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Published at www.nejm.org May 20, 2009 (10.1056/NEJMoa0810440)

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ABSTRACT

Background Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown.

Methods To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis.

Results We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ β chain 1) had the strongest association (P=1.78x10^–19; odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12), rs6441286 (P=2.42x10^–14; odds ratio, 1.54) and rs574808 (P=1.88x10^–13; odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor β2), rs3790567 (P=2.76x10^–11; odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3' flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10^–34). We found a modest genomewide association (P<5.0x10^–5) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte–associated protein 4) and 10 other loci.

Conclusions Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125 [ClinicalTrials.gov] .)

Source Information

From the University of Toronto (G.M.H., X.L., C.X., G.X., Yan Lu, E.J.W., E.J.H., K.A.S.) and Liver Center, Toronto Western Hospital (G.M.H., C.C., E.J.H.) — both in Toronto; University of Alberta, Edmonton (A.L.M.); University of Calgary, Calgary, AB (R.P.M.); Dalhousie University, Halifax, NS (K.M.P.); and London Health Sciences Centre, London, ON (C.N.G.) — all in Canada; M.D. Anderson Cancer Center, Houston (Yue Lu, X.G., K.J., C.I.A.); and Mayo Clinic College of Medicine, Rochester, MN (B.D.J., E.J.A., K.N.L.).

Drs. Hirschfield and Liu contributed equally to this article.

This article (10.1056/NEJMoa0810440) was published at NEJM.org on May 20, 2009. It will appear in the June 11 issue of the Journal.

Address reprint requests to Dr. Siminovitch at Mount Sinai Hospital, 600 University Ave., Room 778D, Toronto, ON M5G 1X5, Canada, or at ksimin{at}mshri.on.ca.

Full Text of this Article

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