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GWAS Meta-Analysis Finds Five Genetic Loci Associated With Non-Alcoholic Fatty Liver Disease

NEW YORK – A genome-wide meta-analysis of patients with non-alcoholic fatty liver disease has identified five potential susceptibility loci for the disease, as well as a potentially causal effect of lower expression of the LPL gene in adipose tissue.

In a study published on Wednesday in Cell Reports Medicine, researchers in Canada, the US, and Estonia described their GWAS meta-analysis of four cohorts of electronic health records from patients with documented NAFLD, a complex condition that's linked to several chronic diseases such as cardiovascular disease, type 2 diabetes, dyslipidemia, and chronic kidney disease. The analysis included GWAS summary statistics from the eMERGE and FinnGen cohorts, an updated NAFLD GWAS in the UK Biobank, and a new GWAS performed in the Estonian Biobank, for a total of 8,434 NAFLD cases and 770,180 controls, all of European ancestry.

In addition to the five potential susceptibility loci for NAFLD (located at or near GCKR, TRIB1, MAU2/TM6SF2, APOE, and PNPLA3) and the causal effect of lower expression of LPL (which makes the lipoprotein lipase enzyme) in adipose tissue, the researchers also found that the fat mass and obesity-associated, or FTO, genotype also had an effect on NAFLD.

They observed positive genetic correlations between NAFLD and cardiometabolic diseases, and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance, and coronary artery disease. They also saw negative genetic correlations between the condition and parental lifespan, socioeconomic status, and acetoacetate levels.

TM6SF2 and PNPLA3 had been identified in previous studies as potential susceptibility loci for NAFLD, the researchers said. Their analysis re-affirmed the association of these two loci, and identified five potentially new candidate genetic regions for a clinical diagnosis of NAFLD (GCKR, TRIB1, LPL, FTO, APOE).

They then conducted further analyses that adjusted for patient obesity status by including BMI as a variable. Through this analysis, the association with the variant at the FTO locus was no longer significantly associated with NAFLD, the researchers said.

Additionally, an analysis of LPL found that a minor allele was associated with protection against NAFLD. This allele has been predicted to disrupt a microRNA recognition element seed site for human microRNA miR-410, resulting in higher LPL expression. After performing a transcriptome-wide association study for NAFLD, the researchers determined that there was a negative association between genetically predicted LPL expression in subcutaneous adipose tissue and the disease.

Therefore, they said, LPL and FTO may be associated with NAFLD through their effects on disease risk factors such as BMI and triglycerides.

"Interestingly, combined with the results of other studies that have linked variation at LPL as being associated with lower lipid levels and risk of CAD, our analysis suggests that targeting the LPL pathway may prevent NAFLD as well as other diseases such as hyperlipidemia and CAD without increasing the risk of other human diseases," the authors concluded. "Drugs targeting the LPL pathway under investigation for NAFLD include the angiopoietin-like protein-3 (ANGPTL3) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dual glucose-dependent insulinotropic peptide (GIP)/GLP-1 receptor agonists."