Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.
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 beta 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-12alpha), 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 beta2), 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.)
Hirschfield
Gideon M
GM
University of Toronto and Liver Center, Toronto Western Hospital, Toronto, ON, Canada.
Liu
Xiangdong
X
Xu
Chun
C
Lu
Yue
Y
Xie
Gang
G
Lu
Yan
Y
Gu
Xiangjun
X
Walker
Erin J
EJ
Jing
Kaiyan
K
Juran
Brian D
BD
Mason
Andrew L
AL
Myers
Robert P
RP
Peltekian
Kevork M
KM
Ghent
Cameron N
CN
Coltescu
Catalina
C
Atkinson
Elizabeth J
EJ
Heathcote
E Jenny
EJ
Lazaridis
Konstantinos N
KN
Amos
Christopher I
CI
Siminovitch
Katherine A
KA
D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006801:Humans; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000235:genetics*; D053765:Interleukin-12 Subunit p35 / Q000235:genetics*; D053759:Interleukin-23 / Q000235:genetics; D008105:Liver Cirrhosis, Biliary / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053707:Receptors, Interleukin-12 / Q000235:genetics
D006680:HLA Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D053712:Interleukin-12 Receptor beta 2 Subunit; D053765:Interleukin-12 Subunit p35; D053759:Interleukin-23; D053707:Receptors, Interleukin-12