Genome-wide association study identifies variants associated with autoimmune hepatitis type 1.
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de Boer Ynto S, van Gerven Nicole M F, Zwiers Antonie, Verwer Bart J, van Hoek Bart, van Erpecum Karel J, Beuers Ulrich, van Buuren Henk R, Drenth Joost P H, den Ouden Jannie W, Verdonk Robert C, Koek Ger H, Brouwer Johannes T, Guichelaar Maureen M J, Vrolijk Jan M, Kraal Georg, Mulder Chris J J, van Nieuwkerk Carin M J, Fischer Janett, Berg Thomas, Stickel Felix, Sarrazin Christoph, Schramm Christoph, Lohse Ansgar W, Weiler-Normann Christina, Lerch Markus M, Nauck Matthias, Völzke Henry, Homuth Georg, Bloemena Elisabeth, Verspaget Hein W, Kumar Vinod, Zhernakova Alexandra, Wijmenga Cisca, Franke Lude, Bouma Gerd, Dutch Autoimmune Hepatitis Study Group, LifeLines Cohort Study, Study of Health in Pomerania
Аннотация
METHODS: 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.
RESULTS: We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-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.
CONCLUSIONS: 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.