View Item 

Show simple item record

Population-based meta-analysis and gene-set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids
dc.contributor.authorHandelman, Samuel K.
dc.contributor.authorPuentes, Yindra M.
dc.contributor.authorKuppa, Annapurna
dc.contributor.authorChen, Yanhua
dc.contributor.authorDu, Xiaomeng
dc.contributor.authorFeitosa, Mary F.
dc.contributor.authorPalmer, Nicholette D.
dc.contributor.authorSpeliotes, Elizabeth K.
dc.date.accessioned2022-11-09T21:16:25Z
dc.date.available2023-12-09 16:16:23en
dc.date.available2022-11-09T21:16:25Z
dc.date.issued2022-11
dc.identifier.citationHandelman, Samuel K.; Puentes, Yindra M.; Kuppa, Annapurna; Chen, Yanhua; Du, Xiaomeng; Feitosa, Mary F.; Palmer, Nicholette D.; Speliotes, Elizabeth K. (2022). "Population-based meta-analysis and gene-set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids." Hepatology Communications (11): 3120-3131.
dc.identifier.issn2471-254X
dc.identifier.issn2471-254X
dc.identifier.urihttps://hdl.handle.net/2027.42/175051
dc.description.abstractNonalcoholic 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.
dc.publisherEndotext
dc.publisherWiley Periodicals, Inc.
dc.titlePopulation-based meta-analysis and gene-set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelInternal Medicine
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/175051/1/hep42066.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/175051/2/hep42066_am.pdf
dc.identifier.doi10.1002/hep4.2066
dc.identifier.sourceHepatology Communications
dc.identifier.citedreferenceKostapanos MS, Kei A, Elisaf MS. Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease. World J Hepatol. 2013; 5: 470 – 8.
dc.identifier.citedreferenceHua X, Li M, Pan F, Xiao Y, Cui W, Hu Y. Non-alcoholic fatty liver disease is an influencing factor for the association of SHBG with metabolic syndrome in diabetes patients. Sci Rep. 2017; 7: 14532.
dc.identifier.citedreferenceMurakami T, Walczak R, Caron S, Duhem C, Vidal V, Darteil R, et al. The farnesoid X receptor induces fetuin-B gene expression in human hepatocytes. Biochem J. 2007; 407: 461 – 9.
dc.identifier.citedreferenceSiddiqui MS, Van Natta ML, Connelly MA, Vuppalanchi R, Neuschwander-Tetri BA, Tonascia J, et al. Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J Hepatol. 2020; 72: 25 – 33.
dc.identifier.citedreferenceGhosh Laskar M, Eriksson M, Rudling M, Angelin B. Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C-III. J Intern Med. 2017; 281: 575 – 85.
dc.identifier.citedreferenceBriand F, Brousseau E, Quinsat M, Burcelin R, Sulpice T. Obeticholic acid raises LDL-cholesterol and reduces HDL-cholesterol in the Diet-Induced NASH (DIN) hamster model. Eur J Pharmacol. 2018; 818: 449 – 56.
dc.identifier.citedreferencePencek R, Marmon T, Roth JD, Liberman A, Hooshmand-Rad R, Young MA. Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes Metab. 2016; 18: 936 – 40.
dc.identifier.citedreferenceTakei K, Han SI, Murayama Y, Satoh A, Oikawa F, Ohno H, et al. Selective peroxisome proliferator-activated receptor-alpha modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-alpha pathway and improves lipid metabolism in mice. J Diabetes Investig. 2017; 8: 446 – 52.
dc.identifier.citedreferenceZhang Y, Hagedorn CH, Wang L. Role of nuclear receptor SHP in metabolism and cancer. Biochim Biophys Acta. 2011; 1812: 893 – 908.
dc.identifier.citedreferenceHsiao PJ, Lee MY, Wang YT, Jiang HJ, Lin PC, Yang YH, et al. MTTP-297H polymorphism reduced serum cholesterol but increased risk of non-alcoholic fatty liver disease-a cross-sectional study. BMC Med Genet. 2015; 16: 93.
