Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
Department of Internal Medicine, Armed Forces Capital Hospital, Gyeonggi-do, South Korea.
BMC Med. 2022 Feb 3;20(1):44. doi: 10.1186/s12916-022-02251-1.
Previous observational studies suggested that a reduction in estimated glomerular filtration rate (eGFR) or a supranormal eGFR value was associated with adverse cardiovascular risks. However, a previous Mendelian randomization (MR) study under the linearity assumption reported null causal effects from eGFR on myocardial infarction (MI) risks. Further investigation of the nonlinear causal effect of kidney function assessed by eGFR on the risk of MI by nonlinear MR analysis is warranted.
In this MR study, genetic instruments for log-eGFR based on serum creatinine were developed from European samples included in the CKDGen genome-wide association study (GWAS) meta-analysis (N=567,460). Alternate instruments for log-eGFR based on cystatin C were developed from a GWAS of European individuals that included the CKDGen and UK Biobank data (N=460,826). Nonlinear MR analysis for the risk of MI was performed using the fractional polynomial method and the piecewise linear method on data from individuals of white British ancestry in the UK Biobank (N=321,024, with 12,205 MI cases).
Nonlinear MR analysis demonstrated a U-shaped (quadratic P value < 0.001) association between MI risk and genetically predicted eGFR (creatinine) values, as MI risk increased as eGFR declined in the low eGFR range and the risk increased as eGFR increased in the high eGFR range. The results were similar even after adjustment for clinical covariates, such as blood pressure, diabetes mellitus, dyslipidemia, or urine microalbumin levels, or when genetically predicted eGFR (cystatin C) was included as the exposure.
Genetically predicted eGFR is significantly associated with the risk of MI with a parabolic shape, suggesting that kidney function impairment, either by reduced or supranormal eGFR, may be causally linked to a higher MI risk.
先前的观察性研究表明，估算肾小球滤过率（eGFR）的降低或超正常 eGFR 值与不良心血管风险相关。然而，在先前基于线性假设的孟德尔随机化（MR）研究中，eGFR 与心肌梗死（MI）风险之间的因果关系呈零效应。因此，有必要通过非线性 MR 分析进一步研究 eGFR 评估的肾功能的非线性因果效应对 MI 风险的影响。
在这项 MR 研究中，基于血清肌酐的 eGFR 的遗传工具是从包括在 CKDGen 全基因组关联研究（GWAS）荟萃分析中的欧洲样本中开发的（N=567460）。基于包括 CKDGen 和英国生物库数据的欧洲个体的 GWAS 开发了基于胱抑素 C 的 eGFR 的替代遗传工具（N=460826）。在英国生物库中具有白种英国人种背景的个体（N=321024 例，12205 例 MI 病例）的数据上，使用分数多项式方法和分段线性方法进行 MI 风险的非线性 MR 分析。
非线性 MR 分析表明，MI 风险与遗传预测的 eGFR（肌酐）值之间呈 U 形（二次 P 值<0.001）关系，当 eGFR 在低 eGFR 范围内下降时，MI 风险增加，当 eGFR 在高 eGFR 范围内增加时，风险增加。即使在校正了血压、糖尿病、血脂异常或尿微量白蛋白水平等临床协变量，或者将遗传预测的 eGFR（胱抑素 C）作为暴露因素纳入后，结果仍然相似。
遗传预测的 eGFR 与 MI 风险显著相关，呈抛物线形状，表明肾功能受损，无论是由于 eGFR 降低还是超正常，都可能与更高的 MI 风险有因果关系。
