Population-based meta-analysis and gene-set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids.
Population-based meta-analysis and gene-set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids.
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DOI：
10.1002/hep4.2066
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发表时间：
2022-11
影响因子：
5.1
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中科院分区：
文献类型：
--
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非酒精性脂肪性肝病(NAFLD)在世界范围内流行。非酒精性脂肪肝与血清甘油三酯(TG)、低密度脂蛋白胆固醇(LDL)和降低高密度脂蛋白胆固醇(HDL)有关。非酒精性脂肪性肝病和血脂水平都受遗传因素的影响，可能具有共同的遗传病因。我们使用全基因组关联研究(GWAS)排序的基因和基因集浓缩分析来识别影响血脂和非酒精性脂肪肝的途径。我们在这些途径中确定了可靠的基因，并确定了这些途径中的错义变异对血清特性的影响。我们使用洋红从公开可用的TG、LDL和HDLGWA(n=0.99,000)中识别出58条丰富的途径。其中三条途径也丰富了与欧洲血统NAFLD GWAS(n=17176)的联系。一条途径，法尼类X受体(FXR)/维甲酸X受体(RXR)激活，被复制到非洲血统的NAFLD GWA(n=3214)中，并在血脂和NAFLD中发挥作用。参与FXR/RXR激活的可靠基因(蛋白质)包括与胆固醇/胆汁/胆红素转运/吸收(ABCC2(MRP2)[ATP结合盒亚家族C成员(多药耐药相关蛋白2)]、ABCG5、ABCG8[ATP结合盒(ABC)转运体G5和G8]、APOB(APOB)[载脂蛋白B]、FABP6(ILBP)[脂肪酸结合蛋白6(回肠脂结合蛋白)]、MTTP(MTP)[微体甘油三酯转移蛋白]、SLC4A2(AE2)[溶质载体家族4成员(阴离子交换蛋白2)]、核激素介导的代谢调控(NR0B2(SHP)[核受体亚家族0组B成员2(小异二聚体伙伴)]，NR1H4(FXR)[核受体亚家族1组H成员4(FXR)]，PPARA(PPAR)[过氧化物酶体增殖物激活受体α]，FOXO1(FOXO1A)[叉头盒O1])或其他途径(FETUB(FETUB)[FETUB])。ABCC2(MRP2)、ABCG5(ABCG5)、ABCG8(ABCG8)、APOB(APOB)、MTTP(MTP)、NR0B2(SHP)、NR1H4(FXR)和PPARA(PPAR)错义变异与血清低密度脂蛋白水平相关，也与英国生物银行的血清肝功能测试有关。结论：防止肝脏脂肪变性的NR1H4(FXR)基因变异会增加血清低密度脂蛋白胆固醇，而该家族其他成员的变异对这些特征也有相同的影响。人类遗传途径丰富分析可以通过确定NAFLD/血脂操作的有效靶点来帮助指导治疗开发，同时将副作用降至最低。此外，错义变异可以用于伴随诊断，以确定它们对药物效果的影响。
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.
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影响因子：
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通讯作者：
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