Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis

被引：38

作者：

Srivastava, Brijesh ^{[2
]}

Mells, George F. ^{[2
]}

Cordell, Heather J. ^{[3
]}

Muriithi, Agnes ^{[2
]}

Brown, Matthew ^{[2
]}

Ellinghaus, Eva ^{[4
]}

Franke, Andre ^{[4
]}

Karlsen, Tom H. ^{[1
,5
,6
]}

Sandford, Richard N. ^{[2
]}

Alexander, Graeme J. ^{[7
]}

Chapman, Roger W. ^{[8
]}

Rushbrook, Simon M. ^{[9
]}

Melum, Espen ^{[1
,5
,6
]}

机构：

[1] Univ Oslo, Rikshosp, Norwegian PSC Res Ctr, Div Canc Surg & Transplantat,Oslo Univ Hosp, N-0027 Oslo, Norway

[2] Univ Cambridge, Acad Dept Med Genet, Cambridge, England

[3] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[4] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[5] Univ Oslo, Rikshosp, Oslo Univ Hosp, Res Inst Internal Med,Div Canc Surg & Transplanta, N-0027 Oslo, Norway

[6] Univ Oslo, Inst Clin Med, N-0027 Oslo, Norway

[7] Univ Cambridge, Dept Med, Div Hepatol, Cambridge CB2 2QQ, England

[8] John Radcliffe Univ Hosp NHS Trust, Dept Hepatol, Oxford, England

[9] Norfolk & Norwich Univ Hosp NHS Trust, Dept Hepatol, Norwich, Norfolk, England

来源：

SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY | 2012年 / 47卷 / 07期

关键词：

fine mapping study; genetic association; IL-2/IL-21; IL2RA; primary sclerosing cholangitis; GENOME-WIDE ASSOCIATION; ULCERATIVE-COLITIS; MECHANISMS; DISEASE; REGION; TOOL;

D O I：

10.3109/00365521.2012.682090

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background and aims. 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 x 10(-6), ORA (vs) (G) = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 x 10(-4), ORA (vs) (G) = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 x 10(-4), ORA (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 x 10(-12)) and rs4147359 (10p15 (IL2RA), P-combined = 1.5 x 10(-8)). Conclusion. 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.

引用

页码：820 / 826

页数：7

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