2002 Fiscal Year Annual Research Report

新しい家系内相関解析法と連鎖不平衡マッピング法を用いた高脂血症の修飾遺伝子の同定

Research Project

Project/Area Number	14657611
Research Institution	Nippon Medical School
Principal Investigator	江見充日本医科大学, 老人病研究所, 教授 (90221118)
Keywords	家族性高脂血症 / 一塩基多型 / 家系内相関解析 / LDL受容体遺伝子 / 成長ホルモン受容体 / アポリポプロテインH / 修飾遺伝 / 遺伝子相互
Research Abstract	家族性高脂血症は、高LDL血症を呈する以外にも、様々な表現型を呈する例がしばしば認められることが知られている。今回同定された1135名に及ぶ高脂質血症家系においても、血清脂質値における表現型の多様性が観察された。我々はこの多様性について、LDL受容体遺伝子変異以外にも遺伝的関与を想定し、これら修飾遺伝子の同定を試みた。1135名に及ぶ家族性高脂血症一大家系を同定し、このうち200名余りの血液を採取、これらのsampleの血清脂質値を測定するとともに、LDL受容体突然変異(IVS14+1)のスクリーニングを行い、変異(+)群100名と変異(-)群100名に分類した。血清脂質値(総コレステロール、中性脂肪、HDLコレステロール、LDLコレステロール、VLDL)の変動と100種余の候補修飾遺伝子の一塩基多型(SNP)の遺伝子型との間で家系内相関解析を行った。その結果、(1)成長ホルモン受容体(GHR)の遺伝子上に存在するcoding-SNP(L357I)と、LDL受容体変異(IVS14+1)を持つ患者群においてのみ、血清HDLコレステロール値との間に有意な相関関係を認めた。(2)アポリポプロテインH(apoH)に存在する4つの一塩基多型ではLDL受容体変異(IVS14+1)を持つ患者群において、さらにapoH(V247L)のleucin alleleを持つ場合、高LDL血症に加え有意に高い血清中性脂肪値、VLDL値を示し、表現型の変化(type IIb)が認められた。さらに、LDL受容体変異を持たない家系内構成員においては、この効果は認められないことから、LDL受容体遺伝子とGHR遺伝子またはLDL受容体遺伝子とapoH遺伝子の2つの遺伝子座の相互作用が、表現型の修飾に効果を及ぼしているものと考えられた。

Research Products

(41 results)

All Other

All Publications (41 results)

