, H7 62 A,
  • the presence of one or more of the haplotypes disclosed herein can indicate whether the female subject is appropriate for a complement-mediated disease clinical trial.
  • the complement- mediated disease can be age-related macular degeneration (AMD), and the clinical trial can be an age-related macular degeneration clinical trial.
  • AMD age-related macular degeneration
  • the methods described herein can be used to identify a female Caucasian subject that is appropriate for an age-related macular degeneration clinical trial.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject is appropriate for a complement-mediated disease clinical trial.
  • Such hapltoypes can be risk haplotypes.
  • a risk haplotype can be H1 62 A, H2 62 A, H1 5 I B, H2 5 I B, or a complement thereof.
  • methods for identifying a female Caucasian subject that is appropriate for a complement- mediated disease clinical trial comprising determining in the female Caucasian subject the identity of one or more haplotypes described herein, wherein a risk haplotype can indicate that the female subject is appropriate for the clinical trial.
  • the method of identifying a female subject for the clinical trial can further comprise administering a therapeutic composition to the subject identified as being appropriate for the clinical trial.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the female subject is not appropriate for a complement-mediated disease clinical trial.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be H3 62 A, H5 62 A, HI 1_62_A, H3 51 B, H5 51 B, H12 51 B, H14 51 B, or a complement thereof.
  • a female subject identified to have a protective haplotype described herein can be excluded from participation in a clinical trial designed to evaluate a treatment for a complement-mediated disease.
  • determining the identity of a certain haplotype or certain haplotypes in a female subject can indicate that the subject may be appropriate for a complement-mediated disease clinical trial.
  • haplotypes can be neutral haplotypes.
  • a neutral haplotype can be
  • methods identifying a female Caucasian subject appropriate for a complement- mediated disease clinical trial comprising determining in the female Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype can indicate a female that may be appropriate for a complement-mediated disease clinical trial.
  • haplotypes can include, but are not limited to H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A, H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, H11 62 A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 B, H2 51 B, H3 51 B, H4 51 B, H5 51 B, H6 51 B, H7 51 B, H8 51 B,
  • the presence of one or more of the haplotypes disclosed herein can indicate whether the male subject is appropriate for a complement-mediated disease clinical trial.
  • the complement-mediated disease can be age-related macular degeneration (AMD), and the clinical trial can be an age-related macular degeneration clinical trial.
  • AMD age-related macular degeneration
  • the methods described herein can be used to identify a male Caucasian subject that is appropriate for an age-related macular degeneration clinical trial.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject is appropriate for a complement-mediated disease clinical trial.
  • hapltoypes can be risk haplotypes.
  • a risk haplotype can be H2 62 A, HI 5 I B, H2 51 B, or a complement thereof.
  • described herein are methods for identifying a male Caucasian subject that is appropriate for a complement-mediated disease clinical trial comprising determining in the male Caucasian subject the identity of one or more haplotypes described herein, wherein a risk haplotype can indicate that the male subject is appropriate for the clinical trial.
  • the method of identifying a male subject for the clinical trial can further comprise administering a therapeutic composition to the male subject identified as being appropriate for the clinical trial.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the male subject is not appropriate for a complement-mediated disease clinical trial.
  • haplotypes can be protective haplotypes.
  • a protective haplotype can be HI 1 62 A, H3 5 I B, H14 5 I B, or a complement thereof.
  • described herein are methods for identifying a male Caucasian subject that is appropriate for a complement-mediated disease clinical trial comprising determining in the male Caucasian subject the identity of one or more haplotypes described herein, wherein a protective haplotype can indicate that the male subject is not appropriate for a complement-mediated disease clinical trial.
  • a male subject identified to have a protective haplotype described herein can be excluded from participation in a clinical trial designed to evaluate a treatment for a complement-mediated disease.
  • determining the identity of a certain haplotype or certain haplotypes in a male subject can indicate that the subject may be appropriate for a complement-mediated disease clinical trial.
  • Such haplotypes can be neutral haplotypes.
