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  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
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  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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  • C12Q1/6844—Nucleic acid amplification reactions
  • C12Q1/6858—Allele-specific amplification
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  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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  • C12Q2600/00—Oligonucleotides characterized by their use
  • C12Q2600/118—Prognosis of disease development
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  • C12Q2600/00—Oligonucleotides characterized by their use
  • C12Q2600/156—Polymorphic or mutational markers
• • C—CHEMISTRY; METALLURGY
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  • C12Q2600/00—Oligonucleotides characterized by their use
  • C12Q2600/172—Haplotypes
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/18—Dental and oral disorders

Definitions

• the present invention relates generally to an improved method for determining a patient's risk of severe periodontal disease and/or risk of periodontal disease progression and a kit for use in such an improved method.
• Gingivitis is an early stage of the periodontal disease where the gums may become red, swollen and bleed easily. Gingivitis is usually painless and, if not treated, can advance to periodontitis, which may be classified by the magnitude of tissue destruction as mild, moderate, or severe. Periodontitis is primarily a disease of adults and is usually not detectable until after the age of 35. Usually bacteria that are present in dental plaque initiate periodontal disease. Toxins produced by the bacteria in the plaque activate the body's inflammatory and other immune mechanisms which ultimately lead to the destruction of the bone and gum tissue that support the teeth.
• U.S. Pat. No. 5,328,829 discloses a method for determination of active periodontal disease sites within the oral cavity by measuring interleukin IL-1.beta. at the site. Smoking has been associated with an increased prevalence and severity of periodontitis. However, a significant number of individuals with periodontitis have never smoked.
• a genetic testing kit was developed to predicts risk for periodontal diseases using two variations in the human genome, one located in IL1A gene (IL1A +4845) and the other in IL1B gene (IL1B +3954). Carriers of at least one copy of the minor allele in each of these gene variations have increased susceptibility to periodontal disease. See U.S. Pat. No. 5,686,246. However, such a test has a limited utility in some ethnic populations and the test identifies only a small portion of people who are at risk for periodontal diseases in those populations. There is the need to find more sensitive method of determining risks of periodontal disease in all ethnic populations.
• the present invention is directed to a method of determining whether a patient is predisposed to having severe periodontal disease and/or having high risk of progression of periodontal disease, comprising the steps of (i) taking a biological sample from said patient; (ii) genotyping said biological sample for genetic polymorphism pattern comprising IL 1B (rs16944), IL 1B (rs1143623) and IL 1B (rs4848306); and (iii) comparing said genetic polymorphism patterns to a reference composite genotype pattern; wherein the similarity of said genetic polymorphism patterns to said reference pattern indicate said patient's predisposition to having severe periodontal disease and/or having high risk of progression of periodontal disease.
• the present invention is also directed to a testing kit for determining whether a patient is predisposed to having severe periodontal disease and/or having high risk of progression of periodontal disease, comprising (i) biological sample collection means; (ii) a means for determining genetic polymorphism pattern; and (iii) a control sample containing IL 1B (rs16944), IL 1B (rs1143623), IL 1B (rs4848306) and IL 1B ((rs1143633).
• the invention relates to the discovery of a polymorphism in the IL-1B gene which is associated with susceptibility to periodontal disease. Accordingly, ascertainment of genotype at this polymorphism provides a useful genetic test for susceptibility to periodontal disease.
• Asian means people whose ancestral homes are in one of the countries in Asia, including, but is not limited to China, India, Japan, regardless of where they live currently.
• African means people whose ancestral homes are in one of the countries in African regardless of where they live currently.
• a method of determining whether a patient is predisposed to having severe periodontal disease and/or having high risk of progression of periodontal disease comprising the steps of (i) taking a biological sample from said patient; (ii) genotyping said biological sample for genetic polymorphism pattern comprising IL 1B (rs16944), IL 1B (rs1143623) and IL 1B (rs4848306); and (iii) comparing said genetic polymorphism pattern to a reference composite genotype pattern; wherein the similarity of said genetic polymorphism patterns to said reference pattern indicate said patient's predisposition to having severe periodontal disease and/or having high risk of progression of periodontal disease.
