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Lookup NU author(s): Professor Heather Cordell
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© 2021. Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease that appears to be strongly influenced by genetic factors. Recently, an international meta-analysis of genome-wide association studies (GWAS) identified CC-Motif Chemokine Receptor-6 (CCR6) and FGFR1 Oncogene-Partner (FGFR1OP) as PBC-susceptibility genes. However, the lead single nucleotide polymorphisms (SNPs) of CCR6/FGFR1OP showed low linkage disequilibrium with each other in East Asian and European populations. Additionally, the primary functional variants and the molecular mechanisms responsible for PBC-susceptibility remain unclear. Here, among the PBC-susceptibility SNPs identified by high-density association mapping in our previous meta-GWAS (Patients: n = 10,516; healthy controls: n = 20,772) within the CCR6/FGFR1OP locus, rs9459874 and rs1012656 were identified as primary functional variants. These functional variants accounted for the effects of GWAS-identified lead SNPs in CCR6/FGFR1OP. Additionally, the roles of rs9459874 and rs1012656 in regulating FGFR1OP transcription and CCR6 translation, respectively, were supported by expression quantitative trait loci (eQTL) analysis and gene editing technology using the CRISPR/Cas9 system. Immunohistochemistry showed higher expression of CCR6 protein in the livers of patients with PBC than in those of a non-diseased control. In conclusion, we identified primary functional variants in CCR6/FGFR1OP and revealed the molecular mechanisms by which these variants confer PBC-susceptibility in an eQTL-dependent or -independent manner. The approach in this study is applicable for the elucidation of the pathogenesis of other autoimmune disorders in which CCR6/FGFR1OP is known as a susceptibility locus, as well as PBC.
Author(s): Hitomi Y, Aiba Y, Ueno K, Nishida N, Kawai Y, Kawashima M, Yasunami M, Gervais O, Ito M, Cordell HJ, Mells GF, Nagasaki M, Tokunaga K, Tsuiji M, Nakamura M
Publication type: Article
Publication status: Published
Journal: Journal of Autoimmunity
Year: 2022
Volume: 126
Print publication date: 01/01/2022
Online publication date: 02/12/2021
Acceptance date: 23/11/2021
ISSN (print): 0896-8411
ISSN (electronic): 1095-9157
Publisher: Academic Press
URL: https://doi.org/10.1016/j.jaut.2021.102775
DOI: 10.1016/j.jaut.2021.102775
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