Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population

• Published in: PloS one 2014-12, Vol.9 (12), p.e114486-e114486
• Main Authors: Næss, Sigrid, Lie, Benedicte A, Melum, Espen, Olsson, Marita, Hov, Johannes R, Croucher, Peter J P, Hampe, Jochen, Thorsby, Erik, Bergquist, Annika, Traherne, James A, Schrumpf, Erik, Boberg, Kirsten Muri, Schreiber, Stefan, Franke, Andre, Karlsen, Tom H
• Format: Article
• Language: English
• Subjects: Alleles; Amino acids; Antigens; Authorship; Biological Sciences; Biologiska vetenskaper; Biology and Life Sciences; Cancer; Case-Control Studies; Cholangitis; Cholangitis, Sclerosing - genetics; Chromosomes; Clinical medicine; Confidence intervals; Diabetes; Disease; Drb1 protein; Gastroenterology; Genetic diversity; Genetic variance; Genetics; Genetik; Genomes; Genotype & phenotype; Haplotypes; Histocompatibility antigen HLA; HLA antigens; HLA-B Antigens - genetics; HLA-DRB1 Chains - genetics; Hospitals; Humans; Immunoglobulin-like receptors; Immunology; Inflammation; Inflammatory bowel disease; Internal medicine; Linkage disequilibrium; Liver; Major histocompatibility complex; Medicin och hälsovetenskap; Medicine; Medicine and Health Sciences; MICA protein; Molecular biology; Multiple sclerosis; Polymorphism; Polymorphism, Single Nucleotide; Population genetics; Proto-Oncogene Proteins - genetics; Psoriasis; Receptor mechanisms; Receptor, Notch4; Receptors; Receptors, Notch - genetics; Regression analysis; Rheumatoid arthritis; Risk analysis; Risk factors; Scandinavian and Nordic Countries; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Statistical analysis; Surgery; Tissue typing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0114486

Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel. A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRβ, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10-11). Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region.