• Also provided herein is a method of determining whether a patient is predisposed to having severe periodontal disease and/or having high risk of progression of periodontal disease, comprising the steps of (i) taking a biological sample from said patient; (ii) genotyping said biological sample for genetic polymorphism pattern comprising IL 1B (rs16944), IL 1B (rs1143623) and IL 1B (rs4848306), wherein the presence of one of the genetic polymorphism patterns listed in Tables 4-6 indicates said patient's predisposition to having severe periodontal disease and/or having high risk of progression of periodontal disease.
• the composite genotypes of IL1B gene can be defined by the conventional alleles. Two composite genotype patterns are shown below as examples.
• the biological sample is selected from the group consisting of saliva, buccal cells, blood, tissue samples and urine.
• the method is for determining whether said patient is predisposed to having severe periodontal disease or for determining said patient's risk of progression of periodontal disease.
• the patient is Caucasian, African, Chinese or of other ethnicities.
• the present invention has identified IL1 SNPs and haplotypes that are highly prevalent in all major ethnic populations. Specific composite genotypes were significantly associated with more severe periodontitis in Caucasians, African-Americans and Chinese. Any difference between ethnic groups may be caused by different gene-gene interactions between ethnic groups may contribute to these different findings and that the gene-environment interactions may differ between ethnic groups.
• the patient is Caucasian, African, Chinese or of other ethnicities.
• This kit may contain one or more oligonucleotides, including 5′ and 3′ oligonucleotides that hybridize 5′ and 3′ to at least one allele of an IL-1 locus haplotype.
• PCR amplification oligonucleotides should hybridize between 25 and 2500 base pairs apart, preferably between about 100 and about 500 bases apart, in order to produce a PCR product of convenient size for subsequent analysis.
• Suitable primers for the detection of a human polymorphism in these genes can be readily designed using this sequence information and standard techniques known in the art for the design and optimization of primers sequences.
• Optimal design of such primer sequences can be achieved, for example, by the use of commercially available primer selection programs such as Primer 2.1, Primer 3 or GeneFisher (See also, Nicklin M. H. J., Weith A. Duff G. W., “A Physical Map of the Region Encompassing the Human Interleukin-1 ⁇ , interleukin-1 ⁇ , and Interleukin-1 Receptor Antagonist Genes” Genomics 19: 382 (1995); Nothwang H. G., et al.
• oligonucleotides may be any of a variety of natural and/or synthetic compositions such as synthetic oligonucleotides, restriction fragments, cDNAs, synthetic peptide nucleic acids (PNAs), and the like.
• the assay kit and method may also employ labeled oligonucleotides to allow ease of identification in the assays. Examples of labels which may be employed include radio-labels, enzymes, fluorescent compounds, streptavidin, avidin, biotin, magnetic moieties, metal binding moieties, antigen or antibody moieties, and the like.
• the kit may, optionally, also include DNA sampling means.
• DNA sampling means are well known to one of skill in the art and can include, but not be limited to substrates, such as filter papers, the AmpliCardTM (University of Sheffield, Sheffield, England S10 2JF; Tarlow, J W, et al., J. of Invest. Dermatol.
• DNA purification reagents such as NucleonTM kits, lysis buffers, proteinase solutions and the like
• PCR reagents such as 10 ⁇ reaction buffers, thermostable polymerase, dNTPs, and the like
• allele detection means such as the HinfI restriction enzyme, allele specific oligonucleotides, degenerate oligonucleotide primers for nested PCR from dried blood.
• Instructions e.g., written, tape, VCR, CD-ROM, etc.
• Instructions for carrying out the assay may be included in the kit.
• SNPs single nucleotide polymorphisms
• SNPs single nucleotide polymorphisms
• SNPs are major contributors to genetic variation, comprising some 80% of all known polymorphisms, and their density in the human genome is estimated to be on average 1 per 1,000 base pairs. SNPs are most frequently biallelic-occurring in only two different forms (although up to four different forms of an SNP, corresponding to the four different nucleotide bases occurring in DNA, are theoretically possible).
