Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids
Year: 2022
Type: review
Abstract: Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide. NAFLD is associated with elevated serum triglycerides (TG), low-density lipoprotein cholesterol (LDL), and reduced high-density lipoprotein cholesterol (HDL). Both NAFLD and blood lipid levels are genetically influenced and may share a common genetic etiology. We used genome-wide association studies (GWAS)-ranked genes and gene-set enrichment analysis to identify pathways that affect serum lipids and NAFLD. We identified credible genes in these pathways and characterized missense variants in these for effects on serum traits. We used MAGENTA to identify 58 enriched pathways from publicly available TG, LDL, and HDL GWAS (n = 99,000). Three of these pathways were also enriched for associations with European-ancestry NAFLD GWAS (n = 7176). One pathway, farnesoid X receptor (FXR)/retinoid X receptor (RXR) activation, was replicated for association in an African-ancestry NAFLD GWAS (n = 3214) and plays a role in serum lipids and NAFLD. Credible genes (proteins) in FXR/RXR activation include those associated with cholesterol/bile/bilirubin transport/absorption (ABCC2 (MRP2) [ATP binding cassette subfamily C member (multidrug resistance-associated protein 2)], ABCG5, ABCG8 [ATP-binding cassette (ABC) transporters G5 and G8], APOB (APOB) [apolipoprotein B], FABP6 (ILBP) [fatty acid binding protein 6 (ileal lipid-binding protein)], MTTP (MTP) [microsomal triglyceride transfer protein], SLC4A2 (AE2) [solute carrier family 4 member 2 (anion exchange protein 2)]), nuclear hormone-mediated control of metabolism (NR0B2 (SHP) [nuclear receptor subfamily 0 group B member 2 (small heterodimer partner)], NR1H4 (FXR) [nuclear receptor subfamily 1 group H member 4 (FXR)], PPARA (PPAR) [peroxisome proliferator activated receptor alpha], FOXO1 (FOXO1A) [forkhead box O1]), or other pathways (FETUB (FETUB) [fetuin B]). Missense variants in ABCC2 (MRP2), ABCG5 (ABCG5), ABCG8 (ABCG8), APOB (APOB), MTTP (MTP), NR0B2 (SHP), NR1H4 (FXR), and PPARA (PPAR) that associate with serum LDL levels also associate with serum liver function tests in UK Biobank. Conclusion: Genetic variants in NR1H4 (FXR) that protect against liver steatosis increase serum LDL cholesterol while variants in other members of the family have congruent effects on these traits. Human genetic pathway enrichment analysis can help guide therapeutic development by identifying effective targets for NAFLD/serum lipid manipulation while minimizing side effects. In addition, missense variants could be used in companion diagnostics to determine their influence on drug effectiveness.
Source: Hepatology Communications
DOI: 10.1002/hep4.2066
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,700
Funders: Jackson State University, Mississippi State Department of Health, Hjartavernd, National Institutes of Health, Medical School, University of Michigan, Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Minority Health and Health Disparities
Awards: Genetics of Adiposity and Glucose Homeostastis, G1295889178, THE AGES STUDY - THE REYKJAVIK STUDY OF HEALTHY AGING FOR THE NEW MILLENUM, Identification and Characterization of Loci Associated with Non-alcoholic Fatty Liver Disease, G2050560213, G2105483136, G2136672813, G222498687, Genetic Architecture of Adiposity in Multiple Large Cohorts, G230712557, Diabetes Research and Training Center, G2415573643, G250621538, Longevity Genes in Founder Populations, GENETICS OF ADIPOSITY AND GLUCOSE HOMEOSTASIS, G265762973, G278200998, G2809357584, G3042145041, G3205625555, G3402222819, G3405256882, Genome-wide Association in Families: Data Integrity, Design and Methods Issue, Genomic Predictors of Arteriosclerosis in Hypertensives, G3479217851, G350245564, G36937976, Genetic and Epidemiological Predictors of Glucose Homeostasis Measures, G4690953377, G47192932, G4897018079, G4976486911, G4983810294, G5101955913, G5249188777, G5267604781, UK Biobank (core renewal), Human population based genetic studies to elucidate the biology of NAFLD, Molecular genetics of glucose homeostasis and fat, G579045871, G5825472970, Genetics of Adiposity and Glucose Homeostasis, G6130872683, G6156766399, Genetic Influences on Coronary Artery Calcification, The Framingham Heart Study, Genetics of Hypertension Risk Factors and Sequela in African Americans, Genetic Epidemiology of NAFLD and T2DM, G6571475356, Genetics of Adiposity and Glucose Homeostasis, SNP HEALTH ASSOCIATION RESOURCE (SHARE), Mid-Atlantic Nutrition Obesity Research Center, G7091571603, Identification and functional impact of NAFLD associated genetic variants, G7373387228, G7526106616, G7852589027, Probing The Dark Matter of the Genome in the NHLBI Family Heart Study, G857349569, G8683204365, Predictors of Coronary Artery Calcification in an African-American Cohort, G89699440, G9000050004, G9000077244, G9000124674, G9000196033, Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease
OpenAlex ID: W4295367129