  • a neutral haplotype can be
  • identifying a male Caucasian subject appropriate for a complement- mediated disease clinical trial comprising determining in the male Caucasian subject the identity of one or more haplotypes described herein, wherein a neutral haplotype can indicate a male that may be appropriate for a complement-mediated disease clinical trial.
  • Also described herein are methods of identifying a Caucasian subject appropriate for complement-mediated disease clinical trial comprising determining in the subject the identity of one or more SNPs in the CFH-to-F13B locus.
  • the SNPs can be, but are not limited to: (i) rsl061170, rsl410996, rs2274700, rs3753395, rs403846, or rs3753396 or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of one or more of the SNPs described herein can indicate whether the subject is appropriate for the clinical trial.
  • an A at the rsl061170 SNP can indicate the subject is appropriate for the clinical trial.
  • an A at the rsl410996 SNP, an A at the rs2274700 SNP, a T at the rs3753395 SNP, or a G at the rs403846 SNP can indicate the subject is not appropriate for the clinical trial.
  • the subject when it is determined that a Caucasian subject has an A at the rsl410996 SNP, an A at the rs2274700 SNP, a T at the rs3753395 SNP, or a G at the rs403846 SNP, the subject can be excluded from a complement-mediated disease clinical trial.
  • a G at the rs3753396 SNP can indicate the subject may be appropriate for the clinical trial.
  • Also described herein are methods of identifying a Caucasian subject appropriate for an a complement-mediated disease clinical trial comprising determining in the subject the identity of a deletion tagging SNP in the CFH-to-F13B locus.
  • the SNP can include, but is not limited to: (i) rs 12144939 or (ii) a SNP in linkage disequilibrium with rs 12144939.
  • the presence of one or more of the SNPs can indicate whether the subject is appropriate for the clinical trial.
  • a T at the rsl2144939 SNP can indicate the subject is not appropriate for the clinical trial.
  • Also described herein are methods of identifying a Caucasian subject appropriate for a complement-mediated disease clinical trial comprising determining in the Caucasian subject the identity of at least six SNPs in the CFH-to-F13B locus.
  • the SNPs can be, but are not limited to: (i) rs35928059, rs800292, rsl061170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs can indicate whether the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a T at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, an A at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • Also described herein are methods of identifying a female Caucasian subject appropriate for a complement-mediated disease clinical trial comprising determining in the female Caucasian subject the identity of at least six SNPs in the CFH-to-F13B locus.
  • the SNPs can include, but are not limited to: (i) rs35928059, rs800292, rsl061170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs can indicate whether the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an G at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a T at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, an A at rsl409153, a T at rsl0922153, or a G at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, an A at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rs 1061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • Also described herein are methods of identifying a male Caucasian subject appropriate for a complement-mediated disease clinical trial comprising determining in the male Caucasian subject the identity of at least six SNPs in the CFH-to-F13B locus.
  • the SNPs can be, but are not limited to: (i) rs35928059, rs800292, rsl061170, rsl2144939, rs7546940, rsl409153, rsl0922153, or rs698859, or (ii) a SNP in linkage disequilibrium with the SNPs of (i).
  • the presence of at least six of the SNPs can indicate whether the subject is appropriate for the clinical trial.
  • G at rsl2144939, a G at rs7546940, a G at rsl409153, a G at rsl0922153, or an A at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a C at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a C at rsl061170, a G at rsl2144939, a G at rs7546940, a C at rsl409153, a G at rsl0922153, or a T at rs698859 can indicate the subject is appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, an A at rs7546940, an A at rsl409153, a T at rsl0922153, or an A at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, an A at rs800292, a T at rsl061170, a G at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a C at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • an A at rs35928059, a G at rs800292, a T at rsl061170, a T at rsl2144939, a G at rs7546940, a T at rsl409153, a T at rsl0922153, or a T at rs698859 can indicate the subject is not appropriate for the clinical trial.
  • kits for enhancing clinical trials comprising choosing appropriate patient populations for those clinical trials.
