Mendelian Randomisation study of the influence of eGFR on coronary heart disease.

Pimphen Charoen,Tina Shah,Frank Dudbridge,Dorothea Nitsch,Jonathan White,Stela Mclachlan,Yoav Ben-Shlomo,Meena Kumari,Jorgen Engmann,Goya Wannamethee,Delilah Zabaneh,Claudia Langenberg,Mika Kivimäki ,Aroon D Hingorani ,Peter H Whincup ,Barbara J Jefferis ,Juan P Casas ,Tom R Gaunt ,John C Whittaker ,Jacqueline F Price ,Ian N.m Day ,Amy Mulick ,Eric J Brunner

doi:10.1038/srep28514

Abstract

Impaired kidney function, as measured by reduced estimated glomerular filtration rate (eGFR), has been associated with increased risk of coronary heart disease (CHD) in observational studies, but it is unclear whether this association is causal or the result of confounding or reverse causation. In this study we applied Mendelian randomisation analysis using 17 genetic variants previously associated with eGFR to investigate the causal role of kidney function on CHD. We used 13,145 participants from the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium and 194,427 participants from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease (CARDIoGRAMplusC4D) consortium. We observed significant association of an unweighted gene score with CHD risk (odds ratio = 0.983 per additional eGFR-increasing allele, 95% CI = 0.970–0.996, p = 0.008). However, using weights calculated from UCLEB, the gene score was not associated with disease risk (p = 0.11). These conflicting results could be explained by a single SNP, rs653178, which was not associated with eGFR in the UCLEB sample, but has known pleiotropic effects that prevent us from drawing a causal conclusion. The observational association between low eGFR and increased CHD risk was not explained by potential confounders, and there was no evidence of reverse causation, therefore leaving the remaining unexplained association as an open question.

Highlights

Blood pressure lowering drugs and statins to prevent poor outcomes
By using a richly phenotyped data set in the UCLEB consortium, we thoroughly examined whether our gene score meets the assumptions of Mendelian Randomisation studies, in that it is associated with estimated glomerular filtration rate (eGFR), not associated with potential confounders of the eGFR-coronary heart disease (CHD) association, and not associated with other biomarkers of CHD that might represent alternative pathways than that through eGFR
The gene scores appeared to meet these assumptions we noted associations with additional kidney function traits that might represent alternative pathways through kidney function to that measured by eGFR

Summary

Mean age

NA to be conservative, finding that the overall level of correlation is negligible in this context (see Supplementary Methods). The unweighted score has wj = 1 for all SNPs, whereas the weighted score sets wj to the linear regression coefficient of SNP j for eGFR, here estimated from the UCLEB data (weights and odds ratios were calculated for the eGFR increasing alleles). This is an example of two-sample Mendelian randomization[18] in which the exposure and outcome associations are measured in different samples. We constructed an weighted gene score from 51 SNPs associated with CHD at genome-wide significance, as reported by CARDIoGRAMplusC4D14 and tested this score for association with eGFR in the UCLEB data using summary odds ratios as above

Results

Discussion

Author Contributions

Additional Information