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

Summary The prevalence of non-alcoholic fatty liver disease (NAFLD), now also known as metabolic dysfunction-associated fatty liver disease (MAFLD), is rapidly increasing worldwide due to the ongoing obesity epidemic. However, currently the NALFD diagnosis requires non-readily available imaging technologies or liver biopsy, which has drastically limited the sample sizes of NAFLD studies and hampered the discovery of its genetic component. Here we utilized the large UK Biobank (UKB) to accurately estimate the NAFLD status in UKB based on common serum traits and anthropometric measures. Scoring all individuals in UKB for NAFLD risk resulted in 28,396 NAFLD cases and 108,652 healthy individuals at a >90% confidence level. Using this imputed NAFLD status to perform the largest NAFLD genome-wide association study (GWAS) to date, we identified 94 independent (R 2 < 0.2) NAFLD GWAS loci, of which 90 have not been identified before; built a polygenic risk score (PRS) model to predict the genetic risk of NAFLD; and used the GWAS variants of imputed NAFLD for a tissue-aware Mendelian randomization analysis that discovered a significant causal effect of NAFLD on coronary artery disease (CAD). In summary, we accurately estimated the NAFLD status in UKB using common serum traits and anthropometric measures, which empowered us to identify 90 GWAS NAFLD loci, build NAFLD PRS, and discover a significant causal effect of NAFLD on CAD.

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“…Noteworthy, 7 of the 19 eGenes are Human Leukocyte Antigen ( HLA ) genes that replicated the recent report by Yoshida et al. 35 …”

Section: Resultssupporting

confidence: 62%

Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease

Zong

Garske

Pan

et al. 2022

Human Genetics and Genomics Advances

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“…These data suggest that the PNPLA3 variant could play an essential role in the pathogenesis of non-obese NAFLD. Emerging evidence also showed some other gene variants, such as CETP ( 35 ), SREBF-2 ( 36 ), and HLA ( 37 ), associated with the development of non-obese NALFD. Genetic and mechanistic studies are warranted to dissect the contribution of those genetic variants to non-obese NAFLD.…”

Section: Discussionmentioning

confidence: 98%

The Risk of Type 2 Diabetes and Coronary Artery Disease in Non-obese Patients With Non-alcoholic Fatty Liver Disease: A Cohort Study

Dai

Zhang

Zhao

2021

Front. Cardiovasc. Med.

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Background: Non-alcoholic fatty liver disease (NAFLD) is not uncommon in non-obese subjects, referred to as non-obese NAFLD. It is not fully determined whether non-obese NAFLD is associated with increased risks of type 2 diabetes (T2D) and coronary artery disease (CAD) in Chinese. This study aimed to examine the association between NAFLD and risks of T2D and CAD in a non-obese Chinese population.Methods: The present cohort study included two stages. In the first cross-sectional study, 16,093 non-obese subjects with a body max index (BMI) < 25.0 kg/m2 were enrolled from The Second Xiangya Hospital, China, from 2011 to 2014. Hepatic steatosis was evaluated by ultrasonography examination. Logistic regression analyses were used to examine the association of non-obese NAFLD with T2D and CAD at baseline. In the subsequent 5-year follow-up study, 12,649 subjects free of T2D and CAD at baseline were included, and the incidence of T2D and CAD were observed. Cox proportional hazard regression analyses were performed to determine the risk of incident T2D and CAD with NAFLD.Results: At baseline, the prevalence of NAFLD, T2D and CAD were 10.7% (1,717/16,093), 3.3% (529/16,093) and 0.7% (113/16,093), respectively. The univariate logistic regression analyses showed NAFLD associated with both T2D and CAD. Moreover, in a multivariate logistic regression model, NAFLD remained independently associated with T2D (OR: 2.7, 95% CI: 2.2–3.3, p < 0.001). However, no significant association was found between NAFLD and CAD by the multivariate logistic regression analyses (OR: 1.1, 95% CI: 0.6–1.8, p = 0.854). During a 5-year follow-up period, 177 (1.4%) patients developed T2D, and 134 (1.1%) developed CAD, respectively. In univariate Cox regression models, NAFLD associated with both T2D and CAD. Moreover, the multivariate Cox regression analysis revealed that NAFLD independently associated with an increased risk of T2D (HR: 2.3, 95% CI: 1.7–3.2, p < 0.001). However, the association between NAFLD and incident CAD was lost in the multivariate Cox regression analysis (HR = 1.5, 95% CI: 1.0–2.4, p = 0.059).Conclusions: NAFLD was an independent risk factor for T2D in non-obese subjects. However, no significant association was observed between non-obese NAFLD and incident CAD after adjusting other traditional cardiovascular risk factors, suggesting these factors might mediate the increased incidence of CAD in non-obese NAFLD patients.

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“…These studies have highlighted several loci and candidate mechanisms underlying NAFLD pathogenesis. ( 4‐24 )…”

mentioning

confidence: 99%

Genome‐Wide Association Study of NAFLD Using Electronic Health Records

et al. 2021

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Genome‐wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case‐control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co‐existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta‐analysis using available summary association statistics. Six risk loci were identified (P < 5*10−8) (apolipoprotein E [APOE], patatin‐like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co‐existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta‐analysis. Rs429358 (P = 2.17*10−11) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78‐0.90] and homozygotes 0.64 [0.50‐0.79]). Conclusion: This GWAS replicates six known NAFLD‐susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.

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

Cited by 20 publications

References 49 publications

Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease

Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease

The Risk of Type 2 Diabetes and Coronary Artery Disease in Non-obese Patients With Non-alcoholic Fatty Liver Disease: A Cohort Study

Genome‐Wide Association Study of NAFLD Using Electronic Health Records

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