dc.identifier.citedreferenceBlom DJ, Averna MR, Meagher EA, du Toit TH, Sirtori CR, Hegele RA, et al. Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia. Circulation. 2017; 136: 332 – 5.
dc.identifier.citedreferenceFeingold KR. Introduction to Lipids and Lipoproteins. South Dartmouth, MA: Endotext; 2021.
dc.identifier.citedreferenceYu XH, Qian K, Jiang N, Zheng XL, Cayabyab FS, Tang CK. ABCG5/ABCG8 in cholesterol excretion and atherosclerosis. Clin Chim Acta. 2014; 428: 82 – 8.
dc.identifier.citedreferenceYu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC, et al. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest. 2002; 110: 671 – 80.
dc.identifier.citedreferenceBanales JM, Prieto J, Medina JF. Cholangiocyte anion exchange and biliary bicarbonate excretion. World J Gastroenterol. 2006; 12: 3496 – 511.
dc.identifier.citedreferenceLiss KH, Finck BN. PPARs and nonalcoholic fatty liver disease. Biochimie. 2017; 136: 65 – 74.
dc.identifier.citedreferenceIp E, Farrell G, Hall P, Robertson G, Leclercq I. Administration of the potent PPARalpha agonist, Wy-14643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology. 2004; 39: 1286 – 96.
dc.identifier.citedreferenceShipman KE, Strange RC, Ramachandran S. Use of fibrates in the metabolic syndrome: a review. World J Diabetes. 2016; 7: 74 – 88.
dc.identifier.citedreferenceRodriguez-Calvo R, Chanda D, Oligschlaeger Y, Miglianico M, Coumans WA, Barroso E, et al. Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytes. Biochim Biophys Acta Mol Cell Biol Lipids. 2017; 1862: 541 – 51.
dc.identifier.citedreferencePostic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008; 34: 643 – 8.
dc.identifier.citedreferenceJiao N, Baker SS, Chapa-Rodriguez A, Liu W, Nugent CA, Tsompana M, et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut. 2018; 67: 1881 – 91.
dc.identifier.citedreferenceDistrutti E, Santucci L, Cipriani S, Renga B, Schiaroli E, Ricci P, et al. Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa. J Gastroenterol. 2015; 50: 707 – 19.
dc.identifier.citedreferenceKettunen J, Demirkan A, Wurtz P, Draisma HH, Haller T, Rawal R, et al. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nat Commun. 2016; 7: 11122.
dc.identifier.citedreferenceLazarus JV, Mark HE, Anstee QM, Arab JP, Batterham RL, Castera L, et al. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol. 2022; 19: 60 – 78.
dc.identifier.citedreferenceWilson PWF, D’Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation. 2005; 112: 3066 – 72.
dc.identifier.citedreferenceSpeliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011; 7: e1001324.
dc.identifier.citedreferenceSegre AV, DIAGRAM Consortium, MAGIC investigators, Groop L, Mootha VK, Daly MJ, Altshuler D. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet. 2010; 6: e1001058.
dc.identifier.citedreferenceTeslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010; 466: 707 – 13.
dc.identifier.citedreferencePalmer ND, Musani SK, Yerges-Armstrong LM, Feitosa MF, Bielak LF, Hernaez R, et al. Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent. Hepatology. 2013; 58: 966 – 75.
dc.identifier.citedreferenceIwasaki M, Takada Y, Hayashi M, Minamiguchi S, Haga H, Maetani Y, et al. Noninvasive evaluation of graft steatosis in living donor liver transplantation. Transplantation. 2004; 78: 1501 – 5.
dc.identifier.citedreferenceSpeliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, et al. Association analysis of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010; 42: 937 – 48.
dc.identifier.citedreferenceHeid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V, et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. 2010; 42: 949 – 60.
