{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:12:11Z","timestamp":1792098731555,"version":"4.4.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,11]]},"abstract":"Abstract<\/jats:title>\n Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide. NAFLD is associated with elevated serum triglycerides (TG), low\u2010density lipoprotein cholesterol (LDL), and reduced high\u2010density lipoprotein cholesterol (HDL). Both NAFLD and blood lipid levels are genetically influenced and may share a common genetic etiology. We used genome\u2010wide association studies (GWAS)\u2013ranked genes and gene\u2010set 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\u00a0=\u00a099,000). Three of these pathways were also enriched for associations with European\u2010ancestry NAFLD GWAS (n\u00a0=\u00a07176). One pathway, farnesoid X receptor (FXR)\/retinoid X receptor (RXR) activation, was replicated for association in an African\u2010ancestry NAFLD GWAS (n\u00a0=\u00a03214) 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<\/jats:italic> (MRP2) [ATP binding cassette subfamily C member (multidrug resistance\u2010associated protein 2)], ABCG5<\/jats:italic>, ABCG8<\/jats:italic> [ATP\u2010binding cassette (ABC) transporters G5 and G8], APOB<\/jats:italic> (APOB) [apolipoprotein B], FABP6<\/jats:italic> (ILBP) [fatty acid binding protein 6 (ileal lipid\u2010binding protein)], MTTP<\/jats:italic> (MTP) [microsomal triglyceride transfer protein], SLC4A2<\/jats:italic> (AE2) [solute carrier family 4 member 2 (anion exchange protein 2)]), nuclear hormone\u2013mediated control of metabolism (NR0B2<\/jats:italic> (SHP) [nuclear receptor subfamily 0 group B member 2 (small heterodimer partner)], NR1H4<\/jats:italic> (FXR) [nuclear receptor subfamily 1 group H member 4 (FXR)], PPARA<\/jats:italic> (PPAR) [peroxisome proliferator activated receptor alpha], FOXO1<\/jats:italic> (FOXO1A) [forkhead box O1]), or other pathways (FETUB<\/jats:italic> (FETUB) [fetuin B]). Missense variants in ABCC2<\/jats:italic> (MRP2), ABCG5<\/jats:italic> (ABCG5), ABCG8<\/jats:italic> (ABCG8), APOB<\/jats:italic> (APOB), MTTP<\/jats:italic> (MTP), NR0B2<\/jats:italic> (SHP), NR1H4<\/jats:italic> (FXR), and PPARA<\/jats:italic> (PPAR) that associate with serum LDL levels also associate with serum liver function tests in UK Biobank. Conclusion<\/jats:italic>: Genetic variants in NR1H4<\/jats:italic> (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.<\/jats:p>","DOI":"10.1002\/hep4.2066","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T12:08:52Z","timestamp":1663070932000},"page":"3120-3131","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":17,"title":["Population\u2010based meta\u2010analysis and gene\u2010set enrichment identifies FXR\/RXR pathway as common to fatty liver disease and serum lipids"],"prefix":"10.1097","volume":"6","author":[{"given":"Samuel K.","family":"Handelman","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology,University of Michigan Health System,Ann Arbor,Michigan,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yindra M.","family":"Puentes","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,University of Michigan Health System,Ann Arbor,Michigan,USA"},{"name":"Department of Computational Medicine and Bioinformatics,University of Michigan Medical School,Ann Arbor,Michigan,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annapurna","family":"Kuppa","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,University of Michigan Health System,Ann Arbor,Michigan,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,University of Michigan Health System,Ann Arbor,Michigan,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Du","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,University of Michigan Health System,Ann Arbor,Michigan,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary F.","family":"Feitosa","sequence":"additional","affiliation":[{"name":"Division of Statistical Genomics, Department of Genetics,Washington University,St. Louis,Missouri,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholette D.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry,Wake Forest School of Medicine,Winston\u2010Salem,North Carolina,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1002-4140","authenticated-orcid":false,"given":"Elizabeth K.","family":"Speliotes","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,University of Michigan Health System,Ann Arbor,Michigan,USA"},{"name":"Department of Computational Medicine and Bioinformatics,University of Michigan Medical School,Ann 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