  • the methods can be used to ensure patients are identified to participate in clinical trials based upon whether or not they are responsive to the experimental therapeutic agent or agents being studied.
  • the methods can comprise monitoring the condition of subjects receiving treatment for a complement-mediated disease such as AMD.
  • a successful treatment outcome can be indicated by return of complement pathway activity, such as expression level, biochemical activity (e.g., enzymatic activity of a complement component), or serum auto antibodies against complement pathway associated molecules, from abnormal levels to or toward normal levels.
  • the methods can comprise measuring an initial value for the level of abnormal activity (e.g., abnormal presence of an autoantibody, or abnormal levels of complement pathway molecules) before the subject has received treatment.
  • Repeat measurements can then be made over a period of time.
  • that period of time can be about 1 day, 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, or greater than 1 year.
  • the initial level is elevated relative to the mean level in a control population, a significant reduction in level in subsequent measurements can indicate a positive treatment outcome.
  • the initial level of a measure marker is reduced relative to the mean in a control population, a significant increase in measured levels relative to the initial level can signal a positive treatment outcome.
  • Subsequently measured levels are considered to have changed significantly relative to initial levels if a subsequent measured level differs by more than one standard deviation from the mean of repeat measurements of the initial level. If monitoring reveals a positive treatment outcome, that indicates a patient that can be chosen to participate in a clinical trial for that particular therapeutic agent or agents. If monitoring reveals a negative treatment outcome, that indicates a patient that should not be chosen to participate in a clinical trial for that particular therapeutic agent or agents. S
  • kits for utilizing the methods described herein can comprise an assay or assays for detecting one or more haplotypes in a nucleic acid sample of a subject, wherein the one or more haplotypes are the haplotypes described herein.
  • the one or more haplotypes can be H1 62 A, H2 62 A, H3 62 A, H4 62 A, H5 62 A , H6 62 A, H7 62 A, H8 62 A, H9 62 A, H10 62 A, HI 1_62_A, H12 62 A, H13 62 A, H14 62 A, H15 62 A, H1 51 A, H2 51 A, H3 51 A, H4 51 A, H5 51 A, H6 51 A, H7 51 A, H8 51 A, H9 51 A, H10 51 A, H1 1 51 A, H12 51 A, H13 51 A, H14 51 A, H15 51 A, H16 51 A, H17 51 A, H1 51 B,
  • the one or more haplotypes can be the haplotype tagging haplotypes described herein as well as the haplotype tagging haplotypes shown in Figure 41.
  • kits described herein can further comprise amplification reagents for amplifying the CHF-to-F13B locus, or any of the genes or nucleic acids described herein.
  • Example 1 Patient Cohorts
  • DNA samples derived from well-characterized cohorts of study patients with and without AMD were used for the various studies described herein (see Abrera- Abeleda et al 2006; Allikmets et al 2009; Baird et al 2006; DeAngelis et al 2008; Gold et al 2006; Hageman et al, 2005, 2006, 2011; Lim et al 2012; Robman et al
  • DNA samples from several additional cohorts were also available: 1) early onset drusen cases (EOD) (103); 2) Caucasian newborns (1,870); 3) MPGN II (65); atypical hemolytic uremic syndrome (aHUS) (211); 4) glaucoma (330); 5) Alzheimer's disease
  • Example 2 Determination of Deletion Status and Extended Haplotypes Spanning the Chromosome lq32 CFH-to-F13B Locus; Discovery Phase
  • DNA samples from study patients, including sib pairs, with and without AMD were used.
  • DNA samples from the 1,073 subjects employed for this study (referred to as ' 1,073 Cohort', 'GSH Cohort' or 'ParAllele Cohort') were of
  • SNPs single nucleotide polymorphisms
  • F13B genes were genotyped using SSCP-based genotyping [5], Taqman based genotyping (ABI), Sanger sequencing, and molecular inversion probe genotyping (ParAllele Bioscience) [6] in 1,073 human genomic DNA samples. SNPs were selected based on significance of association in a prior ParAllele Study (a study in which 1,162 DNA samples were genotyped using the Affymetrix 3K 'Iowa AMD
  • the deletion status of the CFHR-3/CFHR- 1 genes was assessed using SSCP and a qPCR assay developed to detect the deletion on single chromosomes.