[Publications] Shinohara, Y.: "Three TNFα single nucleotide polymorphisms in the Japanese population"An. Hum. Bio.. 29(5). 579-583 (2002)
[Publications] Ota, N.: "Association of a single nucleotide variant in the human tumor necrosis factor alpha promoter region with decreased bone mineral density"An. Hum. Bio.. 29(5). 550-558 (2002)
[Publications] Hattori, H.: "Eight Novel Mutations and Functional Impairments of the LDL Receptor in Familial Hypercholestherolemia in the North of Japan"J. Hum. Genet.. 47(2). 80-87 (2002)
[Publications] Nakata, T.: "Differential Expression of Multiple Isoforms of the ELKS mRNAs Involved in a Papillary Thyroid Carcinoma"Genes, Chrom. Cancer. 35(1). 30-37 (2002)
[Publications] Harada, H.: "Genomic Structure of the Human NLK (nemo-like kinase) Gene and Analysis of its Promoter Region"Gene. 285(1-2). 175-182 (2002)
[Publications] Nakajima, T.: "Nucleotide Diversity and Haplotype Structure of the Human Angiotensinogen Gene in Two Populations"Am. J. Hum. Genet.. 70(1). 108-123 (2002)
[Publications] Tsuneizumi, M.: "Association of Allelic loss at 8p22 with Poor prognosis among Breast Cancers Cases treated with high-dose adjuvant chemotherapy"Cancer Lett.. 180(1). 75-82 (2002)
[Publications] Fujiwara, H.: "Association of common missense changes in ELAC2 (HPC2) with prostate cancer in a Japanese case-control series"J. Hum. Genet.. 47(12). 641-648 (2002)
[Publications] Nagahata, T.: "Molecular Diagnosis for Breast Cancer"Jpn. Med. Assoc. J.. 45(6). 265-260 (2002)
[Publications] Yasui, K.: "TFDP1, CUL4A, and CDC16 Identified as Targets for Amplification at 13q34 in Hepatocellular Carcinomas"Hepatology. 35(6). 1476-1484 (2002)
[Publications] Sugiyama, H.: "Ethnic difference in contribution of alleles of the Interleukin-1 Receptor Antagonist (IL-1RA) gene to predisposition to osteoporosis"Geriatr. Gerontol. Int.. 2. 87-90 (2002)
[Publications] Nagai, H.: "DNA Alterations during Multi-step Development of Human Hepatocellular Carcinomas Revealed by Laser Capture Microdissection"Hepatology Res.. (in press). (2002)
[Publications] Nagahata, T.: "Correlation of Allelic Losses and Clinicopathological Factors in 504 Primary Breast Cancers"Breast Cancer. 9(3). 208-215 (2002)
[Publications] Iwasaki, H.: "Accuracy of Genotyping for Single Nucleotide Polymorphism Typing Method Involving_hybridization_of Short Allele-Specific Oligonucleotides"DNA Res.. 9(2). 59-62 (2002)
[Publications] Takada, D.: "Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-ll promoter: Molecular study in a 1135-member familial hypercholesterolemia kindred"J. Hum. Genet.. 47(12). 656-664 (2002)
[Publications] Ogawa, S.: "Association of amino acid variation (Yrp64Arg) in the beta3-adrenergic Receptor Gene with Bone Mineral Density"Geriatr. Gerontol. Int.. 2. 138-142 (2002)
[Publications] Harada, H.: "Genomic structure and eight novel exonic polymorphisms of human N-cadherin gene"J. Hum. Genet.. 47(6). 330-332 (2002)
[Publications] Yoshida, S.: "Head-to-head Juxtaposition of Fas-Associated Phosphatase-1(FAP-1)and c-Jun NH_2-terminal Kinase 3 (JNK3) genes : genomic structure and five polymorphisms of FAP-1 gene"J. Hum. Genet.. 47(11). 614-619 (2002)
[Publications] Nagai, H.: "Combined Hypermethylation and Chromosome Loss Associated with Inactivation of SSI-1/SOCS-1/JAB Gene in Human Hepatocellular Carcinomas"Cancer Lett. 186. 59-65 (2002)
[Publications] Shimizu, M.: "Universal Fluorescent Labeling (UFL) Method for Automated Microsatellite Analysis"DNA Res.. 9(5). 173-178 (2002)