• SNPs are mutationally more stable than other polymorphisms, making them suitable for association studies in which linkage disequilibrium between markers and an unknown variant is used to map disease-causing mutations.
• SNPs typically have only two alleles, they can be genotyped by a simple plus/minus assay rather than a length measurement, making them more amenable to automation.
• the method includes the steps of (i) collecting a sample of cells from a patient, (ii) isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, (iii) contacting the nucleic acid sample with one or more primers which specifically hybridize 5′ and 3′ to at least one allele of an IL-1 proinflammatory haplotype under conditions such that hybridization and amplification of the allele occurs, and (iv) detecting the amplification product.
• nucleic acid e.g., genomic, mRNA or both
• the allele of an IL-1 proinflammatory haplotype is identified by alterations in restriction enzyme cleavage patterns.
• sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis.
• allele refers to the different sequence variants found at different polymorphic regions.
• IL-1RN VNTR
• the sequence variants may be single or multiple base changes, including without limitation insertions, deletions, or substitutions, or may be a variable number of sequence repeats.
• allelic pattern refers to the identity of an allele or alleles at one or more polymorphic regions.
• an allelic pattern may consist of a single allele at a polymorphic site, as for IL-1RN (VNTR) allele 1, which is an allelic pattern having at least one copy of IL-1 RN allele 1 at the VNTR of the IL-1RN gene loci.
• VNTR IL-1RN
• an allelic pattern may consist of either a homozygous or heterozygous state at a single polymorphic site.
• IL-1-RN (VNTR) allele 2,2 is an allelic pattern in which there are two copies of the second allele at the VNTR marker of IL-1RN that corresponds to the homozygous IL-RN (VNTR) allele 2 state.
• an allelic pattern may consist of the identity of alleles at more than one polymorphic site.
• control refers to any sample appropriate to the detection technique employed.
• the control sample may contain the products of the allele detection technique employed or the material to be tested. Further, the controls may be positive or negative controls.
• the control sample may comprise DNA fragments of an appropriate size.
• the control sample may comprise a sample of a mutant protein.
• the control sample comprises the material to be tested.
• the controls may be a sample of genomic DNA or a cloned portion of the IL-1 gene cluster.
• the control sample is preferably a highly purified sample of genomic DNA.
• haplotype as used herein is intended to refer to a set of alleles that are inherited together as a group (are in linkage disequilibrium) at statistically significant levels (P corr ⁇ 0.05).
• an IL-1 haplotype refers to a haplotype in the IL-1 loci.
• An IL-1 inflammatory or proinflammatory haplotype refers to a haplotype that is indicative of increased agonist and/or decreased antagonist activities.
• IL-1 gene cluster and “IL-1 loci” as used herein include all the nucleic acid at or near the 2q13 region of chromosome 2, including at least the IL-1A, IL-1B and IL-1RN genes and any other linked sequences. (Nicklin et al., Genomics 19: 382-84, 1994).
• the gene accession number for IL-1A, IL-1B, and IL-1RN are X03833, X04500, and X64532, respectively.
• IL-1 X (Z) allele Y refers to a particular allelic form, designated Y, occurring at an IL-1 locus polymorphic site in gene X, wherein X is IL-1 A, B, or RN and positioned at or near nucleotide Z, wherein nucleotide Z is numbered relative to the major transcriptional start site, which is nucleotide +1, of the particular IL-1 gene X.
• IL-1 X allele (Z) refers to all alleles of an IL-1 polymorphic site in gene X positioned at or near nucleotide Z.
• IL-1RN (+2018) allele refers to alternative forms of the IL-1RN gene at marker +2018.
• IL-1RN (+2018) allele 2 refers to a form of the IL-1RN gene which contains a cytosine (C) at position +2018 of the sense strand.