  • SSCP assay was used to identify all individuals homozygous for the CFHR3/CFHR1 deletion.
  • Using a pair of PCR primers that amplify both CFH exon 22 and a homologous region in CFHR1 see Hageman et al 2006 for primers), one of the resulting SSCP conformations (referred to as 'shift 4') was diagnostic of a subject for which both copies of CFHR1 were absent.
  • mrd_3855-PROBE (6-FAM-AAC AGC ATG GAA TAT C-MGB SEQ ID NO. 287).
  • the reference amplicon was of RNase P, a single copy gene, and reagents were purchased from Applied Biosystems (part number 4316844) with a VIC fluorescent tag attached.
  • Applied Biosystems Fast Universal PCR Master Mix provided both the polymerase and ROX exogenous non-amplifying background fluorophore.
  • Biosystems 7900HT Fast Real-Time PCR System was used for all experiments.
  • chromosomes (homozygous normal) if most sample replicates had Ct values for both the deletion amplicon and RNase P similar to the normal control. Samples heterozygous for the CFHR3/CFHR1 deletion had Ct values for the deletion amplicon approximately one cycle later than expected based on their RNase P Ct values.
  • the qPCR deletion assay was used to classify 536 (and 801 in a second assay) individuals as homozygous deletion (DD), heterozygous deletion (ND), or homozygous non-deletion (NN). All remaining individuals were classified according to their genotypes for SNPs in CFHR3 and CFHRl . All individuals containing more than one heterozygous SNP in CFHR3 or CFHRl were assumed to be not consistent with a deletion on either chromosome (genotype NN). All other individuals were assigned to have one normal chromosome and one unknown chromosome (N?).
  • SNPs being inconsistent with a heterozygous deletion, were replaced with two unknown alleles (??). All homozygous deletion individuals were assigned two unknown alleles (??) for each SNPs in the same region.
  • PHASE version 2.1.1 was used to impute missing genotypes and phase genotypes for each individual, care was taken to correctly handle the presence or deletion of CFHR3/1 SNPs as a group. Chromosomal positions for each SNP were obtained from NCBI dbSNP build 129 using the reference human genome (build 18). All individuals typed at SNPs in the CFHR3/CFHR1 region and seven distinct four- SNP haplotypes were imputed for the CFHR3/CFHR1 deletion region using the four SNPs in the deletion region spanning from rsl 1807997 through rs414628. Five independent runs of PHASE were used to confirm haplotype consistency and two haplotypes were assigned to each individual.
  • the multi-allelic deletion status was expanded back into four separate tri-allelic SNPs, with a D allele representing the deletion haplotype.
  • all minor haplotypes with frequency less than 1% were iteratively re-assigned to the most similar remaining haplotype.
  • PHASE provided probability-weighted, imputed, and phased genotypes for all individuals. Each individual run of PHASE produced multiple weighted estimates of each individual's phased genotypes (using the pairs output file from PHASE). The five independent runs of PHASE produced up to five different imputations of missing genotypes, all of which were then equally weighted.
  • Input was a collection of individuals where each individual had a set of potential diplotypes and its estimated probability (from PHASE pairs output files); 2) The active set was initialized to include all possible haplotypes; 3) Individual diplotypes were assigned based on the individual's diplotype probabilities with the constraint that diplotypes could only use haplotypes in the active set.
  • Step #7 was skipped to if any individual was not assigned a diplotype; 5) The assigned individual diplotypes were saved as the current solution; 6) The least-used haplotype was removed from the active set and step #3 was returned to; 7) The current solution was outputted as the list of individual diplotypes, and thus haplotypes, present in the population.