dc.identifier.citedreferenceInternational Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011; 478: 103 – 9.
dc.identifier.citedreferenceSudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015; 12: e1001779.
dc.identifier.citedreferenceWang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38: e164.
dc.identifier.citedreferenceO’Connor LJ, Price AL. Distinguishing genetic correlation from causation across 52 diseases and complex traits. Nat Genet. 2018; 50: 1728 – 34.
dc.identifier.citedreferenceZheng J, Erzurumluoglu AM, Elsworth BL, Kemp JP, Howe L, Haycock PC, et al. LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics. 2017; 33: 272 – 9.
dc.identifier.citedreferenceGluud C. Testosterone and alcoholic cirrhosis. Epidemiologic, pathophysiologic and therapeutic studies in men. Dan Med Bull. 1988; 35: 564 – 75.
dc.identifier.citedreferenceCarlson CS, Matise TC, North KE, Haiman CA, Fesinmeyer MD, Buyske S, et al. Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. PLoS Biol. 2013; 11: e1001661.
dc.identifier.citedreferenceDing K, Kullo IJ. Geographic differences in allele frequencies of susceptibility SNPs for cardiovascular disease. BMC Med Genet. 2011; 12: 55.
dc.identifier.citedreferencePriest C, Tontonoz P. Inter-organ cross-talk in metabolic syndrome. Nat Metab. 2019; 1: 1177 – 88.
dc.identifier.citedreferenceHiguchi N, Kato M, Tanaka M, Miyazaki M, Takao S, Kohjima M, et al. Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease. Exp Ther Med. 2011; 2: 1077 – 81.
dc.identifier.citedreferenceYamakawa-Kobayashi K, Ishiguro H, Arinami T, Miyazaki R, Hamaguchi H. A Val227Ala polymorphism in the peroxisome proliferator activated receptor alpha (PPARalpha) gene is associated with variations in serum lipid levels. J Med Genet. 2002; 39: 189 – 91.
dc.identifier.citedreferenceLefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest. 2006; 116: 571 – 80.
dc.identifier.citedreferenceIp E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology. 2003; 38: 123 – 32.
dc.identifier.citedreferenceFernandez-Miranda C, Perez-Carreras M, Colina F, Lopez-Alonso G, Vargas C, Solis-Herruzo JA. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis. 2008; 40: 200 – 5.
dc.identifier.citedreferenceGraf GA, Yu L, Li WP, Gerard R, Tuma PL, Cohen JC, et al. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J Biol Chem. 2003; 278: 48275 – 82.
dc.identifier.citedreferenceEscola-Gil JC, Llaverias G, Julve J, Jauhiainen M, Mendez-Gonzalez J, Blanco-Vaca F. The cholesterol content of Western diets plays a major role in the paradoxical increase in high-density lipoprotein cholesterol and upregulates the macrophage reverse cholesterol transport pathway. Arterioscler Thromb Vasc Biol. 2011; 31: 2493 – 9.
dc.identifier.citedreferenceYu L, Hammer RE, Li-Hawkins J, Von Bergmann K, Lutjohann D, Cohen JC, et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci U S A. 2002; 99: 16237 – 42.
dc.identifier.citedreferenceGluud C, Bennett P, Svenstrup B, Micic S. Effect of oral testosterone treatment on serum concentrations of sex steroids gonadotrophins and prolactin in alcoholic cirrhotic men. Copenhagen Study Group for Liver Diseases. Aliment Pharmacol Ther. 1988; 2: 119 – 28.
dc.working.doiNOen
dc.owningcollnameInterdisciplinary and Peer-Reviewed


Files in this item

Name:
hep42066.pdf
Size:
2.290MB
Format:
PDF
View/Open
Name:
hep42066_am.pdf
Size:
2.127MB
Format:
PDF
View/Open

Show simple item record

Remediation of Harmful Language

The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.

Accessibility

If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.