• C cytosine
• IL-1RN (+2018) allele 1 refers to a form of the IL-1 RN gene which contains a thymine (T) at position +2018 of the plus strand.
• IL-1RN (+2018) allele 2 refers to the homozygous IL-1RN (+2018) allele 2 state.
• IL-1RN (+2018) allele 1,1 refers to the homozygous IL-1RN (+2018) allele 1 state.
• IL-1RN (+2018) allele 1,2 refers to the heterozygous allele 1 and 2 state.
• an allele is named by the nucleotide at the polymorphic site.
• IL-1RN (+2018) allele T refers to a form of the IL-1 RN gene which contains a thymine (T) at position +2018 of the plus strand.
• “Increased risk” refers to a statistically higher frequency of occurrence of the disease or condition in an individual carrying a particular polymorphic allele in comparison to the frequency of occurrence of the disease or condition in a member of a population that does not carry the particular polymorphic allele.
• an isolated nucleic acid encoding one of the subject IL-1 polypeptides preferably includes no more than 10 kilobases (kb) of nucleic acid sequence which naturally immediately flanks the IL-1 gene in genomic DNA, more preferably no more than 5 kb of such naturally occurring flanking sequences, and most preferably less than 1.5 kb of such naturally occurring flanking sequence.
• kb kilobases
• isolated also refers to a nucleic acid or peptide that is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.
• isolated nucleic acid is meant to include nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state.
• isolated is also used herein to refer to polypeptides which are isolated from other cellular proteins and is meant to encompass both purified and recombinant polypeptides.
• a “non-human animal” of the invention includes mammals such as rodents, non-human primates, sheep, dogs, cows, goats, etc. amphibians, such a s members of the Xenopus genus, and transgenic avians (e.g. chickens, birds, etc.).
• the term “chimeric animal” is used herein to refer to animals in which the recombinant gene is found, or in which the recombinant gene is expressed in some but not all cells of the animal.
• tissue-specific chimeric animal indicates that one of the recombinant IL-1 genes is present and/or expressed or disrupted in some tissues but not others.
• non-human mammal refers to any member of the class Mammalia, except for humans.
• nucleic acid refers to polynucleotides or oligonucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA).
• DNA deoxyribonucleic acid
• RNA ribonucleic acid
• the term should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs (e.g. peptide nucleic acids) and as applicable to the embodiment being described, single (sense or antisense) and double-stranded polynucleotides.
• polymorphism refers to the coexistence of more than one form of a gene or portion (e.g., allelic variant) thereof.
• a portion of a gene of which there are at least two different forms, i.e., two different nucleotide sequences, is referred to as a “polymorphic region of a gene”.
• a specific genetic sequence at a polymorphic region of a gene is an allele.
• a polymorphic region can be a single nucleotide, the identity of which differs in different alleles.
• a polymorphic region can also be several nucleotides long.
• propensity to disease means that certain alleles are hereby discovered to be associated with or predictive of a subject's incidence of developing a particular disease (e.g. a periodontal disease). The alleles are thus over-represented in frequency in individuals with disease as compared to healthy individuals. Thus, these alleles can be used to predict disease even in pre-symptomatic or pre-diseased individuals.
• wild-type allele refers to an allele of a gene which, when present in two copies in a subject results in a wild-type phenotype. There can be several different wild-type alleles of a specific gene, since certain nucleotide changes in a gene may not affect the phenotype of a subject having two copies of the gene with the nucleotide changes.
• Genetic screening can be broadly defined as testing to determine if a patient has mutations (alleles or polymorphisms) that either cause a disease state or are “linked” to the mutation causing a disease state.
• Linkage refers to the phenomenon that DNA sequences which are close together in the genome have a tendency to be inherited together. Two sequences may be linked because of some selective advantage of co-inheritance. More typically, however, two polymorphic sequences are co-inherited because of the relative infrequency with which meiotic recombination events occur within the region between the two polymorphisms.
