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

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 () in chromosome 6 (chr6) ( = 6.73E-08), microRNA (MIR) in chr7 ( = 4.25E-07), myosin light chain 2 () in chr12 ( = 4.39E-07), and glycoprotein precursor () in chr13 ( = 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;  = 2.10E-06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04-1.27;  = 6.19E-03) with increased NAFLD risk. Imputation-based typing of showed a significant difference in the distribution of DR-beta chain 1 (), and DQ-beta chain 1 () alleles in lean NAFLD GWAS. Next-generation sequence-based typing of in 5,649 members of the general population replicated the significant difference of allele distribution and the significant increase of the 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 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and allele carriers as in NAFLD. : was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.