RESUMO
BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: 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). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
Assuntos
Cromossomos Humanos X/genética , Predisposição Genética para Doença/genética , Cirrose Hepática Biliar/genética , Adulto , Povo Asiático/genética , Proteínas de Transporte/genética , Linhagem da Célula/genética , Proteínas de Ligação a DNA/genética , Endopeptidases/genética , Feminino , Fatores de Transcrição Forkhead/genética , Loci Gênicos/genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Masculino , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/genética , Proteínas de Transporte de Monossacarídeos/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Canais de Potássio Shal/genética , População Branca/genéticaRESUMO
Minnesota is home to a large population of immigrants from Laos as well as one of the largest disparities in hepatitis B (HBV) infection; in Minnesota, Asians are 80 times more likely to be infected than Whites. In response to community concern, a community-based participatory research project was conducted involving a cross-sectional study of 167 adult Laotian immigrants in the Minneapolis/St. Paul metropolitan area assessing knowledge and behaviors related to HBV and its vaccine. Fifty-eight percent of the participants reported not knowing about HBV and just under half incorrectly reported on person-to-person transmission. As expected, vaccination and screening for HBV was more common among those who knew of HBV (p = 0.02 for both). Fourteen (8.4 %) of the participants had been vaccinated, however, only 2 (14.8 %) of those individuals received all three doses. This study outlines gaps in knowledge and resources that could address the staggering HBV disparity in this community.