Abstract
We genotyped individuals with primary biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 × 10−4) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 × 10−13), 17q12-21 (combined P = 3.50 × 10−13) and MMEL1 (combined P = 3.15 × 10−8) as new primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases.
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Acknowledgements
This research was supported by grants from the Canadian Institutes for Health Research (MOP 74621), the Ontario Research Fund (RE01-061), the Canadian Primary Biliary Cirrhosis Society, the Canadian Foundation for Innovation, the Ben and Hilda Katz Charitable Foundation, the US National Institutes of Health (K23 DK68290, RO3 DK78527 and RO1 DK80670), the American Gastroenterological Association and the A.J. and Sigismunda Palumbo Charitable Trust. K.A.S. is a recipient of a Canada Research Chair award. We thank all the study subjects and supporting physicians as well as the technical staff of the University Health Network Analytical Genetics Technology Centre for their assistance in this research.
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G.M.H., X.L., C.I.A. and K.A.S. designed the study. X.L., Y.H., I.P.G., Y.L., C.X., Y.L., W.C., J.Z. and C.I.A. performed the genotyping and data analysis. G.M.H., B.D.J., C.C., A.L.M., P.M., R.P.M., J.A.O., V.A.L., D.S., C.V., C.L., P.K.G., E.J.H., K.N.L. and K.A.S. developed the clinical network and sample collection and processing framework required for case and control accrual. G.M.H., C.I.A. and K.A.S. wrote the manuscript. G.M.H., X.L., C.I.A. and K.A.S. vouch for the data and its analysis. G.M.H., C.I.A. and K.A.S. (the senior and corresponding author) decided in agreement with all other authors to publish this paper.
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G.M.H. reports receiving lecture and consultancy fees from Axcan Pharma and A.L.M. received grant support from Novartis and Schering-Plough. J.H. reports receiving lecture fees and grant support from Axcan Pharma.
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Hirschfield, G., Liu, X., Han, Y. et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet 42, 655–657 (2010). https://doi.org/10.1038/ng.631
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DOI: https://doi.org/10.1038/ng.631
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