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.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep4.1529

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

From fatty hepatocytes to impaired bile flow: Matching model systems for liver biology and disease.

Background Autoantibodies are frequently positive in adults with nonalcoholic fatty liver disease (NAFLD) without concurrent autoimmune hepatitis (AIH). The clinical significance of this is unknown in children. Objective To determine the prevalence of autoantibody positivity in pediatric NAFLD and to evaluate its association with disease severity. Methods Multicenter, retrospective study of patients ≤18 years of age with biopsy-confirmed NAFLD. Descriptive statistics were used and groups were compared using Wilcoxon-Mann Whitney or χ2 testing, and multivariable logistic regression was used for binary or ordinal outcomes. Results One hundred and thirty six patients with a median age of 14 years were included. The median body mass index Z-score was 2.5 (interquartile range 2.2, 2.6). Positive antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver-kidney microsomal antibody, or any combination of autoantibodies were observed in 22%, 14%, 0%, and 33% of patients, respectively. The proportion of patients with a steatosis score ≥2 was significantly higher in those with positive ANA (P = .045). In the multivariable regression analysis, positive ANA was associated with increased odds of steatosis score ≥2 (odds ratio, 5.91; 95% confidential interval, 1.50-23.26), after controlling for potential confounders. No other significant histology differences were seen between the groups. Conclusions Positive ANA and ASMA are common in children with NAFLD; however, anti-LKM positivity is not. ANA positivity is associated with more severe steatosis.

Significance of autoantibody seropositivity in children with obesity and non-alcoholic fatty liver disease.

Analysis of Common Pathways and Markers From Non-Alcoholic Fatty Liver Disease to Immune-Mediated Diseases

Major histocompatibility complex class I-related chain A (MICA) is a highly polymorphic gene that modulates immune surveillance by binding to its receptor on natural killer cells, and its genetic polymorphisms have been associated with chronic immune-mediated diseases. The progressive form of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), is characterized by accumulation of fat and inflammatory cells in the hepatic parenchyma, potentially leading to liver cell injury and fibrosis. To date, there are no data describing the potential role of MICA in the pathogenesis of NAFLD. Therefore, our aim was to assess the association between MICA polymorphism and NASH and its histologic features. A total of 134 subjects were included. DNA from patients with biopsy-proven NAFLD were genotyped using polymerase chain reaction-sequence-specific oligonucleotide for MICA alleles. Liver biopsies were assessed for histologic diagnosis of NASH and specific pathologic features, including stage of fibrosis and grade of inflammation. Multivariate analysis was performed to draw associations between MICA alleles and the different variables; P ≤ 0.05 was considered significant. Univariate analysis showed that MICA*011 (odds ratio [OR], 7.14; 95% confidence interval [CI], 1.24-41.0; P = 0.04) was associated with a higher risk for histologic NASH. Multivariate analysis showed that MICA*002 was independently associated with a lower risk for focal hepatocyte necrosis (OR, 0.24; 95% CI, 0.08-0.74; P = 0.013) and advanced fibrosis (OR, 0.11; 95% CI, 0.02-0.70; P = 0.019). MICA*017 was independently associated with a higher risk for lymphocyte-mediated inflammation (OR, 5.12; 95% CI, 1.12-23.5; P = 0.035). Conclusion: MICA alleles may be associated with NASH and its histologic features of inflammation and fibrosis. Additional research is required to investigate the potential role of MICA in increased risk or protection against NAFLD.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep4.1610

Siddharth Hariharan

Papers

Analysis of human leukocyte antigen allele polymorphism in patients with non alcoholic fatty liver disease.

Major Histocompatibility Complex Class I‐Related Chain A Alleles and Histology of Nonalcoholic Fatty Liver Disease

Serum Amyloid A Is Strongly Associated With Hyperlipidemia in Patients With Non-alcoholic Fatty Liver Disease (NAFLD): 2090