- Email: [email protected]
A Novel Common Variant in CLDN14 is Associated with Primary Biliary Cirrhosis
POSTER PRESENTATIONS Gastroenterology, Karolinska Institute, Stockholm, Sweden; 28 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 29Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy and University Hospital, Gothenburg, Sweden; 30Department of Gastroenterology, Università Politecnica delle Marche, Ospedali Riuniti University Hospital, Ancona, Italy; 31Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada; 32 Department of Internal Medicine, Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany; 33Liver Unit and Liver Research Laboratories, Pomeranian Medical University, Szczecin, Poland; 34Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain; 35UCL Institute for Liver and Digestive Health, University College London, Royal Free Hospital; 36Division of Medicine, Institute for Liver and Digestive Health, Royal Free Hospital & University College London, London, United Kingdom; 37Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany; 38Department of Gastroenterology and Hepatology, Norfolk and Norwich, University Hospitals NHS Trust, Norwich, United Kingdom; 39 Department of Medicine 2, Grosshadern, University of Munich, Munich, Germany; 40Department of Surgery, Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory; 41 Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom; 421st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 43 Inflammatory Bowel Disease (IBD) Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital Toronto, Toronto, Canada; 44 Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg; 451st Department of Medicine, University of Mainz, Mainz; 46Institute for Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany; 47Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, Netherlands; 48Department of Internal Medicine, University of Thessaly, Larissa, Greece E-mail: [email protected] Background and Aims: Primary sclerosing cholangitis (PSC) is a severe disease of the bile ducts without curative medical treatment, often leading to liver transplantation (LTx) or death in young patients. Recently genetic variants that are associated with PSC susceptibility have been identified through genome wide association analyses. Little is known on the role of genetics in disease behaviour or progression in complex diseases in general or PSC in particular. Methods: To identify genetic variants driving PSC subphenotypes, the International PSC Study Group has collected extensive clinical data for 3,402 PSC patients from 13 countries. Phenotypes include dates of birth and diagnosis, cause of death, dates of LTx, cooccurrence with IBD etc. Patients were genotyped using Illumina Immunochip. We performed within-cases association analysis for binary outcomes and Cox proportional hazards modeling for time-toevent phenotypes using 130,422 SNPs after quality control. We corrected for clinical parameters like smoking status by adding them to the model. We imputed the HLA using SNP2HLA. Results: We identify a genomic region on chromosome 6 harbouring RSPO3 to be significantly associated with liver transplant-free survival (SNP rs853974, p = 2.87 × 10−8) When including cholangiocarcinoma as an endpoint the association remained significant ( p = 2.04 × 10−9). Kaplan-Meier analysis shows that homozygous AA allele carriers of rs853974 have a 55% chance of liver transplant-free survival of 10 years, as opposed to GG carriers having a chance of 75%. Using RNA-Seq on cholangiocytes (control and DDC treated mice) as well as multiple tissues in mice we showed significantly elevated expression of RSPO3 in cholangiocytes. Also, we were able to demonstrate high expression of RPSO3 in cholangiocytelike cells as compared with human induced pluripotent stem cells and confirmed this by qPCR. Binary outcomes revealed several suggestive associations including AIH-like HLA associations in patients with PSC-AIH overlap features.
Conclusions: In this large international PSC study group cohort we show that a genetic variant next to RSPO3 is associated with liver transplant-free survival. The protein RSPO3 is an agonist of the canonical Wnt/β-catenin signaling pathway which plays a central role in stem cell maintenance and pro- and regression of liver fibrosis. Findings of RSPO3 being highly expressed in both mouse and human cholangiocytes warrant further assessments in querying the role of this potential key PSC modifier gene. SAT-373 A NOVEL COMMON VARIANT IN CLDN14 IS ASSOCIATED WITH PRIMARY BILIARY CIRRHOSIS R. Tang1, Y. Wei1, Z. Li2, H. Chen1, M.F. Seldin3, M.E. Gershwin4, W. Liao5, Y. Shi2, X. Ma1. 1Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University Medical School Renji Hospital; 2Shanghai Jiao Tong University Bio-X Institute, Shanghai, China; 3Department of Biological Chemistry, University of California at Davis; 4Division of Rheumatology, University of California at Davis School of Medicine, Davis; 5Department of Dermatology, University of California San Francisco School of Medicine, San Francisco, United States E-mail: [email protected] Background and Aims: Primary biliary cirrhosis (PBC) is the most common autoimmune liver disease characterized by destruction of intrahepatic bile ducts. PBC has been associated with increased incidence of osteoporosis. Intriguingly, two PBC susceptibility loci identified through genome-wide association studies are also involved in bone mineral density (BMD), a key measurable risk factor for osteoporosis. These observations led us to systematically investigate the genetic variants shared between PBC and BMD. Methods: We evaluated 72 genome-wide significant BMD SNPs for association with PBC using two European GWAS data sets (n = 8,392), with replication of significant findings in a Chinese cohort (685 cases, 1,152 controls). We developed a polygenic risk score