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

Authors:
Sigrid Næss, Benedicte A Lie, Espen Melum, Marita Olsson, Johannes R Hov, Peter J P Croucher, Jochen Hampe, Erik Thorsby, Annika Bergquist, James A Traherne, Erik Schrumpf, Kirsten Muri Boberg, Stefan Schreiber, Andre Franke, Tom H Karlsen
Year of publication:
2014
Volume:
9
Issue:
12
Issn:
1932-6203
Journal title abbreviated:
PLoS ONE
Journal title long:
PloS one
Impact factor:
2.806
Abstract:
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.