Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

Barrett’s Esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia. Barrett’s Esophagus strongly predisposes to esophageal adenocarcinoma (EAC), a tumour with a very poor prognosis. We have undertaken the first genome-wide association study on Barrett’s Esophagus, comprising 1,852 UK cases and 5,172 UK controls in discovery and 5,986 cases and 12,825 controls in the replication. Two regions were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10−9, OR(95%CI) =1.21(1.13-1.28)) and chromosome 16q24, rs9936833 (Pcombined=2.74×10−10, OR(95%CI) =1.14(1.10-1.19)). The top SNP on chromosome 6p21 is within the major histocompatibility complex, and the closest protein-coding gene to rs9936833 on chromosome 16q24 is FOXF1, which is implicated in esophageal development and structure. We found evidence that the genetic component of Barrett’s Esophagus is mediated by many common variants of small effect and that SNP alleles predisposing to obesity also increase risk for Barrett’s Esophagus.

The influence of biallelic polymorphisms in the tumour necrosis factor-alpha (TNF␣), lymphotoxin-alpha (LT␣) and interleukin-10 (IL-10) genes on stimulated TNF␣ and IL-10 production was studied in ulcerative colitis (UC) patients, Crohn's disease (CD) patients and in healthy controls. A polymerase chain reaction sequence-specific primer (PCR-SSP) system was developed to type nine biallelic polymorphisms, three in each of the TNF␣, LT␣ and IL-10 genes. Production of the TNF␣ and IL-10 was measured by ELISA in lipopolysaccharide (LPS) stimulated whole blood. Four haplotypes of the TNF␣ gene, three haplotypes of LT␣ and three haplotypes of IL-10 were identified. No significant differences in haplotype frequencies were found between patients and controls overall. On subgroup analysis however, haplotype TNF-2 was more frequent in women with extensive colitis compared to distal colitis (31% vs 12%; P = 0.028). This difference was even greater for the combined TNF-2-LT␣-2 haplotype (56% vs 21%; P = 0.0007). The TNF-2 and LT␣-2 haplotypes were associated with higher TNF␣ production in CD patients, and the TNF-4 haplotype was associated with lower TNF␣ production in UC patients. The A allele in the IL-10 promoter region at position −1082 was associated with decreased IL-10 production in CD patients and controls (P = 0.005, P = 0.015 respectively). These data provide evidence that the effect of TNF␣, LT␣ and IL-10 gene polymorphisms on cytokine production differ in CD, UC patients and controls. Genes and Immunity (2000) 1, 185-190.