WO2012063829A1 - Nouveau gène et méthode de détection de l'ostéoporose basée sur un polymorphisme d'un seul nucléotide sur le locus du gène fong - Google Patents

Nouveau gène et méthode de détection de l'ostéoporose basée sur un polymorphisme d'un seul nucléotide sur le locus du gène fong Download PDF

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WO2012063829A1
WO2012063829A1 PCT/JP2011/075744 JP2011075744W WO2012063829A1 WO 2012063829 A1 WO2012063829 A1 WO 2012063829A1 JP 2011075744 W JP2011075744 W JP 2011075744W WO 2012063829 A1 WO2012063829 A1 WO 2012063829A1
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base
seq
osteoporosis
protein
sequence
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志郎 池川
郁代 稲葉
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独立行政法人理化学研究所
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1003—Transferases (2.) transferring one-carbon groups (2.1)
    • C12N9/1014—Hydroxymethyl-, formyl-transferases (2.1.2)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • 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
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/172—Haplotypes

Definitions

  • the present invention relates to a test method for predicting or determining osteoporosis and a reagent used in the test method.
  • the present invention further relates to a gene associated with osteoporosis, a protein expressed from the gene, and an antibody against the protein.
  • osteoporosis is one of the most common diseases. Osteoporosis develops after middle age and about 80% of patients are women. Currently, more than 200 million people worldwide suffer from osteoporosis, and the number of patients is expected to increase rapidly as the population ages.
  • Bone mineral density is a phenotype commonly used in the examination of osteoporosis, and is a useful tool for evaluating the risk of fracture due to osteoporosis. It is widely known that BMD is affected by genetic factors, and the heritability is estimated to be 50-90%.
  • Non-Patent Documents 1-3 Several experimental approaches can be considered to identify loci involved in osteoporosis risk. For example, attempts have been made to identify candidate genes by extensive screening of genes related to bone metabolism and pathogenic genes of rare single gene bone diseases (Non-Patent Documents 1-3). However, only a few genes are reproducible.
  • GWAS genome-wide correlation analysis
  • An object of the present invention is to provide a method for accurately examining the onset risk of osteoporosis and the presence or absence of onset, and a test reagent used in the method.
  • the present invention also provides a gene associated with osteoporosis, a protein expressed from the gene, and an antibody against the protein.
  • SNP single nucleotide polymorphism
  • the present invention is as follows. (1) A method for determining the risk of osteoporosis and / or the presence or absence of osteoporosis, comprising analyzing a single nucleotide polymorphism present in the FONG locus and examining osteoporosis based on the analysis result. (2) The single nucleotide polymorphism is a single nucleotide polymorphism in a base corresponding to the 61st base of the base sequence of SEQ ID NO: 1 or a base in a linkage disequilibrium relationship with the base (1 ) Method.
  • (B) hybridizes under stringent conditions with a nucleotide sequence complementary to the nucleotide sequence 389 to 832 in the nucleotide sequence shown in SEQ ID NO: 2 or a probe that can be prepared from the nucleotide sequence; DNA encoding a protein having a function equivalent to a protein consisting of an amino acid sequence.
  • (C) DNA encoding a protein comprising the amino acid sequence shown in SEQ ID NO: 3.
  • A a protein comprising the amino acid sequence shown in SEQ ID NO: 3;
  • B A protein having the same function as the protein consisting of the amino acid sequence of SEQ ID NO: 3, comprising an amino acid sequence containing substitution, deletion, insertion or addition of one or several amino acids in the amino acid sequence of SEQ ID NO: 3.
  • the present invention it is possible to accurately and easily predict the risk of developing osteoporosis that has been difficult to predict. Moreover, the onset of osteoporosis can be determined accurately and simply. Therefore, the present invention contributes to the prevention and early treatment of osteoporosis.
  • a white portion indicates an untranslated region, and a black portion indicates a code region.
  • B The figure which shows the expression level of the FONG gene in each human tissue. The vertical axis shows the relative value of the FONG mRNA amount to the ⁇ -actin (ACTB) mRNA amount (mean ⁇ standard error based on two independent tests).
  • ACTB ⁇ -actin
