Back to Search
Start Over
Primary Biliary Cirrhosis Associated with HLA, IL12A, and IL12RB2 Variants.
- Source :
-
New England Journal of Medicine . 6/11/2009, Vol. 360 Issue 24, p2544-2555. 12p. 3 Diagrams. - Publication Year :
- 2009
-
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=1.78×10−19; 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-12α), rs6441286 (P=2.42×10−14; odds ratio, 1.54) and rs574808 (P=1.88×10−13; odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor β2), rs3790567 (P=2.76×10−11; 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=1.15×10−34). We found a modest genomewide association (P<5.0×10−5) 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.) N Engl J Med 2009;360:2544-55. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CIRRHOSIS of the liver
*IMMUNOGLOBULINS
*MEDICAL genetics
*GENETIC polymorphisms
Subjects
Details
- Language :
- English
- ISSN :
- 00284793
- Volume :
- 360
- Issue :
- 24
- Database :
- Academic Search Index
- Journal :
- New England Journal of Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 41425970
- Full Text :
- https://doi.org/10.1056/NEJMoa0810440