  • Phased genotypes were also processed in some analyses using Beagle (version 3.0.1) to obtain two haplotype networks— one merging similar haplotypes in the 5' ⁇ 3' direction, the second in the 3 ' ⁇ 5' direction. All ten phased genotypes for each individual from the five independent runs of PHASE were used as input to account for uncertainty in the phasing or imputation of missing genotypes.
  • the scale parameter for Beagle's haplotype merging process was set to 4.0.
  • the directed acyclic graph haplotype output by Beagle indicated which SNPs form haplotype blocks and how those blocks were interrelated. Each chromosome was assigned a haplotype based on its path through the two networks leading to the rs4230 SNP. Haplotypes accounting for less than 1% of the chromosomes were not reported. [00286] 2.8 Methods: Haplotype Validation
  • Genotype calling was carried out using the CRLMM calling algorithm from the Bioconductor 2.3 Oligo Package. Genotype calls whose confidence was less than 0.95 were replaced with missing values. SNP markers whose call rate was less than 95% were also dropped. Taqman
  • SNP genotyping assays were also carried out to obtain genotypes for 23 additional SNP markers.
  • PedCheck program was used to detect Mendelian inconsistencies and misinherited genotype calls were removed.
  • Phased haplotypes were constructed based on the Mendelian inheritance model in each of the three-generation families. None of the haplotype inference programs were used. Haplotype frequencies were calculated on 136 unrelated UGRP individuals, who were mostly first generation grandparents, using Haploview program's phased haplotype input mode, Haps format ( Figure 33).
  • genotyping five were unreported in the literature ( Figure 27) at the time of their discovery. These were identified using mismatch repair detection (MRD) to amplify a variant-enriched pool of amplified genomic DNA. This pool of amplified DNA was then sequenced to identify rare alleles.
  • the rare mrd_3876 and mrd_3877 SNPs were located within the promoter region of CFHR4.
  • the minor allele of mrd_3876 was present in haplotype(s) that skewed toward risk for AMD, and the minor allele of mrd_3877 occurred in haplotype(s) that skewed significantly with AMD risk.
  • the minor allele of mrd_3902 located within exon 2 of CFHR2, results in a Cys72Tyr coding mutation and occurred in haplotypes that appeared to skew toward protection for AMD.
  • the minor alleles of SNPs mrd_3905 and mrd_3906 were more common (minor allele frequencies of approximately 20%) and were located within the promoter region of CFHR5; they did not appear to skew with AMD risk or protection
  • one experiment produced 192 replicates for each of two DNA samples— one homozygous non-deletion sample and a related heterozygous deletion sample.
  • Each qPCR assay was perfomed using total genomic DNA between lOOng and 0.6ng. Based on these data, for a given amount of genomic DNA, an assay using heterozygous deletion DNA was predicted to have a Ct value 0.645 ⁇ 0.002 cycles greater than an identical assay utilizing homozygous normal DNA.
  • the expected power for correctly classifying a heterozygous deletion of the CFHR3/CFHR1 genes using five to six qPCR replicates was 83%. This is similar to the 75% call rate shown in ( Figure 28). Thus, to obtain a power of 95% with a 5% type-I error rate, nine replicates were run on each DNA sample.
  • rsl2406509 and rs7546940 slightly increased the sensitivity and specificity of the deletion prediction.
  • Haplotypes HI and H2 the two most prevalent haplotypes (approximately 47% of the chromosomes in this cohort), contained the vast majority of the CFH Y402H variant.
  • the CFH I62V protective variant was contained primarily in haplotypes H4, H9, and H12. Eleven SNPs (arrows in
  • Example 3 Refined Assessment of Extended Haplotypes Spanning the Chromosome lq32 CFH-to-F13B Locus
  • PHASE 2.1.1 was employed to determine the SNP-based haplotypes present in the 1,073 patient cohort. Chromosomal positions used were from the NCBI dbSNP build 129 using the reference human genome (build 18). Following genotype phasing, the multi-allelic deletion status was expanded back into four separate tri- allelic SNPs (major, minor, and deleted). [00309] In addition, 51 SNP-based haplotypes were generated for the highly discordant sib-pair cohort, the AMD case-control cohorts ascertained in Utah, Iowa, Australia ('Combined Cohort') and the UGRP cohort. Of the 62 SNPs employed for the 62 SNP-based haplotype determinations, the four SNPs lying within the
  • Haploview program's phased haplotype input mode Haps Format (Bioinformatics 21 :263-265, 2005).
