Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids
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 ma...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2022-11-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.2066 |
| _version_ | 1797758300830302208 |
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| author | Samuel K. Handelman Yindra M. Puentes Annapurna Kuppa Yanhua Chen Xiaomeng Du Mary F. Feitosa Nicholette D. Palmer Elizabeth K. Speliotes |
| author_facet | Samuel K. Handelman Yindra M. Puentes Annapurna Kuppa Yanhua Chen Xiaomeng Du Mary F. Feitosa Nicholette D. Palmer Elizabeth K. Speliotes |
| author_sort | Samuel K. Handelman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T18:28:01Z |
| format | Article |
| id | doaj.art-6137dffe57de48ee805a74226afa396a |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-03-12T18:28:01Z |
| publishDate | 2022-11-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-6137dffe57de48ee805a74226afa396a2023-08-02T08:27:28ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2022-11-016113120313110.1002/hep4.2066Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipidsSamuel K. Handelman0Yindra M. Puentes1Annapurna Kuppa2Yanhua Chen3Xiaomeng Du4Mary F. Feitosa5Nicholette D. Palmer6Elizabeth K. Speliotes7Division of Gastroenterology and Hepatology University of Michigan Health System Ann Arbor Michigan USADivision of Gastroenterology and Hepatology University of Michigan Health System Ann Arbor Michigan USADivision of Gastroenterology and Hepatology University of Michigan Health System Ann Arbor Michigan USADivision of Gastroenterology and Hepatology University of Michigan Health System Ann Arbor Michigan USADivision of Gastroenterology and Hepatology University of Michigan Health System Ann Arbor Michigan USADivision of Statistical Genomics, Department of Genetics Washington University St. Louis Missouri USADepartment of Biochemistry Wake Forest School of Medicine Winston‐Salem North Carolina USADivision of Gastroenterology and Hepatology University of Michigan Health System Ann Arbor Michigan USAAbstract 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.https://doi.org/10.1002/hep4.2066 |
| spellingShingle | Samuel K. Handelman Yindra M. Puentes Annapurna Kuppa Yanhua Chen Xiaomeng Du Mary F. Feitosa Nicholette D. Palmer Elizabeth K. Speliotes Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids Hepatology Communications |
| title | Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids |
| title_full | Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids |
| title_fullStr | Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids |
| title_full_unstemmed | Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids |
| title_short | Population‐based meta‐analysis and gene‐set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids |
| title_sort | population based meta analysis and gene set enrichment identifies fxr rxr pathway as common to fatty liver disease and serum lipids |
| url | https://doi.org/10.1002/hep4.2066 |
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