  • test method of the present invention comprises analyzing the SNPs contained in the human FONG locus, and testing osteoporosis based on the analysis results, and / or the risk of developing osteoporosis and / or Or it is the determination method of the presence or absence of onset. That is, in the present invention, “examination” includes an examination of the risk of developing osteoporosis and an examination of the presence or absence of osteoporosis.
  • the FONG gene locus is a region including a gene encoding the FONG gene product, which is present in the long arm 33.1 region of human chromosome 2.
  • the FONG locus is preferably GenBank Accession No. 2 on human chromosome 2. It means the area from 20062258 to 200176734 in NC_00000.11.
  • SNPs present in the FONG locus include human rs7605378.
  • the rs number indicates the registration number of the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP/) of the National Center for Biotechnology Information.
  • rs7605378 is present in intron 3 of the FONG locus.
  • rs7605378 is GenBank Accession No. It means a polymorphism of adenine (A) / cytosine (C) at the 50886343rd base of NT_005403.16, and when this base is A, the possibility of osteoporosis is high.
  • rs7605378 has a high possibility of osteoporosis in the order of AA> AC> CC.
  • rs7605378 a sequence having a total length of 121 bp including the SNP base and a region of 60 bp before and after that is shown in SEQ ID NO: 1.
  • the 61st base has a polymorphism.
  • a base corresponding to the above base is analyzed.
  • a base corresponding to the above-mentioned base means a corresponding base of the human FONG gene locus. That is, “analyzing a base corresponding to the above-mentioned base” includes analyzing the corresponding base in the sequence even if the sequence is slightly changed at a position other than the SNP due to a difference in race. It is.
  • the base to be analyzed in the present invention is not limited to the above, and a polymorphism of a base in linkage disequilibrium with the above base may be analyzed.
  • the “base in linkage disequilibrium with the above-mentioned base” satisfies the relationship of r 2 > 0.5, preferably r 2 > 0.8, more preferably r 2 > 0.9 with the above-mentioned base.
  • the base in linkage disequilibrium with the above base can be identified using, for example, the HapMap database (http://www.hapmap.org/index.html.ja).
  • DNA collected from a plurality of people can be identified by sequence analysis using a sequencer and searching for SNPs in linkage disequilibrium.
  • bases that are in linkage disequilibrium with the above bases include rs10194676, rs57696619, rs2346662, rs75777763, rs2689763, rs769699, rs796363, rs769957, rs769958, rs7976963, rs2689766, and rs59093685, 01. Details of these SNPs are shown in Table 1. In Table 1, r 2 represents an r 2 of each SNP against Rs7605378.
  • rs10194076 is GenBank Accession No. This means a polymorphism of thymine (T) / cytosine (C) at the 50888080 position of NT_005403.16.
  • T thymine
  • C cytosine
  • rs57696619 has a high possibility of osteoporosis when thymine (T) is deleted.
  • rs59036985 has a high possibility of osteoporosis when 4 bases (AAAG) are inserted.
  • the risk of osteoporosis increases in the order of homozygote of risk allele> heterozygote of risk allele and non-risk allele> nonzygote of non-risk allele.
  • sequences having a total length of 121 bp (124 bp in the case of rs59093685) including these SNP bases and a region of 60 bp before and after that are shown in SEQ ID NOs: 4 to 17, respectively.
  • the 61st base has a polymorphism.
  • the “61st base” may be appropriately read as the 61st to 64th bases in SEQ ID NO: 16.
  • the osteoporosis can be examined by examining the base type of the SNP and associating the obtained result with osteoporosis based on the above criteria.
  • the SNP may be analyzed alone, or a plurality of SNPs including at least one of the SNPs may be collectively analyzed (haplotype analysis).
  • the sequence of the FONG gene locus may be analyzed for the sense strand or the antisense strand.
  • the sample used for the analysis of the SNP contained in the FONG gene locus is not particularly limited as long as it is a sample containing chromosomal DNA. Examples thereof include body fluid samples such as blood and urine, cells such as oral mucosa, and hair such as hair. Can be mentioned. Although these samples can be used directly for the analysis of SNP, it is preferable to isolate chromosomal DNA from these samples by a conventional method and analyze it.
  • the analysis of SNPs contained in the FONG gene locus can be performed by a normal gene polymorphism analysis method. Examples include, but are not limited to, sequence analysis, PCR, hybridization, invader method and the like.