evaluating the aggregate effects of BMD associated variants in prediction of PBC status in WTCCC and Italian GWAS data. Furthermore, expression quantitative trait locus (eQTL) analysis using Genevar database was used to explore the cis-regulatory effect of the candidate SNP on gene expression. Results: Apart from confirming previously reported loci near/in TNFSF11 (rs9533090, Pfdr = 4.14E−5) and MAPT (rs1864325, Pfdr = 1.58E−5), our analysis identified one novel variant in the intron of the CLDN14 gene (rs170183, Pfdr = 0.015) after multiple testing correction. The three associated variants were followed-up in the Chinese cohort; however, only SNP rs170183 showed consistent evidence of association in diverse ethnic populations (Pcombined = 2.43E−5). Notably, expression quantitative trait loci (eQTL) data revealed that rs170183 was correlated with decline in CLDN14 expression in both lymphoblastoid cell lines and T cells (Padj = 0.003 and 0.016, respectively). However, polygenic scoring analysis using known BMD associated variants in aggregate revealed no overall evidence for genetic overlap between the two traits. Conclusions: In conclusion, we identified a new locus, rs170183 in CLDN14 at 21q22.13, associated with PBC in ethnically diverse populations. Our findings indicate searching for pleiotropic genes may present an important opportunity for identifying more of the missing heritability of the complex traits. SAT-374 DECREASED MIR-425 INDUCED INFLAMMATORY CYTOKINE PRODUCTION VIA N-RAS UPREGULATION IN CD4+ T CELLS OF PRIMARY BILIAR CHOLANGITIS R. Nakagawa1,2, R. Muroyama1, K. Koike2, C. Saeki2, S. Ito1, S. Morimoto1, K. Goto1, Y. Matsubara1, N. Kato1, M. Zeniya3. 1Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo; 2Department of Gastroenterology and Hepatology, The Jikei University of Medicine; 3Clinical Research Center, International University of Health and Welfare, Tokyo, Japan E-mail: [email protected]
Journal of Hepatology 2016 vol. 64 | S631–S832
S643
Conclusions: In this large international PSC study group cohort we show that a genetic variant next to RSPO3 is associated with liver transplant-free survival. The protein RSPO3 is an agonist of the canonical Wnt/β-catenin signaling pathway which plays a central role in stem cell maintenance and pro- and regression of liver fibrosis. Findings of RSPO3 being highly expressed in both mouse and human cholangiocytes warrant further assessments in querying the role of this potential key PSC modifier gene. SAT-373 A NOVEL COMMON VARIANT IN CLDN14 IS ASSOCIATED WITH PRIMARY BILIARY CIRRHOSIS R. Tang1, Y. Wei1, Z. Li2, H. Chen1, M.F. Seldin3, M.E. Gershwin4, W. Liao5, Y. Shi2, X. Ma1. 1Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University Medical School Renji Hospital; 2Shanghai Jiao Tong University Bio-X Institute, Shanghai, China; 3Department of Biological Chemistry, University of California at Davis; 4Division of Rheumatology, University of California at Davis School of Medicine, Davis; 5Department of Dermatology, University of California San Francisco School of Medicine, San Francisco, United States E-mail: [email protected] Background and Aims: Primary biliary cirrhosis (PBC) is the most common autoimmune liver disease characterized by destruction of intrahepatic bile ducts. PBC has been associated with increased incidence of osteoporosis. Intriguingly, two PBC susceptibility loci identified through genome-wide association studies are also involved in bone mineral density (BMD), a key measurable risk factor for osteoporosis. These observations led us to systematically investigate the genetic variants shared between PBC and BMD. Methods: We evaluated 72 genome-wide significant BMD SNPs for association with PBC using two European GWAS data sets (n = 8,392), with replication of significant findings in a Chinese cohort (685 cases, 1,152 controls). We developed a polygenic risk score evaluating the aggregate effects of BMD associated variants in prediction of PBC status in WTCCC and Italian GWAS data. Furthermore, expression quantitative trait locus (eQTL) analysis using Genevar database was used to explore the cis-regulatory effect of the candidate SNP on gene expression. Results: Apart from confirming previously reported loci near/in TNFSF11 (rs9533090, Pfdr = 4.14E−5) and MAPT (rs1864325, Pfdr = 1.58E−5), our analysis identified one novel variant in the intron of the CLDN14 gene (rs170183, Pfdr = 0.015) after multiple testing correction. The three associated variants were followed-up in the Chinese cohort; however, only SNP rs170183 showed consistent evidence of association in diverse ethnic populations (Pcombined = 2.43E−5). Notably, expression quantitative trait loci (eQTL) data revealed that rs170183 was correlated with decline in CLDN14 expression in both lymphoblastoid cell lines and T cells (Padj = 0.003 and 0.016, respectively). However, polygenic scoring analysis using known BMD associated variants in aggregate revealed no overall evidence for genetic overlap between the two traits. Conclusions: In conclusion, we identified a new locus, rs170183 in CLDN14 at 21q22.13, associated with PBC in ethnically diverse populations. Our findings indicate searching for pleiotropic genes may present an important opportunity for identifying more of the missing heritability of the complex traits. SAT-374 DECREASED MIR-425 INDUCED INFLAMMATORY CYTOKINE PRODUCTION VIA N-RAS UPREGULATION IN CD4+ T CELLS OF PRIMARY BILIAR CHOLANGITIS R. Nakagawa1,2, R. Muroyama1, K. Koike2, C. Saeki2, S. Ito1, S. Morimoto1, K. Goto1, Y. Matsubara1, N. Kato1, M. Zeniya3. 1Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo; 2Department of Gastroenterology and Hepatology, The Jikei University of Medicine; 3Clinical Research Center, International University of Health and Welfare, Tokyo, Japan E-mail: [email protected]
Journal of Hepatology 2016 vol. 64 | S631–S832
S643