X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.
Asselta, Rosanna Paraboschi, Elvezia M Gerussi, Alessio Cordell, Heather J Mells, George F Sandford, Richard N Jones, David E Nakamura, Minoru Ueno, Kazuko Hitomi, Yuki
Asselta, Rosanna
Paraboschi, Elvezia M
Gerussi, Alessio
Cordell, Heather J
Mells, George F
Sandford, Richard N
Jones, David E
Nakamura, Minoru
Ueno, Kazuko
Hitomi, Yuki
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Affiliation
Humanitas University Milan; University of Milano-Bicocca, Monza Italy; Newcastle University; Cambridge University; Sandwell West Birmingham NHS Trust
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Publication date
2021-03-04
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Abstract
Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively).
Citation
Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA; Canadian-US PBC Consortium; Italian PBC Genetics Study Group; UK-PBC Consortium; Japan PBC-GWAS Consortium; Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis. Gastroenterology. 2021 Jun;160(7):2483-2495.e26.
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Article