Abstract

BackgroundPrevious 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.MethodsIn 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).ResultsNonlinear 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.ConclusionGenetically 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.

Highlights

  • Previous observational studies suggested that a reduction in estimated glomerular filtration rate or a supranormal eGFR value was associated with adverse cardiovascular risks

  • The results were similar even after clinical covariates were adjusted, and the slope was steeper in the low eGFR ranges where a higher genetically predicted eGFR was associated with a lower risk of myocardial infarction (MI)

  • The results were similar when the independent summary statistics from the CARDIoGRAMplusC4D consortium were used as the outcome data. In this Mendelian randomization (MR) study, we identified that genetically predicted eGFR is significantly associated with MI risk with a quadratic shape

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Summary

Introduction

Previous observational studies suggested that a reduction in estimated glomerular filtration rate (eGFR) or a supranormal eGFR value was associated with adverse cardiovascular risks. 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. Recent observational studies reported that a state of supranormal eGFR, kidney hyperfiltration, was associated with a higher risk of cardiovascular diseases [4,5,6,7]. To further confirm that the observational findings were from the causal effects on eGFR on MI risks, Mendelian randomization (MR) analysis, an analytical tool widely used in the recent medical literature, can be helpful. Further nonlinear MR analysis is warranted to investigate the shape of the causal estimates on MI according to eGFR values

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