Larsson Susanna C, Michaëlsson Karl, Mola-Caminal Marina, Höijer Jonas, Mantzoros Christos S
Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Metabolism. 2022 Dec;137:155329. doi: 10.1016/j.metabol.2022.155329. Epub 2022 Oct 5.
Fibroblast growth factor 21 (FGF21) is a hepatokine that produces metabolic benefits, such as improvements of lipid profile. We performed a genome-wide association study (GWAS) to identify genetic variants associated with circulating FGF21 and investigated the causal effects of FGF21 on pertinent outcomes using Mendelian randomization (MR).
We conducted a GWAS testing ∼7.8 million DNA sequence variants with circulating FGF21 in a discovery cohort of 6259 Swedish adults with replication in 4483 Swedish women. We then performed two-sample MR analyses of genetically predicted circulating FGF21 in relation to alcohol and nutrient intake, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available GWAS summary statistics data.
Our GWAS identified multiple single-nucleotide polymorphisms with genome-wide significant associations (P < 5 × 10) with circulating FGF21 on chromosomes 2 and 19 in or near the GCKR and FGF21 genes, respectively. The strongest signal at the FGF21 locus (rs2548957, β = 0.181, P < 2.18 × 10) displayed in two-sample MR analyses robust associations with lower alcohol intake, lower circulating low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, gamma-glutamyl transferase, and galectin-3 concentrations, and higher circulating insulin-like growth factor-I and alkaline phosphatase concentrations after correcting for multiple testing (P < 0.0018) whereas associations with fat mass, type 2 diabetes, and cardiovascular disease were largely null.
We identified robust associations of certain genetic variants in or near the GCKR and FGF21 genes with circulating FGF21 concentrations. Furthermore, our results support a strong causal effect of FGF21 on improved lipid profile, reduced alcohol consumption and C-reactive protein concentrations, and liver function biomarkers including fibrosis. We found largely null or weak positive associations with fat mass, diabetes, and cardiovascular disease as well as higher insulin-like growth factor-I concentrations, which could indicate a compensatory increase to regulate the above FGF21 resistant states in humans.
成纤维细胞生长因子21（FGF21）是一种肝脏因子，具有代谢益处，如改善血脂水平。我们进行了一项全基因组关联研究（GWAS），以确定与循环FGF21相关的基因变异，并使用孟德尔随机化（MR）研究FGF21对相关结局的因果效应。
我们在一个由6259名瑞典成年人组成的发现队列中进行了一项GWAS，检测了约780万个DNA序列变异与循环FGF21的关系，并在4483名瑞典女性中进行了重复验证。然后，我们使用公开可用的GWAS汇总统计数据，对基因预测的循环FGF21与酒精和营养摄入、心血管和代谢生物标志物及疾病以及肝功能生物标志物之间的关系进行了两样本MR分析。
我们的GWAS在分别位于GCKR和FGF21基因内或附近的2号和19号染色体上，鉴定出多个与循环FGF21具有全基因组显著关联（P < 5×10）的单核苷酸多态性。FGF21基因座上最强的信号（rs2548957，β = 0.181，P < 2.18×10）在两样本MR分析中显示，在校正多重检验后（P < 0.0018），与较低的酒精摄入量、较低的循环低密度脂蛋白胆固醇、载脂蛋白B、C反应蛋白、γ-谷氨酰转移酶和半乳糖凝集素-3浓度以及较高的循环胰岛素样生长因子-I和碱性磷酸酶浓度具有强关联，而与脂肪量、2型糖尿病和心血管疾病的关联大多为零。
我们鉴定出GCKR和FGF21基因内或附近的某些基因变异与循环FGF21浓度之间存在强关联。此外，我们的结果支持FGF21对改善血脂水平、减少酒精消耗和C反应蛋白浓度以及包括纤维化在内的肝功能生物标志物具有强大的因果效应。我们发现与脂肪量、糖尿病和心血管疾病以及较高的胰岛素样生长因子-I浓度之间大多为零关联或弱正关联，这可能表明在人类中存在一种代偿性增加，以调节上述FGF21抵抗状态。
