Genome-Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus

Ken Yoshida; Kazuha Yokota; Yukinobu Kutsuwada; Kazuhiro Nakayama; Kazuhisa Watanabe; Ayumi Matsumoto; Hiroshi Miyashita; Seik-Soon Khor; Katsushi Tokunaga; Yosuke Kawai; Masao Nagasaki; Sadahiko Iwamoto

doi:10.1002/hep4.1529

Genome-Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus

Hepatol Commun. 2020 May 19;4(8):1124-1135. doi: 10.1002/hep4.1529. eCollection 2020 Aug.

Authors

Ken Yoshida¹, Kazuha Yokota¹, Yukinobu Kutsuwada^{1

2}, Kazuhiro Nakayama^{1

3}, Kazuhisa Watanabe¹, Ayumi Matsumoto¹, Hiroshi Miyashita⁴, Seik-Soon Khor^{5

6}, Katsushi Tokunaga^{5

6}, Yosuke Kawai^{5

6}, Masao Nagasaki^{7

8}, Sadahiko Iwamoto¹

Affiliations

¹ Division of Human Genetics Center for Molecular Medicine Jichi Medical University Shimotsuke Japan.
² Forensic Science Laboratory Tochigi Prefecture Police Headquarters Utsunomiya Japan.
³ Laboratory of Evolutionary Anthropology Department of Integrated Biosciences Graduate School of Frontier Sciences University of Tokyo Kashiwa Japan.
⁴ Jichi Medical University Health Care Center Shimotsuke Japan.
⁵ Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan.
⁶ Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan.
⁷ Tohoku Medical Megabank Organization Tohoku University Sendai Japan.
⁸ Center for the Promotion of Interdisciplinary Education and Research Kyoto University Kyoto Japan.

Abstract

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.