• the co-inherited polymorphic alleles are said to be in linkage disequilibrium with one another because, in a given human population, they tend to either both occur together or else not occur at all in any particular member of the population. Indeed, where multiple polymorphisms in a given chromosomal region are found to be in linkage disequilibrium with one another, they define a quasi-stable genetic “haplotype.” In contrast, recombination events occurring between two polymorphic loci cause them to become separated onto distinct homologous chromosomes. If meiotic recombination between two physically linked polymorphisms occurs frequently enough, the two polymorphisms will appear to segregate independently and are said to be in linkage equilibrium.
• the severity of periodontal disease refers to the amount of periodontal ligament fibers that have been lost, termed clinical attachment loss. According to the American Academy of Periodontology, the classification of severity is as follows:
• any range of numbers recited in the specification or paragraphs hereinafter describing or claiming various aspects of the invention, such as that representing a particular set of properties, units of measure, conditions, physical states or percentages, is intended to literally incorporate expressly herein by reference or otherwise, any number falling within such range, including any subset of numbers or ranges subsumed within any range so recited.
• SNPs with high frequency in all ethnic groups included the previously identified functional SNPs in the IL1B promoter (rs16944, rs1143623, rs4848306) and another IL1B SNP (rs1143633).
• Four IL1B promoter haplotypes (B1-B4) predominated with B3 and B4 having very different frequencies across ethnicities.
• Multiple composite genotypes in the IL1B gene were associated with severe periodontitis and elevated gingival fluid IL1 ⁇ in Caucasians.
• IL-1 genes that determine IL-1 biological activity.
• IL1B gene is most relevant. So we initially focused on this gene.
• the three functional SNPs form eight possible haplotypes. Four of them, named B1 through B4, account for more than 95% of all haplotypes observed in major ethnic groups. These four common haplotypes in turn form ten possible diplotypes or haplotype pairs. The results of the analysis are summarized in Tables 2 and 3. It should be noted that the frequency of these haplotypes or diplotypes is different between ethnic populations.
• haplotypes/diplotypes are functional and they influence the clinical levels of the inflammatory markers IL-1beta and CRP. For example, some diplotypes including B3B3, B2B3, and B3B4 are associated with increased levels of both IL-1beta and CRP. While some diplotypes, including B1B1 and B1B3, are only associated with increased levels of IL-1beta. Interestingly, the effect of these haplotypes on IL1-beta expression may be context-dependent. For example, B2 haplotype was associated with lower levels of IL1-beta in gingival crevicular fluid. But, in an in vitro analysis, this haplotype was associated with the highest levels of promoter activity.
• IL1B3877 rs1143633
• Table 4 lists the patterns that are associated with several periodontitis in Caucasians. Some of these patterns are similar and share a subset of identical genotypes. For African Americans, the patterns associated with severe periodontitis are listed in Table 5. Some of these patterns are also associated with severe disease in Caucasians. There are 5 patterns associated with severe periodontitis in Chinese, as shown in Table 6. These patterns are different from those observed in African Americans or Caucasians. Composite genotype patterns associated with severe periodontitis in Caucasians, African Americans and Chinese are listed in Tables 4, 5, and 6, respectively.
• d If there is an “and” between an IL1B diplotype and an IL1B3877 genotype, it means having the respective diplotype and genotype at the two loci.
• B1B1 and IL1B3877 1.1” means that an individual carries diplotype B1B1 at the IL1B promoter region and genotype 1.1 at the IL1B3877 locus.
• IL1B diplotypes B1B1, B1B2, B1B3, B1B4, B2B2, B2B3, B2B4, B3B3, B3B4, and B4B4.
• Table 3 c.
• d If there is an “and” between an IL1B diplotype and an IL1B3877 genotype, it means having the respective diplotype and genotype at the two loci.
• IL1B diplotypes B1B1, B1B2, B1B3, B1B4, B2B2, B2B3, B2B4, B3B3, B3B4, and B4B4. b. If there is an “and” between an IL1B diplotype and an IL1B3877 genotype, it means having the respective diplotype and genotype at the two loci.

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