title: Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis.
abstract: OBJECTIVE
  Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC.
  
  
  METHODS
  We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls.
  
  
  RESULTS
  The most associated SNPs identified were rs3197999 (3p21 (MST1), p = 1.9 × 10⁻⁶, OR(A vs G) = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10⁻⁴, OR(A vs G) = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10⁻⁴, OR(A vs T) = 1.21, 95% CI (1.09-1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 (MST1), P (combined) = 3.8 × 10⁻¹²) and rs4147359 (10p15 (IL2RA), P (combined) = 1.5 × 10⁻⁸).
  
  
  CONCLUSIONS
  We have for the first time confirmed the association of PSC with genetic variants at 10p15 (IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association.
authors.affiliation: Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Brijesh
authors.initials: B
authors.lastname: Srivastava
authors.forename: George F
authors.initials: GF
authors.lastname: Mells
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: Agnes
authors.initials: A
authors.lastname: Muriithi
authors.forename: Matthew
authors.initials: M
authors.lastname: Brown
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.forename: Richard N
authors.initials: RN
authors.lastname: Sandford
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Alexander
authors.forename: Roger W
authors.initials: RW
authors.lastname: Chapman
authors.forename: Simon M
authors.initials: SM
authors.lastname: Rushbrook
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
mesh_terms: D000483:Alleles; D001327:Autoimmune Diseases / Q000150:complications / Q000235:genetics; D015209:Cholangitis, Sclerosing / Q000150:complications / Q000235:genetics*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics*; D007378:Interleukins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000098546:Interleukin-21
chemical_list: C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D000098546:Interleukin-21