Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA.
Department of Computational Medicine and BioinformaticsUniversity of Michigan Medical SchoolAnn ArborMichiganUSA.
Hepatol Commun. 2022 Nov;6(11):3120-3131. doi: 10.1002/hep4.2066. Epub 2022 Sep 13.
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.
非酒精性脂肪性肝病（NAFLD）在全球范围内普遍存在。NAFLD 与血清甘油三酯（TG）、低密度脂蛋白胆固醇（LDL）升高和高密度脂蛋白胆固醇（HDL）降低有关。NAFLD 和血脂水平均受遗传影响，可能具有共同的遗传病因。我们使用全基因组关联研究（GWAS）排名基因和基因集富集分析来确定影响血清脂质和 NAFLD 的途径。我们在这些途径中确定了可信基因，并对这些基因中的错义变体进行了特征描述，以了解它们对血清特征的影响。我们使用 MAGENTA 从公开的 TG、LDL 和 HDL GWAS（n=99000）中确定了 58 个富集途径。其中 3 个途径也与欧洲血统的 NAFLD GWAS（n=7176）的关联富集。一个途径，法尼醇 X 受体（FXR）/视黄醇 X 受体（RXR）激活，在非洲血统的 NAFLD GWAS（n=3214）中也与关联复制，并在血清脂质和 NAFLD 中发挥作用。FXR/RXR 激活的可信基因（蛋白质）包括与胆固醇/胆汁/胆红素转运/吸收相关的基因（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）转运蛋白 G5 和 G8]，APOB（APOB）[载脂蛋白 B]，FABP6（ILBP）[脂肪酸结合蛋白 6（回肠脂质结合蛋白）]，MTTP（MTP）[微粒体甘油三酯转移蛋白]，SLC4A2（AE2）[溶质载体家族 4 成员 2（阴离子交换蛋白 2）]）、核激素介导的代谢控制（NR0B2（SHP）[核受体亚家族 0 组 B 成员 2（小异二聚体伴侣）]，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 alpha]，FOXO1（FOXO1A）[叉头盒 O1]）或其他途径（FETUB（FETUB）[胎球蛋白 B]）。ABCC2（MRP2）、ABCG5（ABCG5）、ABCG8（ABCG8）、APOB（APOB）、MTTP（MTP）、NR0B2（SHP）、NR1H4（FXR）和 PPARA（PPAR）中的错义变体与 LDL 水平相关，也与英国生物银行中的血清肝功能测试相关。结论：保护肝脏脂肪变性的 NR1H4（FXR）中的遗传变异会增加血清 LDL 胆固醇，而该家族的其他成员的变异对这些特征具有相同的影响。人类遗传途径富集分析可以通过确定有效的 NAFLD/血清脂质操作靶点来帮助指导治疗开发，同时尽量减少副作用。此外，错义变体可用作伴随诊断，以确定它们对药物有效性的影响。
