PMID- 32766473 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 2471-254X (Electronic) IS - 2471-254X (Linking) VI - 4 IP - 8 DP - 2020 Aug TI - Genome-Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus. PG - 1124-1135 LID - 10.1002/hep4.1529 [doi] AB - Nonalcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals diagnosed with NAFLD, known as lean NAFLD. We conducted a two-stage analysis to identify NAFLD-associated loci in Japanese patients. In stage I, 275 metabolically healthy normal-weight patients with NAFLD were compared with 1,411 non-NAFLD controls adjusted for age, sex, and alcohol consumption by a genome-wide association study (GWAS). In stage II, human leukocyte antigen (HLA) in chromosome 6 (chr6) (P = 6.73E-08), microRNA (MIR) MIR548F3 in chr7 (P = 4.25E-07), myosin light chain 2 (MYL2) in chr12 (P = 4.39E-07), and glycoprotein precursor (GPC)6 in chr13 (P = 5.43E-07), as suggested by the GWAS, were assessed by single nucleotide polymorphism (SNP) association analysis of whole NAFLD against non-NAFLD in 9,726 members of the general population. A minor allele of the secondary lead SNP in chr6, rs2076529, was significantly associated (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.11-1.28; P = 2.10E-06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04-1.27; P = 6.19E-03) with increased NAFLD risk. Imputation-based typing of HLA showed a significant difference in the distribution of HLA-B, HLA-DR-beta chain 1 (DRB1), and HLA-DQ-beta chain 1 (DQB1) alleles in lean NAFLD GWAS. Next-generation sequence-based typing of HLA in 5,649 members of the general population replicated the significant difference of HLA-B allele distribution and the significant increase of the HLA-B*54:01 allele in whole NAFLD. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta-diversity analysis of rs2076529 and HLA-B*54:01 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and HLA-B*54:01 allele carriers as in NAFLD. Conclusion: HLA was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota. CI - (c) 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. FAU - Yoshida, Ken AU - Yoshida K AUID- ORCID: 0000-0001-9074-9485 AD - Division of Human Genetics Center for Molecular Medicine Jichi Medical University Shimotsuke Japan. FAU - Yokota, Kazuha AU - Yokota K AD - Division of Human Genetics Center for Molecular Medicine Jichi Medical University Shimotsuke Japan. FAU - Kutsuwada, Yukinobu AU - Kutsuwada Y AD - Division of Human Genetics Center for Molecular Medicine Jichi Medical University Shimotsuke Japan. AD - Forensic Science Laboratory Tochigi Prefecture Police Headquarters Utsunomiya Japan. FAU - Nakayama, Kazuhiro AU - Nakayama K AD - Division of Human Genetics Center for Molecular Medicine Jichi Medical University Shimotsuke Japan. AD - Laboratory of Evolutionary Anthropology Department of Integrated Biosciences Graduate School of Frontier Sciences University of Tokyo Kashiwa Japan. FAU - Watanabe, Kazuhisa AU - Watanabe K AD - Division of Human Genetics Center for Molecular Medicine Jichi Medical University Shimotsuke Japan. FAU - Matsumoto, Ayumi AU - Matsumoto A AD - Division of Human Genetics Center for Molecular Medicine Jichi Medical University Shimotsuke Japan. FAU - Miyashita, Hiroshi AU - Miyashita H AD - Jichi Medical University Health Care Center Shimotsuke Japan. FAU - Khor, Seik-Soon AU - Khor SS AD - Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan. AD - Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan. FAU - Tokunaga, Katsushi AU - Tokunaga K AD - Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan. AD - Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan. FAU - Kawai, Yosuke AU - Kawai Y AD - Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan. AD - Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan. FAU - Nagasaki, Masao AU - Nagasaki M AD - Tohoku Medical Megabank Organization Tohoku University Sendai Japan. AD - Center for the Promotion of Interdisciplinary Education and Research Kyoto University Kyoto Japan. FAU - Iwamoto, Sadahiko AU - Iwamoto S AUID- ORCID: 0000-0002-0497-8298 AD - Division of Human Genetics Center for Molecular Medicine Jichi Medical University Shimotsuke Japan. LA - eng PT - Journal Article DEP - 20200519 PL - United States TA - Hepatol Commun JT - Hepatology communications JID - 101695860 PMC - PMC7395061 EDAT- 2020/08/09 06:00 MHDA- 2020/08/09 06:01 PMCR- 2020/05/19 CRDT- 2020/08/09 06:00 PHST- 2020/01/07 00:00 [received] PHST- 2020/04/10 00:00 [revised] PHST- 2020/04/14 00:00 [accepted] PHST- 2020/08/09 06:00 [entrez] PHST- 2020/08/09 06:00 [pubmed] PHST- 2020/08/09 06:01 [medline] PHST- 2020/05/19 00:00 [pmc-release] AID - HEP41529 [pii] AID - 10.1002/hep4.1529 [doi] PST - epublish SO - Hepatol Commun. 2020 May 19;4(8):1124-1135. doi: 10.1002/hep4.1529. eCollection 2020 Aug.