  • Haploview was used to determine descriptive statistics using normal subjects (only one normal sibling per family for the Family Cohort), i.e. deviation from Hardy Weinberg Equilibrium (HWE) and the minor allele in the population.
  • Tests for association of the minor allele with AMD were performed assuming an additive genetic model, and all AMD subtypes were compared to normals in the entire cohort, and then in males only and separately females only.
  • CLR Conditional Logistic Regression
  • one subject of each gender was chosen per family (choosing the subject with the most severe disease), and tested for association with all AMD subtypes using logistic regression.
  • Logistic regression was also used to assess 51 SNP-based haplotypes derived from the '927 GSH Cohort'. All analyses were performed in SAS (v9.1) and/or Haploview. Meta- Analysis was performed using Comprehensive Meta- Analysis 2.0.
  • haplotypes encompassing the CFH-to-F13B locus 1,073 unrelated Caucasians of Northwestern European decent, were genotyped for 62 SNPs using a combination of assays, with missing genotypes imputed using PHASE2.1.1, as described above. Haplotypes for all samples were then determined using PHASE 2.1.1.
  • the hierarchical relationships between the 163 62 SNP-based haplotypes is shown in Figure 21 (H1 62 A through H163 62 A).
  • the 163 haplotypes were clustered based on the number of similar loci into this tree using the R statistical package hclust function using hierarchical clustering analysis. Similar haplotypes are the most related (closer together) and dissimilar haplotypes are further apart in this 'tree', shown in Figure 21.
  • the neutral haplotypes clustered at the left, or top, portion of the tree. Specifically, the neutral haplotype cluster spanned the region from H126 62 A to H163 62 A.
  • the risk haplotypes clustered in the middle portion of the tree. Specifically, the risk haplotype cluster spanned the region from
  • the protective haplotypes clustered at the right, or bottom, portion of the tree. Specifically, the protective haplotype cluster spanned the region from H152 62 A to H98 62 A.
  • H1 62 A and H2 62 A were identical from the region proximal to CFH through CFHR2, based on the variants examined within this region; only in the F13B gene (beginning with rs698859 in the 3' UTR of F13B), do SNPs distinguish the H1 62 A and H2 62 A haplotypes ( Figure 1).
  • Other F13B SNPs that distinguish H1_62_A and H2 62 A include rs5998, rs2990510 and rsl615413.
  • CFH 402H risk allele H8, H12, H14.
  • H3 62 A and H6 62 A contained the protective minor allele "A" for CFH rs800292.
  • 4 major haplotypes contained the CFHR3/CFHR1 deletion (H5 62 A, H11 62 A, H13 62 A, and H15 62 A; Figure 1).
  • the variant rsl409153 is also in near complete LD with all major haplotypes associated with protection. Any of these SNPs, and any other SNP in near LD with these SNPs, singly or in combination, can serve as surrogates for the major protective haplotypes H3 62 A, H6 62 A, H5 62 A, HI 1_62_A, H13 62 A, and H15 62 A, as well as some of the minor protective haplotypes. Other SNPs within this region of DNA that are in near complete LD (and can serve as surrogates) were determined by generating an LD plot using all of the SNPs in HapMap lying within the CFH-to-CFHR4 region. This was done using the CEU cohort (CEU, Utah residents with Northern and Western
  • HapMap Phase 3 genotypes.
  • 51 SNP-based haplotypes were also generated using the 1,073 (927 Subset) Cohort ( Figure 22). Converting from 62 to 51 SNPs caused some of the 62 SNP- based haplotypes to collapse into the 51 SNP-based haploytpes ( Figure 20). 17 major haplotypes occurred at frequencies greater than 1% in this cohort.