[Publications] Ishii, J.: "Clinical Variant of Tangier Disease in Japan : mutation of the ABCA1 gene in hypoalphalipoproteinemia with corneal lipidosis"J. Hum. Genet.. 47(7). 366-369 (2002)
[Publications] Harada, H.: "Down-regulation of a Novel Gene, DRLM, in human Liver Malignancy from 4q22 That Encodes an NAP-like Protein"Gene. 296(1-2). 171-177 (2002)
[Publications] Iwasaki, H.: "Association of a Trp16Ser variation in the Gonadotropin Releasing Hormone (GnRH) Signal Peptide with Bone Mineral Density, revealed by SNP-dependent PCR (Sd-PCR) Typing"Bone. 32(in press). (2003)
[Publications] Ishida, R.: "Association of a haplotype (196Phe/532Ser) of variations in the Interleukin-1-Receptor-Associated Kinase (IRAK1) Gene with Low Radial Bone Mineral Density in Two Independent Poulations"J. Bone. Miner. Res.. 18(in press). (2003)
[Publications] Takada, D.: "Apolipoprotein H Variant Modifies Plasma Triglyceride Phenotype in Familial Hypercholesterolemia : A molecular study in an eight-generation hyperlipidemic kindred"J. Atherosclerosis, Thrombosis.. 10(in press). (2002)
[Publications] Nagai, H.: "Down-regulation in Human Cancers of DRHC, a Novel Helicase-like Gene from 17q25.1 That Inhibit Cell Growth"Cancer Lett.. 10(in press). (2003)
[Publications] Hattori, H.: "A Flow Cytometric Procedure to Measure Functional LDL Receptors for Diagnosis of Familial Hypercholesterolemia. Atherosclerosis : Risk Factors, Diagnosis, and Treatment"Atherosclerosis : Risk Factors, Diagnosis, and Treatment. 1. 357-363 (2002)
[Publications] Tsuneizumi, M.: "A highly polymorphic CA repeat marker at the EBAG9/RCAS1 locus on 8q23 that detected frequent multiplication in breast cancer"Annals Hum. Bio.. 29(4). 457-460 (2002)
[Publications] Watanabe, T.: "Differentially regulated genes as putative targets of amplifications at 2Oqin ovarian cancers"Jpn. J. Cancer. Res.. 93(10). 1114-1122 (2002)
[Publications] Nagai, H.: "Hypermethylation Associated with Inactivation of the SOCS-1 Gene, a JAK/STAT Inhibitor, in Human Hepatoblastomas."J. Hum. Genet.. 48(2). 65-69 (2003)
[Publications] Kajita, M.: "Association of -381T/C Promoter Variation of Brain Natriuretic Peptide Gene with Low Bone Mineral Density and Rapid Postmenopausal Bone Loss"J. Hum. Genet.. 48(2). 77-81 (2003)
[Publications] Omasu, F.: "Association of Genetic Variation of a Gene Encoding a PDZ-LIM Domain Protein, RIL Localized in 5q31.1 with low Bone Mineral Density in Adult Japanese Women"J. Hum. Genet.. (in press). (2003)
[Publications] Ishida, R.: "Association of a promoter haplotype (-1542G/-525C) in the Tumor Necrosis Factor Receptor Associated Factor-Interacting Protein (I-TRAF) Gene with Low Bone Mineral Density in Japanese Postmenopausal Women"Bone. (in press). (2002)
[Publications] Takada, D.: "Growth Hormone Receptor Variant (L526I) Modifies Plasma HDL Cholesterol Phenotype in Familial Hypercholesterolemia : Intrafamilial Association study in an eight-generation hyperlilidemic kindred"Am. J. Med. Genet.. (in press). (2003)
[Publications] Ezura, Y.: "Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density"J. Bone. Miner. Res.. (in press). (2003)
[Publications] 岩崎公典: "ゲノム研究各論〜DNAチップ、マイクロアレイ〜"分子心血管病. 3(3). 109-114 (2002)
[Publications] 高田大輔: "高血圧関連遺伝子は何か"成人病と生活習慣病. 32(4). (2002)
[Publications] 永井尚生: "肝硬変における遺伝子発現異常の解析"消化器科. 34(1). 64-68 (2002)
[Publications] 江面陽一: "骨粗鬆症のゲノム解析"リウマチ科. 28(2). 142-147 (2002)
[Publications] 永井尚生: "癌の遺伝要因の解明と現状"医学のあゆみ. 202(10). 869-876 (2002)
[Publications] 江面陽一: "骨粗鬆症の遺伝子解析"遺伝子医学. (別冊). 265-271 (2003)

