Abstract：
Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD).
We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites).
We report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 × 10-4), higher urinary sodium excretion (p = 5.1 × 10-11), and lower urine albumin-creatinine ratio (p = 3.6 × 10-5). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94-0.98; p = 3.2 × 10-4). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p < 1.0 × 10-07) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 × 10-24) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction.
This study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re-purposing opportunity for the treatment and prevention of kidney disease specifically. Further work is required to triangulate these findings, towards possible clinical development of FGF21 towards the treatment and prevention of kidney disease.
We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites).
We report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 × 10-4), higher urinary sodium excretion (p = 5.1 × 10-11), and lower urine albumin-creatinine ratio (p = 3.6 × 10-5). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94-0.98; p = 3.2 × 10-4). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p < 1.0 × 10-07) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 × 10-24) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction.
This study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re-purposing opportunity for the treatment and prevention of kidney disease specifically. Further work is required to triangulate these findings, towards possible clinical development of FGF21 towards the treatment and prevention of kidney disease.
摘要：
背景：成纤维细胞生长因子21（FGF21）在2期临床试验中已证明具有降低肝脏脂肪和逆转非酒精性脂肪性肝炎的功效。还假定其具有抗纤维化作用,并且因此可适于重新用于预防和治疗慢性肾病(CKD)。
方法：我们利用错义遗传变异，FGF21基因中的rs739320，与磁共振成像衍生的肝脏脂肪相关，作为临床验证和生物学上合理的工具变量，用于研究FGF21类似物的作用。进行孟德尔随机化，我们确定仪器化FGF21和肾脏表型之间的关联，心脏代谢疾病的危险因素，以及循环蛋白质组(Somalogic，4907适体)和代谢组(夜莺平台，249种代谢物）。
结果：我们报告了基因代理FGF21效应的一致的肾脏保护关联，包括更高的肾小球滤过率(p=1.9×10-4)，尿钠排泄较高（p=5.1×10-11），和较低的尿白蛋白-肌酐比值（p=3.6×10-5）。这些有利的作用转化为较低的CKD风险(每rs739320C等位基因的比值比，0.96；95CI，0.94-0.98；p=3.2×10-4)。遗传代理FGF21效应也与较低的空腹胰岛素有关，腰臀比,血压（收缩压和舒张压，p<1.0×10-07)和血脂(低密度脂蛋白胆固醇，甘油三酯和载脂蛋白B，p<6.5×10-24)剖面。后者的关联在我们的代谢组范围的关联研究中被复制。与遗传预测的FGF21效应相关的蛋白质组扰动与纤维化减少一致。
结论：这项研究强调了基因代理FGF21的多效性作用，并支持了专门治疗和预防肾脏疾病的再利用机会。需要进一步的工作来三角测量这些发现，FGF21可能的临床发展，以治疗和预防肾脏疾病。
方法：我们利用错义遗传变异，FGF21基因中的rs739320，与磁共振成像衍生的肝脏脂肪相关，作为临床验证和生物学上合理的工具变量，用于研究FGF21类似物的作用。进行孟德尔随机化，我们确定仪器化FGF21和肾脏表型之间的关联，心脏代谢疾病的危险因素，以及循环蛋白质组(Somalogic，4907适体)和代谢组(夜莺平台，249种代谢物）。
结果：我们报告了基因代理FGF21效应的一致的肾脏保护关联，包括更高的肾小球滤过率(p=1.9×10-4)，尿钠排泄较高（p=5.1×10-11），和较低的尿白蛋白-肌酐比值（p=3.6×10-5）。这些有利的作用转化为较低的CKD风险(每rs739320C等位基因的比值比，0.96；95CI，0.94-0.98；p=3.2×10-4)。遗传代理FGF21效应也与较低的空腹胰岛素有关，腰臀比,血压（收缩压和舒张压，p<1.0×10-07)和血脂(低密度脂蛋白胆固醇，甘油三酯和载脂蛋白B，p<6.5×10-24)剖面。后者的关联在我们的代谢组范围的关联研究中被复制。与遗传预测的FGF21效应相关的蛋白质组扰动与纤维化减少一致。
结论：这项研究强调了基因代理FGF21的多效性作用，并支持了专门治疗和预防肾脏疾病的再利用机会。需要进一步的工作来三角测量这些发现，FGF21可能的临床发展，以治疗和预防肾脏疾病。