  • Sequence analysis can be performed by a normal method. Specifically, a sequence reaction is performed using a primer set at a position of several tens of bases on the 5 ′ side of a base showing polymorphism, and the type of base at the corresponding position is determined from the analysis result. can do. In addition, when performing a sequence, it is preferable to amplify the fragment
  • SNP analysis can be performed by examining the presence or absence of amplification by PCR.
  • a primer having a sequence corresponding to a region containing a base showing a polymorphism and having a 3 'end corresponding to each polymorph is prepared.
  • PCR can be performed using each primer, and the type of polymorphism can be determined depending on the presence or absence of the amplification product.
  • the presence or absence of amplification may be examined by the LAMP method (Japanese Patent No. 3313358), NASBA method (Nucleic Acid Sequence-Based Amplification; Japanese Patent No. 2443586), ICAN method (Japanese Patent Laid-Open No. 2002-233379), and the like. it can.
  • a single-strand amplification method may be used.
  • telomere length a DNA fragment containing a SNP site
  • telomere length a DNA fragment containing a SNP site
  • PCR-SSCP single-strand conformation polymorphism method
  • Genetic. 1992 Jan 1; 12 (1): 139-146. a method for determining which type of polymorphism is based on the mobility of the amplified product in electrophoresis.
  • DNA containing the target SNP contained in the FONG locus is amplified, and the amplified DNA is dissociated into single-stranded DNA.
  • the dissociated single-stranded DNA is separated on a non-denaturing gel, and the type of polymorphism can be determined by the difference in mobility of the separated single-stranded DNA on the gel.
  • a base showing polymorphism when included in the restriction enzyme recognition sequence, it can be analyzed by the presence or absence of cleavage by a restriction enzyme (RFLP method).
  • RFLP method restriction enzyme
  • the DNA sample is cleaved with a restriction enzyme.
  • the DNA fragments can then be separated and the type of polymorphism determined by the size of the detected DNA fragment.
  • Test Reagent of the Present Invention also provides test reagents such as primers and probes for testing osteoporosis.
  • a probe that includes the SNP site at the FONG locus and can determine the type of base at the SNP site based on the presence or absence of hybridization.
  • a probe having a length of 10 bases or more having a sequence containing the 61st base of the base sequence selected from SEQ ID NOs: 1, 4 to 17 or a complementary sequence thereof can be mentioned.
  • the length of the probe is more preferably 15 to 35 bases, still more preferably 20 to 35 bases.
  • the primer examples include a primer that can be used for PCR for amplifying the polymorphic site at the FONG locus, or a primer that can be used for sequence analysis (sequencing) of the polymorphic site. .
  • a primer capable of amplifying or sequencing a region containing the 61st base of the base sequence selected from SEQ ID NOs: 1, 4 to 17 can be mentioned.
  • the length of such a primer is preferably 10 to 50 bases, more preferably 15 to 35 bases, and further preferably 20 to 35 bases.
  • a primer having a sequence 5 ′ side of the base preferably 30 to 100 bases upstream, or a 3 ′ side region of the base, preferably 30 to 100 bases.
  • a primer having a sequence complementary to the downstream region is exemplified.
  • a primer used to determine polymorphism based on the presence or absence of amplification by PCR it has a sequence containing the base, a primer containing the base on the 3 ′ side, a complementary sequence of the sequence containing the base, Examples include a primer containing a base complementary to the above base on the 3 ′ side.
  • the test reagent of the present invention may contain a polymerase for PCR, a buffer, a hybridization reagent and the like in addition to these primers and probes.
  • the gene of the present invention is a human FONG gene.
  • An example of the human FONG gene is DNA containing the nucleotide sequence of SEQ ID NO: 2.
  • the base sequence of SEQ ID NO: 2 is the base sequence of the FONG gene based on the transcription product from the FONG locus.
  • the gene having the above sequence is presumed to encode a protein consisting of the amino acid sequence of SEQ ID NO: 3.
  • the protein consisting of the amino acid sequence of SEQ ID NO: 3 is presumed to have formiminotransferase activity.
  • examples of the gene of the present invention include DNA containing the 389th to 832rd base sequences, which is a region presumed to encode the protein in the base sequence of SEQ ID NO: 2.
