Causal Effects of Genetically Predicted Cardiovascular Risk Factors on Chronic Kidney Disease: A Two-Sample Mendelian Randomization Study

Abstract

Observational studies have demonstrated that cardiovascular risk factors are associated with chronic kidney disease (CKD). However, these observational associations are potentially influenced by the residual confounding, including some unmeasured lifestyle factors and interaction risk factors. Two-sample mendelian randomization analysis was conducted in this study to evaluate whether genetically predicted cardiovascular risk factors have a causal effect on the risk of CKD. We selected genetic variants associated with cardiovascular risk factors and extracted the corresponding effect sizes from the largest GWAS summary-level dataset of CKD. Cardiovascular risk factors contain high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, total cholesterol (TC), triglyceride (TG), glycated hemoglobin (HbA1c), fasting glucose, systolic blood pressure (SBP) and diastolic blood pressure (DBP). A Bonferroni corrected threshold of P = 0.006 was considered as significant, and 0.006 < P < 0.05 was considered suggestive of evidence for a potential association. Genetically predicted DBP was significantly associated with CKD [odds ratio (OR) was 1.35 (95% confidence interval (CI) (1.10, 1.65); P = 0.004)]. There was suggestive evidence for potential associations between genetically predicted higher HDL cholesterol [OR: 0.88, 95%CI (0.80, 0.98), P = 0.025] and lower adds of CKD, and between higher SBP [OR: 1.36, 95%CI (1.07, 1.73), P = 0.013] and higher adds of CKD. However, genetically predicted LDL cholesterol, TC, TG, HbA1c, and fasting glucose did not show any causal association with CKD.

Kidney Function and Blood Pressure: A Bi-directional Mendelian Randomisation Study

“…Another Mendelian randomisation study reported significant causal effects of higher SBP and DBP to CKD using the IVW-FE method, which provides consistent estimates assuming that the sum of horizontal pleiotropic effects of all instruments is zero and horizontal pleiotropic effects are independent of instrument strength across all variants 50 . When applying the IVW-FE method in our study, the causal estimates of SBP and DBP on CKD were also significant and similar to those previously reported 15 . The weighted median method, which is known to be robust under the assumption that at least 50% of the selected instruments are valid, also showed some evidence of these causal effects.…”

“…Similar non-significant causal estimates were observed for DBP on the three kidney function outcomes (eGFRcr, CKD, and BUN) using weighted mode as well as MRMix, the methods most robust to horizontal pleiotropy ( Supplementary Table 6 ). In contrast, using IVW-FE, the causal estimates were significant across all blood pressure and kidney function traits, which might be due to horizontal pleiotropy 15 . For example, using the IVW-FE method, the causal estimate indicated a 27% higher odds ratio for CKD per each SD higher SBP (OR: 1.27, 95% CI: 1.17, 1.37, p = 2.01×10 −8 ).…”

“…Mendelian randomisation is an approach employing genetic variants as instrumental variables of the exposure to estimate causal effects between an exposure and an outcome with the goal of overcoming the confounding inherent in observational studies 14 . Using a Mendelian randomisation analysis approach, Liu et al found that higher genetically-predicted systolic blood pressure (SBP) is causally linked to CKD 15 . Haas et al showed evidence supporting the existence of a feed-forward loop between albuminuria, a marker of kidney damage, and hypertension 16 .…”

A bidirectional Mendelian randomization study supports causal effects of kidney function on blood pressure

“…Using two-sample MR analysis, Liu et al found causal effects of systolic BP (SBP) and diastolic BP (DBP) on CKD. 16 Morris et al reported a significant causal effect of lower kidney function on higher DBP and not on SBP. 17 Taking advantage of the recent largescale meta-analysis of the GWAS of kidney function that included complementary glomerular filtration rate (GFR) biomarkers, we performed two-sample MR analyses to evaluate the potential bidirectional causal relation between kidney function and BP.…”

Causal Effect Between Total Cholesterol and Hdl Cholesterol as Risk Factors for Chronic Kidney Disease: A Mendelian Randomization Study

“…At the same time, we made a judgment on the level of the horizontal pleiotropic pathway and sensitivity, avoiding the interference of false negatives with the conclusion. Liu et al (32) also found that HDL-C is related to the pathogenesis of CKD, while TC, TG and LDL-C are not. Compared with the studies conducted by these researchers, there are some differences in the selected GWAS results in our current study, and we paid more attention to the correlation between the change range and trend of serum lipids and the incidence of CKD to guide the clinical diagnosis and treatment.…”