PBCの疾患感受性遺伝子による病態の解明  [in Japanese] Analysis of disease-pathway by identifying susceptibility genes to primary biliary cirrhosis  [in Japanese]

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Author(s)

    • 中村 稔 NAKAMURA MINORU
    • 長崎大学大学院医歯薬学総合研究科新興感染症病態制御学系専攻肝臓病学講座 Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences

Abstract

  原発性胆汁性肝硬変(PBC)の発症には,家族集積性や双生児による研究から強い遺伝的素因の関与が示唆されていたが,近年,欧米人を対象としたゲノムワイド関連解析(GWAS)により,PBC疾患感受性遺伝子としてHLA領域の遺伝子多型の他に,IL12/IL12Rシグナル伝達,TLR/TNFα-NFkBシグナル伝達,B細胞の成熟・分化,上皮細胞の分化・アポトーシスなどに関連する計21の遺伝子多型が報告された.本邦においても,国立病院機構肝ネットワーク研究班,厚生労働省難治性疾患克服研究事業“難治性の肝・胆道疾患に関する調査研究班に登録されたPBC 1,327名と健常者1,120名のDNA検体を用いて全国規模のGWAS共同研究を実施し,日本人PBCの発症に関わる新規疾患感受性遺伝子を2個(<i>TNFSF15</i>, <i>POU2AF1</i>)同定した.これらの遺伝子は欧米人で報告されたPBCの疾患感受性遺伝子(<i>IL12A</i>, <i>IL12RB2</i>, <i>SPIB</i>)とは異なっていたが,免疫応答においては同一のシグナル伝達系やリンパ球の分化・成熟の経路に位置しており,集団間で疾患感受性遺伝子が異なっていてもPBCの疾患発症経路は共通であることが示唆された.また,欧米で同定された21個の疾患感受性遺伝子の内10遺伝子(<i>CD80</i>, <i>IKZF3</i>, <i>IL7R</i>, <i>NFKB1</i>, <i>STAT4</i>, <i>TNFAIP2</i>, <i>CXCR5</i>, <i>MAP3K7IP1</i>, <i>rs6974491</i>, <i>DENND1B</i>)が日本人でもPBCの疾患感受性遺伝子であることが確認された.複数の集団での疾患感受性遺伝子の比較検討は疾患発症機構の解明のための重要な手がかりとなることが期待される.<br>

  High concordance rate in monozygotic twins and familial clustering of patients with primary biliary cirrhosis (PBC) indicate the involvement of strong genetic factors in the development of PBC. Recent genome-wide association studies (GWASs) and subsequent meta-analyses in European descent have identified <i>HLA</i> and 21 non-<i>HLA</i> susceptibility loci which are involved in IL12/IL12R signaling, TNF/TLR-NFKB signaling and B cell differentiation in the development of PBC. To identify susceptibility loci for PBC in Japanese population, a GWAS and subsequent replication study was performed in a total of 1327 PBC cases and 1120 healthy controls. In addition to the most significant susceptibility region at HLA, two significant (p<5×10<sup>−8</sup>) susceptibility loci (<i>TNFSF15</i> and <i>POU2AF1</i>) were identified. Although these susceptibility loci are different from those identified in European descent (IL12A, IL12RB2, SPIB), these loci are involved in the same signaling pathways, differentiation of T lymphocyte to Th1 cells and differentiation of B lymphocyte to plasma cells. Among 21 non-HLA susceptibility loci for PBC identified in GWASs of European descent, 10 loci (<i>CD80</i>, <i>IKZF3</i>, <i>IL7R</i>, <i>NFKB1</i>, <i>STAT4</i>, <i>TNFAIP2</i>, <i>CXCR5</i>, <i>MAP3K7IP1</i>, <i>rs6974491</i>, <i>DENND1B</i>) showed significant associations in the Japanese population. The comparative analysis of disease-susceptibility genes in multiple ethnicities may provide an important clue for the dissection of disease-pathogenesis.<br>

Journal

  • Japanese Journal of Clinical Immunology

    Japanese Journal of Clinical Immunology 35(6), 503-510, 2012-12-31

    The Japan Society for Clinical Immunology

References:  22

Cited by:  2

Codes

  • NII Article ID (NAID)
    10031147894
  • NII NACSIS-CAT ID (NCID)
    AN00357971
  • Text Lang
    JPN
  • Article Type
    Journal Article
  • ISSN
    09114300
  • Data Source
    CJP  CJPref  J-STAGE 
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