  • the gene of the present invention is not limited to the gene of the above sequence because there is a possibility that substitution or deletion is present in one or a plurality of bases due to differences in race.
  • the gene of the present invention includes an amino acid sequence containing one or several amino acid substitutions, deletions, insertions or additions in the amino acid sequence of SEQ ID NO: 3, and is equivalent to the protein consisting of the amino acid sequence of SEQ ID NO: 3. It may be a DNA encoding a protein having the following functions.
  • the “one or several” specifically means preferably 1 to 20, more preferably 1 to 10, and still more preferably 1 to 5.
  • the gene of the present invention has an identity of 80% or more, preferably 90% or more, more preferably 95% or more, more preferably 97% or more, particularly preferably 99% or more with respect to the entire amino acid sequence of SEQ ID NO: 3. And a DNA encoding a protein having the same function as the protein consisting of the amino acid sequence of SEQ ID NO: 3.
  • the gene of the present invention includes a probe that can be prepared from the above base sequence, for example, a complementary sequence of the base sequence shown in SEQ ID NO: 2 or a complementary sequence of the 389th to 832th base sequences of the base sequence shown in SEQ ID NO: 2 and a string It may be a DNA that hybridizes under a gentle condition and encodes a protein having a function equivalent to that of the protein consisting of the amino acid sequence of SEQ ID NO: 3.
  • stringent conditions refers to conditions under which so-called specific hybrids are formed and non-specific hybrids are not formed.
  • highly homologous DNAs for example, 80% or more, preferably 90% or more, more preferably 95% or more, more preferably 97% or more, particularly preferably 99% or more DNAs having homology.
  • DNAs with lower homology are not hybridized with each other, or normal Southern hybridization washing conditions of 60 ° C., 1 ⁇ SSC, 0.1% SDS, preferably 60 ° C. 0.1 ⁇ SSC, 0.1% SDS, more preferably 68 ° C., 0.1 ⁇ SSC, 0.1% SDS at a salt concentration and temperature of 1 time, more preferably 2 to 3 times. The conditions to do are mentioned.
  • the probe that can be prepared from the base sequence may be a part of the complementary sequence of the DNA.
  • a probe can be prepared by PCR using an oligonucleotide prepared on the basis of a known gene sequence as a primer and a DNA fragment containing these base sequences as a template.
  • hybridization washing conditions include 50 ° C., 2 ⁇ SSC, 0.1% SDS.
  • Protein of the present invention is a protein encoded by the gene of the present invention.
  • Examples of the protein of the present invention include a protein containing the amino acid sequence of SEQ ID NO: 3.
  • a protein comprising the amino acid sequence of SEQ ID NO: 3 is presumed to have formiminotransferase activity.
  • the protein of the present invention includes an amino acid sequence including substitution, deletion, insertion or addition of one or several amino acids in the amino acid sequence of SEQ ID NO: 3, and has the same function as the protein consisting of the amino acid sequence of SEQ ID NO: 3. It may be a protein having The “one or several” specifically means preferably 1 to 20, more preferably 1 to 10, and still more preferably 1 to 5.
  • the protein of the present invention has an identity of 80% or more, preferably 90% or more, more preferably 95% or more, more preferably 97% or more, particularly preferably 99% or more with respect to the entire amino acid sequence of SEQ ID NO: 3. And a protein having the same function as the protein consisting of the amino acid sequence of SEQ ID NO: 3.
  • Antibody of the present invention is an antibody against the protein of the present invention. As long as it specifically recognizes the protein of the present invention, it may be a polyclonal antibody or a monoclonal antibody.
  • a polyclonal antibody can be obtained, for example, by immunizing a non-human mammal such as a mouse or rabbit with an immunogen containing the protein of the present invention, and collecting an antibody that specifically recognizes the protein of the present invention from the antiserum. Can do. It may be used for immunization by binding to a carrier protein such as BSA or KLH. The antibody can be purified by protein A or the like.
  • the monoclonal antibody can be obtained, for example, by immunizing a non-human mammal such as a mouse with an immunogen containing the protein of the present invention and fusing lymphocytes isolated from the mammal with mouse myeloma cells to produce a hybridoma. It can be obtained by selecting an antibody that specifically recognizes the protein of the present invention from the antibodies produced by the hybridoma.