2002 Fiscal Year Annual Research Report

新しい家系内相関解析法と連鎖不平衡マッピング法を用いた高脂血症の修飾遺伝子の同定

Principal Investigator

江見 充 日本医科大学, 老人病研究所, 教授 (90221118)

Research Products

[Publications] Shinohara, Y.: "Three TNFα single nucleotide polymorphisms in the Japanese population"An. Hum. Bio.. 29(5). 579-583 (2002)

[Publications] Ota, N.: "Association of a single nucleotide variant in the human tumor necrosis factor alpha promoter region with decreased bone mineral density"An. Hum. Bio.. 29(5). 550-558 (2002)

[Publications] Hattori, H.: "Eight Novel Mutations and Functional Impairments of the LDL Receptor in Familial Hypercholestherolemia in the North of Japan"J. Hum. Genet.. 47(2). 80-87 (2002)

[Publications] Nakata, T.: "Differential Expression of Multiple Isoforms of the ELKS mRNAs Involved in a Papillary Thyroid Carcinoma"Genes, Chrom. Cancer. 35(1). 30-37 (2002)

[Publications] Harada, H.: "Genomic Structure of the Human NLK (nemo-like kinase) Gene and Analysis of its Promoter Region"Gene. 285(1-2). 175-182 (2002)

[Publications] Nakajima, T.: "Nucleotide Diversity and Haplotype Structure of the Human Angiotensinogen Gene in Two Populations"Am. J. Hum. Genet.. 70(1). 108-123 (2002)

[Publications] Tsuneizumi, M.: "Association of Allelic loss at 8p22 with Poor prognosis among Breast Cancers Cases treated with high-dose adjuvant chemotherapy"Cancer Lett.. 180(1). 75-82 (2002)

[Publications] Fujiwara, H.: "Association of common missense changes in ELAC2 (HPC2) with prostate cancer in a Japanese case-control series"J. Hum. Genet.. 47(12). 641-648 (2002)

[Publications] Nagahata, T.: "Molecular Diagnosis for Breast Cancer"Jpn. Med. Assoc. J.. 45(6). 265-260 (2002)

[Publications] Yasui, K.: "TFDP1, CUL4A, and CDC16 Identified as Targets for Amplification at 13q34 in Hepatocellular Carcinomas"Hepatology. 35(6). 1476-1484 (2002)

[Publications] Sugiyama, H.: "Ethnic difference in contribution of alleles of the Interleukin-1 Receptor Antagonist (IL-1RA) gene to predisposition to osteoporosis"Geriatr. Gerontol. Int.. 2. 87-90 (2002)

[Publications] Nagai, H.: "DNA Alterations during Multi-step Development of Human Hepatocellular Carcinomas Revealed by Laser Capture Microdissection"Hepatology Res.. (in press). (2002)

[Publications] Nagahata, T.: "Correlation of Allelic Losses and Clinicopathological Factors in 504 Primary Breast Cancers"Breast Cancer. 9(3). 208-215 (2002)

[Publications] Iwasaki, H.: "Accuracy of Genotyping for Single Nucleotide Polymorphism Typing Method Involving_hybridization_of Short Allele-Specific Oligonucleotides"DNA Res.. 9(2). 59-62 (2002)

[Publications] Takada, D.: "Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-ll promoter: Molecular study in a 1135-member familial hypercholesterolemia kindred"J. Hum. Genet.. 47(12). 656-664 (2002)

[Publications] Ogawa, S.: "Association of amino acid variation (Yrp64Arg) in the beta3-adrenergic Receptor Gene with Bone Mineral Density"Geriatr. Gerontol. Int.. 2. 138-142 (2002)

[Publications] Harada, H.: "Genomic structure and eight novel exonic polymorphisms of human N-cadherin gene"J. Hum. Genet.. 47(6). 330-332 (2002)

[Publications] Yoshida, S.: "Head-to-head Juxtaposition of Fas-Associated Phosphatase-1(FAP-1)and c-Jun NH_2-terminal Kinase 3 (JNK3) genes : genomic structure and five polymorphisms of FAP-1 gene"J. Hum. Genet.. 47(11). 614-619 (2002)

[Publications] Nagai, H.: "Combined Hypermethylation and Chromosome Loss Associated with Inactivation of SSI-1/SOCS-1/JAB Gene in Human Hepatocellular Carcinomas"Cancer Lett. 186. 59-65 (2002)

[Publications] Shimizu, M.: "Universal Fluorescent Labeling (UFL) Method for Automated Microsatellite Analysis"DNA Res.. 9(5). 173-178 (2002)

[Publications] Ishii, J.: "Clinical Variant of Tangier Disease in Japan : mutation of the ABCA1 gene in hypoalphalipoproteinemia with corneal lipidosis"J. Hum. Genet.. 47(7). 366-369 (2002)

[Publications] Harada, H.: "Down-regulation of a Novel Gene, DRLM, in human Liver Malignancy from 4q22 That Encodes an NAP-like Protein"Gene. 296(1-2). 171-177 (2002)

