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Association of Genetically Predicted Fibroblast Growth Factor-23 with Heart Failure: A Mendelian Randomization Study
Clinical Journal of the American Society of Nephrology ( IF 8.5 ) Pub Date : 2022-08-01 , DOI: 10.2215/cjn.00960122
Elvis Akwo 1 , Mindy M Pike 1, 2 , Lale A Ertuglu 1 , Nicholas Vartanian 1 , Eric Farber-Eger 3, 4 , Loren Lipworth 1, 2 , Farzana Perwad 5 , Edward Siew 1, 6 , Adriana Hung 1, 6 , Nisha Bansal 6 , Ian de Boer 7 , Bryan Kestenbaum 7 , Nancy J Cox 8 , T Alp Ikizler 1 , Quinn Wells 3, 8 , Cassianne Robinson-Cohen 1
Affiliation  

Background and objectives

Elevated fibroblast growth factor-23 (FGF23) has been consistently associated with heart failure, particularly heart failure with preserved ejection fraction, among patients with CKD and in the general population. FGF23 may directly induce cardiac remodeling and heart failure. However, biases affecting observational studies impede robust causal inferences. Mendelian randomization leverages genetic determinants of a risk factor to examine causality. We performed a two-sample Mendelian randomization to assess causal associations between FGF23 and heart failure.

Design, setting, participants, & measurements

Genetic instruments were genome-wide significant genetic variants associated with FGF23, including variants near PIP5K1B, RGS14, LINC01229, and CYP24A1. We analyzed data from the Heart Failure Molecular Epidemiology for Therapeutic Targets and BioVU biobanks to examine associations of the four variants with overall heart failure, heart failure with preserved ejection fraction, and heart failure with reduced and mid-range ejection fraction. We developed an eGFR polygenic risk score using summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) genome-wide association study of eGFR in >1 million individuals and performed stratified analyses across eGFR polygenic risk score strata.

Results

Genetically determined FGF23 was not associated with overall heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium (odds ratio, 1.13; 95% confidence interval, 0.89 to 1.42 per unit higher genetically predicted log FGF23) and the full BioVU sample (odds ratio, 1.32; 95% confidence interval, 0.95 to 1.84). In stratified analyses in BioVU, higher FGF23 was associated with overall heart failure (odds ratio, 3.09; 95% confidence interval, 1.38 to 6.91) among individuals with low eGFR-polygenic risk score (<1 SD below the mean), but not those with high eGFR-polygenic risk score (P interaction = 0.02). Higher FGF23 was also associated with heart failure with preserved ejection fraction among all BioVU participants (odds ratio, 1.47; 95% confidence interval, 1.01 to 2.14) and individuals with low eGFR-polygenic risk score (odds ratio, 7.20; 95% confidence interval, 2.80 to 18.49), but not those high eGFR-polygenic risk score (P interaction = 2.25 x 10–4). No significant associations were observed with heart failure with reduced and midrange ejection fraction.

Conclusion

We found no association between genetically predicted FGF23 and heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium. In BioVU, genetically elevated FGF23 was associated with higher heart failure risk, specifically heart failure with preserved ejection fraction, particularly among individuals with low genetically predicted eGFR.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_07_28_CJN00960122.mp3



中文翻译:

基因预测成纤维细胞生长因子 23 与心力衰竭的关联:孟德尔随机研究

背景和目标

在 CKD 患者和普通人群中,成纤维细胞生长因子 23 (FGF23) 升高一直与心力衰竭相关,特别是射血分数保留的心力衰竭。FGF23可能直接诱发心脏重构和心力衰竭。然而,影响观察性研究的偏见阻碍了强有力的因果推论。孟德尔随机化利用风险因素的遗传决定因素来检查因果关系。我们进行了两个样本孟德尔随机化,以评估 FGF23 与心力衰竭之间的因果关系。

设计、设置、参与者和测量

遗传仪器是与 FGF23 相关的全基因组显着遗传变异,包括PIP5K1BRGS14LINC01229CYP24A1附近的变异。我们分析了来自治疗目标的心力衰竭分子流行病学和 BioVU 生物库的数据,以检查四种变异与总体心力衰竭、射血分数保留的心力衰竭以及射血分数降低和中等范围的心力衰竭的关联。我们利用慢性肾病遗传学联盟 (CKDGen) 对超过 100 万人的 eGFR 全基因组关联研究的汇总统计数据开发了 eGFR 多基因风险评分,并对 eGFR 多基因风险评分分层进行了分层分析。

结果

在心力衰竭分子流行病学治疗目标联盟中,基因确定的 FGF23 与总体心力衰竭无关(比值比,1.13;95% 置信区间,基因预测 log FGF23 每单位高出 0.89 至 1.42)和完整 BioVU 样本(比值比) ,1.32;95% 置信区间,0.95 至 1.84)。在 BioVU 的分层分析中,在 eGFR 多基因风险评分较低(低于平均值 <1 SD)的个体中,较高的 FGF23 与整体心力衰竭相关(优势比为 3.09;95% 置信区间为 1.38 至 6.91),但与那些低 eGFR 多基因风险评分的个体无关。具有高 eGFR 多基因风险评分(P相互作用 = 0.02)。在所有 BioVU 参与者(比值比,1.47;95% 置信区间,1.01 至 2.14)和 eGFR 多基因风险评分较低的个体(比值比,7.20;95% 置信区间)中,较高的 FGF23 也与射血分数保留的心力衰竭相关,2.80 至 18.49),但不是那些高 eGFR 多基因风险评分(P相互作用 = 2.25 x 10 –4)。没有观察到与射血分数降低和中等程度的心力衰竭之间存在显着关联。

结论

我们在心力衰竭治疗目标分子流行病学联盟中发现基因预测的 FGF23 与心力衰竭之间没有关联。在 BioVU 中,基因升高的 FGF23 与较高的心力衰竭风险相关,特别是射血分数保留的心力衰竭,特别是在基因预测 eGFR 较低的个体中。

播客

本文包含播客 https://www.asn-online.org/media/podcast/CJASN/2022_07_28_CJN00960122.mp3

更新日期:2022-08-01
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