  • Monoclonal antibodies also include fragments of monoclonal antibodies such as F (ab ′) 2 antibodies, F (ab ′) antibodies, single chain antibodies (scFv), diabodies, and minibodies. .
  • the antibody of the present invention can be used for detection of fusion protein containing the protein of the present invention, immunoprecipitation, ELISA and the like.
  • Example 1 Identification of SNPs correlated with osteoporosis
  • GWAS genome-wide correlation analysis
  • the osteoporosis subjects (cases) and non-osteoporosis subjects (controls; controls) used for the primary and secondary screening were BioBank Japan (BBJ) (Nakamura, Y. The BioBank Japan Project. Clin Adv). Hematol Oncol 5, 696-7 (2007)).
  • the case group of the first follow-up was obtained from BBJ.
  • Samples of outpatient postmenopausal female volunteers who were not related to each other were used for the secondary follow-up case group and the primary and secondary follow-up control groups.
  • the control group has various diseases other than osteoporosis.
  • Osteoporosis was determined according to the criteria of the Japan Osteoporosis Society, and osteoporosis was determined when both the lumbar spine and femoral neck were less than 70% of the BMD of young adult men.
  • the standard corresponds to a World Health Period (WHO) standard T-score of less than -2.5.
  • WHO World Health Period
  • Genomic DNA extracted from peripheral blood leukocytes by a conventional method was used as a sample, and high density oligonucleotide array (Perlegen Science) was used for analysis.
  • QQ Quantile-quantile
  • RAF risk allele frequency (risk allele frequency)
  • a P value of Pearson's ⁇ 2 test (allele model)
  • b odds ratio (odds ratio; OR) of risk allele from 2 ⁇ 2 frequency table
  • c Results of Breslow-Day test
  • d Meta-analysis of all 4 trials (primary and secondary screening and primary and secondary follow-up) using Japanese subjects
  • e All using Japanese subjects Meta-analysis of 4 trials and trials using Han population
  • haplotype analysis was performed on the 14 tag SNPs selected from the linkage disequilibrium (LD) block in the vicinity of s7605378. Compared to analyzing rs7605378 alone, no haplotypes that were more significantly correlated with osteoporosis were found (Table 5).
  • rs7605378 is the SNP that is most strongly correlated with osteoporosis.
  • LOC348751 is composed of five exons, the predicted exon 1 was not confirmed by RT-PCR in this experiment, and only a part of exon 2 and exons 3-5 were confirmed.
  • the main splicing variant was composed of four exons, and contained exons 3 and 4 of LOC348751 in common.
  • exon 5 is rich in diversity among splicing variants.
  • the predicted gene structure of LOC348751 and the gene structure of FONG are shown in FIG.
  • a cDNA fragment corresponding to the nucleotide sequence of 413-731 of FONG was cloned into the pCR2.1TOPO vector (Invitrogen).
  • the DIG-labeled probe was synthesized using DIG RNA Labeling Kit (Roche) based on the cloned vector.
  • Extraction of mRNA from kidney, liver, skeletal muscle, and bone was performed by FastTrack 2.0 mRNA Isolation kit (Invitrogen). 2 ⁇ g of mRNA extracted from each tissue was subjected to electrophoresis, and mRNA was detected using DIG Easy Hyb and DIG Wash and Block Buffer set (Roche) according to the manufacturer's instructions.
  • a band corresponding to the predicted length of the transcript was detected in all tissues (FIG. 6 (a)).
  • FONG expression was examined in various human tissues by real-time PCR, it was revealed that FONG is highly expressed in liver and skeletal muscle, and is also expressed moderately in bone. (FIG. 6B).
  • the 147 amino acid residue protein comprises a signal peptide and a formiminotransferase domain-N-terminal subdomain (FTCD- N domain).
  • the FTCD-N domain is underlined in FIG.
  • FTCD is a mammalian metabolic enzyme involved in the conversion of histidine to glutamic acid, and its N-terminal domain transfers the formimino group from N-formimino-L-glutamic acid to tetrahydrofolic acid, resulting in L-glutamic acid and 5-formiminotetrahydro Has activity to produce folic acid.
  • Glutamate signaling is important for bone homeostasis, for example, glutamate is secreted by osteoclasts, and glutamate transporter 1 KO mice are known to develop osteoporosis. That is, FONG may control bone metabolism.
  • rs7605378 and 12 SNPs that are completely linked to the SNP are present in intron 3 of the FONG locus or in the 3 'flanking region, and do not affect the amino acid sequence of the protein expressed by FONG. Therefore, these SNPs may be related to osteoporosis by affecting the expression of FONG.
  • FONG was newly identified as a candidate for an osteoporosis susceptibility gene.
  • SNPs related to osteoporosis were found. These SNPs are useful for the examination of osteoporosis.