  • haplotype frequency between the GSH Cohort and the UGRP cohort was expected. However, when compared to the haplotypes shown in Figure 1 , these differences were minor and haplotype
  • H2 62 A exhibited significant risk for AMD ( Figure 6 and Figure 18; p ⁇ 0.0001; note that values vary slightly between Figures 6 & 18 due to clinical reclassification of a few patients between the time these two analyses were conducted).
  • haplotypes tagged by these SNPs are responsible either for risk in H2 62 A or lack of risk in H1 62 A.
  • haplotypes contain the risk allele at rs 1061170 (H1 62 A, H2 62 A, H8 62 A, H12 62 A, and H14 62 A) and yet only one of these haplotypes associated significantly with risk in this cohort, there is likely a risk factor present in the H2 62 A haplotype that is lacking in all other non-H2_62_A 402H haploytpes.
  • haplotypes described herein represent a significant increase in the sensitivity of defining risk at the CFH locus.
  • H2_62_A was the most strongly associated haplotype with AMD risk, whereas major haplotypes H1 62 A, H8 62 A, H12 62 A, and H14 62 A were not significantly associated in this cohort.
  • the minor haplotype H16 62 A trended toward risk in this cohort.
  • H3 62 A (includes the rs800292 A allele) was significantly protective ( Figure 6). Just as H1 62 A and H2 62 A differed in their risk association, so to did H3 62 A (protection) with the other major haplotype containing the rs800292 A Allele, H6 62 A (neutral). Of the haplotypes containing CFHR3/CFHR1 deletions, H5 62 A and HI 1 62 A showed significant protection, while H13 62 A showed marginal protection and H15 62 A was neutral. H3 62 A and H6 62 A are identical until mrd_3905/rs75816959, which is in CFHR5. Similarly the CFHR3/CFHR1 deletion containing haplotypes
  • H5 62 A, H13 62 A, and H15 62 A are identical until mrd_3905.
  • placing these haplotypes in the context of extended haplotypes that included CFHR5 and F13B resulted in significantly refined association with AMD ( Figures 6 & 18).
  • SNPs in LD with rs3753396 at a r2 value of 90 or greater and that can be employed as surrogates for rs3753396 include (listed proximal to distal): rsl0489456, rs70620, rs742855, rsl 1799380, rsl065489, rsl 1582939, rs385390, rs421820, rs426736, rs370953 and rs371075.
  • H2 62 A was barely significant in males but strongly significant in females ( Figure 23).
  • H2 5 I B was more significant in males than H2 62 A, but still less significant than in females ( Figure 24).
  • H1_62_A was significant in females, not at all in males. Whereas, H1 5 I B was significant in both males and females;
  • HI 1_62_A was significant in both males and females, but was more significant in males.
  • H2 62 A, H3 62 A, H5 62 A, and HI 1 62 A were all significantly associated with AMD in all of the subjects ( Figure 6) and also in the females ( Figure 23).
  • Females were slightly more significantly associated than the all-subjects in H1 62 A and H6 62 A, and less significantly associated in H13_62_A, but these differences were fairly minor.
  • a large case-control cohort comprised of individuals with and without AMD from the Iowa, Utah, and Melbourne cohorts (the 'Combined Cohort') was employed to assess 51 SNP-based CFH-to-F13B haplotypes with AMD (controls versus all AMD) risk, protection, and neutrality.
  • Fifty-six haplotypes were generated from the Combined Cohort, 18 of them occurred at frequencies above 1% ( Figure 15).
  • the relationships between the major 51 SNP-based and 62 SNP-based haplotypes are shown in Figure 16 and the relationship between 51 SNP-based haplotypes in the 1,073 and Combined Cohorts is depicted in Figure 19.
  • Hx_62_A Associations similar to those of 62 SNP-based (Hx_62_A) and 51 SNP-based assessments in the GSH 927 Cohort (Hx_51_A) were observed ( Figure 15). H1 51 B, however, became more significant in this larger cohort.