[Publications] Iwasaki, H.: "Association of a Trp16Ser variation in the Gonadotropin Releasing Hormone (GnRH) Signal Peptide with Bone Mineral Density, revealed by SNP-dependent PCR (Sd-PCR) Typing"Bone. 32(in press). (2003)

[Publications] Ishida, R.: "Association of a haplotype (196Phe/532Ser) of variations in the Interleukin-1-Receptor-Associated Kinase (IRAK1) Gene with Low Radial Bone Mineral Density in Two Independent Poulations"J. Bone. Miner. Res.. 18(in press). (2003)

[Publications] Takada, D.: "Apolipoprotein H Variant Modifies Plasma Triglyceride Phenotype in Familial Hypercholesterolemia : A molecular study in an eight-generation hyperlipidemic kindred"J. Atherosclerosis, Thrombosis.. 10(in press). (2002)

[Publications] Nagai, H.: "Down-regulation in Human Cancers of DRHC, a Novel Helicase-like Gene from 17q25.1 That Inhibit Cell Growth"Cancer Lett.. 10(in press). (2003)

[Publications] Hattori, H.: "A Flow Cytometric Procedure to Measure Functional LDL Receptors for Diagnosis of Familial Hypercholesterolemia. Atherosclerosis : Risk Factors, Diagnosis, and Treatment"Atherosclerosis : Risk Factors, Diagnosis, and Treatment. 1. 357-363 (2002)

[Publications] Tsuneizumi, M.: "A highly polymorphic CA repeat marker at the EBAG9/RCAS1 locus on 8q23 that detected frequent multiplication in breast cancer"Annals Hum. Bio.. 29(4). 457-460 (2002)

[Publications] Watanabe, T.: "Differentially regulated genes as putative targets of amplifications at 2Oqin ovarian cancers"Jpn. J. Cancer. Res.. 93(10). 1114-1122 (2002)

[Publications] Nagai, H.: "Hypermethylation Associated with Inactivation of the SOCS-1 Gene, a JAK/STAT Inhibitor, in Human Hepatoblastomas."J. Hum. Genet.. 48(2). 65-69 (2003)

[Publications] Kajita, M.: "Association of -381T/C Promoter Variation of Brain Natriuretic Peptide Gene with Low Bone Mineral Density and Rapid Postmenopausal Bone Loss"J. Hum. Genet.. 48(2). 77-81 (2003)

[Publications] Omasu, F.: "Association of Genetic Variation of a Gene Encoding a PDZ-LIM Domain Protein, RIL Localized in 5q31.1 with low Bone Mineral Density in Adult Japanese Women"J. Hum. Genet.. (in press). (2003)

[Publications] Ishida, R.: "Association of a promoter haplotype (-1542G/-525C) in the Tumor Necrosis Factor Receptor Associated Factor-Interacting Protein (I-TRAF) Gene with Low Bone Mineral Density in Japanese Postmenopausal Women"Bone. (in press). (2002)

[Publications] Takada, D.: "Growth Hormone Receptor Variant (L526I) Modifies Plasma HDL Cholesterol Phenotype in Familial Hypercholesterolemia : Intrafamilial Association study in an eight-generation hyperlilidemic kindred"Am. J. Med. Genet.. (in press). (2003)

[Publications] Ezura, Y.: "Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density"J. Bone. Miner. Res.. (in press). (2003)

[Publications] 岩崎公典: "ゲノム研究各論〜DNAチップ、マイクロアレイ〜"分子心血管病. 3(3). 109-114 (2002)

[Publications] 高田大輔: "高血圧関連遺伝子は何か"成人病と生活習慣病. 32(4). (2002)

[Publications] 永井尚生: "肝硬変における遺伝子発現異常の解析"消化器科. 34(1). 64-68 (2002)

[Publications] 江面陽一: "骨粗鬆症のゲノム解析"リウマチ科. 28(2). 142-147 (2002)

[Publications] 永井尚生: "癌の遺伝要因の解明と現状"医学のあゆみ. 202(10). 869-876 (2002)

[Publications] 江面陽一: "骨粗鬆症の遺伝子解析"遺伝子医学. (別冊). 265-271 (2003)

江見充日本医科大学, 老人病研究所, 教授 (90221118)