Abstract

La présente invention concerne une méthode de détection de l'ostéoporose. Un polymorphisme d'un seul nucléotide sur un locus de gène FONG est analysé, et l'ostéoporose est détectée à partir des résultats de l'analyse.
PCT/JP2011/075744 2010-11-08 2011-11-08 Nouveau gène et méthode de détection de l'ostéoporose basée sur un polymorphisme d'un seul nucléotide sur le locus du gène fong WO2012063829A1 (fr)

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JP2010249929A JP2012100557A (ja) 2010-11-08 2010-11-08 新規遺伝子およびｆｏｎｇ遺伝子座の一塩基多型に基づく骨粗鬆症の検査方法

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002010789A (ja) * 1999-08-05 2002-01-15 Genset Corp Ｅｓｔおよびコードされるヒトタンパク質

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002010789A (ja) * 1999-08-05 2002-01-15 Genset Corp Ｅｓｔおよびコードされるヒトタンパク質

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GUO Y. ET AL.: "Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis", PLOS GENET., vol. 6, no. 1, 8 January 2010 (2010-01-08), pages EL000806 *
HSU Y.H. ET AL.: "Large-scale genome-wide linkage analysis for loci linked to BMD at different skeletal sites in extreme selected sibships", J BONE MINER RES., vol. 22, no. 2, February 2007 (2007-02-01), pages 184 - 194 *
KUNG A.W. ET AL.: "Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies", AM J HUM GENET., vol. 86, no. 2, 12 February 2010 (2010-02-12), pages 229 - 239 *

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