  • the 'Combined Cohort' was also employed to assess the association of single SNP associations of the 51 SNP panel and 51 SNP-based CFH-to-F13B haplotypes with the various phenotypes/stages of AMD, including comparisons of controls (stage 0) to all AMD (stages 1B-4C), early stage AMD (stages 1B-3), and the late stages of geographic atrophy (stage 4 A) and CNV (stage 4B).
  • Single marker associations in this cohort ( Figure 42) did not differ from those of the 1 ,073 and highly discordant sib-pair cohorts when controls were compared to all AMD.
  • a single HI haplotype when combined with another HI haplotype, or a H2, H8 or HI 3 haplotype was associated with increased risk for developing AMD whereas combination of HI haplotype with a H3 or H5 haplotype was associated with protection. Only when a single H2 haplotype occurred with another H2 haplotype, a HI haplotype or a HI 0 haplotype was there an association with risk. No
  • SNP -based CFH-to-F13B diplotypes with the various phenotypes/stages of AMD including comparisons of controls (stage 0) to all AMD (stages 1B-4C), to early stage AMD (stages 1B-3), and to CNV only (stage 4B).
  • Diplotype associations with risk, protection and neutrality did not vary significantly between the following groups: 1) controls compared to all AMD stages ( Figure 35); and 2) controls compared to CNV only ( Figure 48). Nor did these associations differ from those in other cohorts.
  • Each of the major 62 SNP -based haplotypes and each of the major 51 SNP- based haplotypes can be uniquely identified using a combination of eight haplotype tagging SNPs (htSNPs; Figure 7; note that rs800292 and rs35928059 are optional for tagging the 62 and 51 SNP -based haplotypes). Case/control analysis was repeated on the GSH 1,073 Cohort using only the eight htSNPs to define haplotypes using Haploview 4.2.
  • haplotypes were constructed for the CEU dataset and their frequencies calculated ( Figures 39 and 40). There is substantial overlap between the AMD case/control ('combined cohort') 51 SNP-based haplotypes and the HapMap haplotypes ( Figures 38, 39 and 40). These overlapping SNPs were used as 'tagging' SNPs to match case/control haplotypes to their equivalent HapMap CEU haplotypes ( Figures 38 and 41). AMD association with haplotype was previously established in the 51 SNP-based case/control ('combined') cohort ( Figure 22); thus association could be extended to the equivalent HapMap haplotypes.
  • 51 SNP-based haplotypes overlapped with multiple HapMap haplotypes and vice versa due to the presence of HapMap SNPs that were not included in the 51 SNP-based haplotypes.
  • key SNPs were identified that further refined the discriminative value of our major 51 SNP-based haplotypes.
  • the 'combined cohort' haplotype HI Figures 39 and 41
  • matched the two most frequent of the major HapMap generated haplotypes Figures 39 and 41.
  • the only SNP that differentiated these two HapMap haplotypes was rs 10494745.
  • Quantitative PCR was performed on multiple CEPH individuals representing each deletion tagging SNP genotype. Three qPCR primer sets were designed to amplify both duplicated regions equally, and two additional probes were designed in the sequence between the segmental duplications. All experiments were performed using QuantiFast SYBR RT-PCR Master Mix (Qiagen) and the MyiQ Single Color Real-Time PCR Detection System (BioRad). Non-deletion
  • homozygotes showed the presence of both segmental duplications, as well as normal amplification of probes between the duplications. Heterozygotes showed
  • a predesigned Taqman CNV assay was run on all 604 CEPH individuals in order to confirm deletion status. This assay was located on chrl : 195011298- 195011397, just proximal to the CFHR3 gene. Assays were run on a 7900HT Fast Real-Time PCR System (Applied Biosystems) and analyzed using CopyCaller software (Applied Biosystems). Copy number calls were compared against rsl2144939 (deletion tagging SNP) genotypes.
  • Gold B Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT; AMD Genetics Clinical Study Group, Hageman GS,

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