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

Pimphen Charoen; Dorothea Nitsch; Jorgen E L Engmann; Tina Shah; Jonathan White; Delilah Zabaneh; Barbara J Jefferis; S Goya Wannamethee; Peter H Whincup; Amy Mulick Cassidy; Tom Gaunt; Ian Day; Stela McLachlan; Jacqueline F Price; Meena Kumari; Mika Kivimäki; Eric J Brunner; Claudia Langenberg; Yoav Ben-Shlomo; Aroon D Hingorani; John Whittaker; Juan-Pablo Casas; Frank Dudbridge

doi:10.1038/srep28514

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

Pimphen Charoen, Dorothea Nitsch, Jorgen E L Engmann, Tina Shah, Jonathan White, Delilah Zabaneh, Barbara J Jefferis, S Goya Wannamethee, Peter H Whincup, Amy Mulick Cassidy, Tom Gaunt, Ian Day, Stela McLachlan, Jacqueline F Price, Meena Kumari, Mika Kivimäki, Eric J Brunner, Claudia Langenberg, Yoav Ben-Shlomo, Aroon D HingoraniJohn Whittaker, Juan-Pablo Casas, Frank Dudbridge

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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 risk 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.

Original language	English
Article number	28514
Number of pages	8
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep28514
Publication status	Published - 24 Jun 2016

Keywords

Cardiology
Genetics

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Charoen, P., Nitsch, D., Engmann, J. E. L., Shah, T., White, J., Zabaneh, D., Jefferis, B. J., Goya Wannamethee, S., Whincup, P. H., Mulick Cassidy, A., Gaunt, T., Day, I., McLachlan, S., Price, J. F., Kumari, M., Kivimäki, M., Brunner, E. J., Langenberg, C., Ben-Shlomo, Y., ... Dudbridge, F. (2016). Mendelian Randomisation study of the influence of eGFR on coronary heart disease. Scientific Reports, 6, Article 28514. https://doi.org/10.1038/srep28514

@article{78ca52a8afa8438b94595ca001664d95,

title = "Mendelian Randomisation study of the influence of eGFR on coronary heart disease",

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 risk 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. ",

keywords = "Cardiology, Genetics",

author = "Pimphen Charoen and Dorothea Nitsch and Engmann, {Jorgen E L} and Tina Shah and Jonathan White and Delilah Zabaneh and Jefferis, {Barbara J} and {Goya Wannamethee}, S and Whincup, {Peter H} and {Mulick Cassidy}, Amy and Tom Gaunt and Ian Day and Stela McLachlan and Price, {Jacqueline F} and Meena Kumari and Mika Kivim{\"a}ki and Brunner, {Eric J} and Claudia Langenberg and Yoav Ben-Shlomo and Hingorani, {Aroon D} and John Whittaker and Juan-Pablo Casas and Frank Dudbridge",

year = "2016",

month = jun,

day = "24",

doi = "10.1038/srep28514",

language = "English",

volume = "6",

journal = "Scientific Reports",

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Charoen, P, Nitsch, D, Engmann, JEL, Shah, T, White, J, Zabaneh, D, Jefferis, BJ, Goya Wannamethee, S, Whincup, PH, Mulick Cassidy, A, Gaunt, T, Day, I, McLachlan, S, Price, JF, Kumari, M, Kivimäki, M, Brunner, EJ, Langenberg, C, Ben-Shlomo, Y, Hingorani, AD, Whittaker, J, Casas, J-P & Dudbridge, F 2016, 'Mendelian Randomisation study of the influence of eGFR on coronary heart disease', Scientific Reports, vol. 6, 28514. https://doi.org/10.1038/srep28514

TY - JOUR

T1 - Mendelian Randomisation study of the influence of eGFR on coronary heart disease

AU - Charoen, Pimphen

AU - Nitsch, Dorothea

AU - Engmann, Jorgen E L

AU - Shah, Tina

AU - White, Jonathan

AU - Zabaneh, Delilah

AU - Jefferis, Barbara J

AU - Goya Wannamethee, S

AU - Whincup, Peter H

AU - Mulick Cassidy, Amy

AU - Gaunt, Tom

AU - Day, Ian

AU - McLachlan, Stela

AU - Price, Jacqueline F

AU - Kumari, Meena

AU - Kivimäki, Mika

AU - Brunner, Eric J

AU - Langenberg, Claudia

AU - Ben-Shlomo, Yoav

AU - Hingorani, Aroon D

AU - Whittaker, John

AU - Casas, Juan-Pablo

AU - Dudbridge, Frank

PY - 2016/6/24

Y1 - 2016/6/24

N2 - 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 risk 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.

AB - 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 risk 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.

KW - Cardiology

KW - Genetics

U2 - 10.1038/srep28514

DO - 10.1038/srep28514

M3 - Article (Academic Journal)

C2 - 27338949

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 28514

ER -

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

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