Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

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• 作者：Ynto S. de Boer¹ ; ^&lowast ; ; Nicole M.F. van Gerven¹ ; ^&lowast ; ; Antonie Zwiers¹ ; ² ; Bart J. Verwer¹ ; Bart van Hoek³ ; Karel J. van Erpecum⁴ ; Ulrich Beuers⁵ ; Henk R. van Buuren⁶ ; Joost P.H. Drenth⁷ ; Jannie W. den Ouden⁸ ; Robert C. Verdonk⁹ ; ¹⁰ ; Ger H. Koek¹¹ ; Johannes T. Brouwer¹² ; Maureen M.J. Guichelaar¹³ ; Jan M. Vrolijk¹⁴ ; Georg Kraal² ; Chris J.J. Mulder¹ ; Carin M.J. van Nieuwkerk¹ ; Janett Fischer¹⁵ ; Thomas Berg¹⁵ ; Felix Stickel¹⁶ ; Christoph Sarrazin¹⁷ ; Christoph Schramm¹⁸ ; Ansgar W. Lohse¹⁸ ; Christina Weiler-Normann¹⁸ ; Markus M. Lerch¹⁹ ; Matthias Nauck²⁰ ; Henry Vö ; lzke²¹ ; Georg Homuth²² ; Elisabeth Bloemena²³ ; Hein W. Verspaget³ ; Vinod Kumar²⁴ ; Alexandra Zhernakova²⁴ ; Cisca Wijmenga²⁴ ; Lude Franke²⁴ ; ^§ ; ; Gerd Bouma¹ ; ² ; ^§ ; ; ^{g.bouma@vumc.nl" class="auth_mail" title="E-mail the corresponding author} ; The Dutch Autoimmune Hepatitis Study Group ; The LifeLines Cohort Study ; The Study of Health in Pomerania
• 关键词：Autoimmunity ; Genetics ; GWAS ; SH2B Adaptor Protein 3
• 刊名：Gastroenterology
• 出版年：2014
• 出版时间：August 2014
• 年：2014
• 卷：147
• 期：2
• 页码：443-452.e5
• 全文大小：1328 K

文摘

Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH.

<h4 id="absSec_2">Methodsh4>

We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region.

<h4 id="absSec_3">Resultsh4>

We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10^&minus;78). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10^&minus;49) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10^&minus;18) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10^&minus;8) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10^&minus;6). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits.

<h4 id="absSec_4">Conclusionsh4>

In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.