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 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.
authors.affiliation: Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, UK.|Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Thailand.
authors.forename: Pimphen
authors.initials: P
authors.lastname: Charoen
authors.affiliation: Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, UK.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Nitsch
authors.affiliation: Institute of Cardiovascular Science, University College London, UK.
authors.forename: Jorgen
authors.initials: J
authors.lastname: Engmann
authors.affiliation: Institute of Cardiovascular Science, University College London, UK.
authors.forename: Tina
authors.initials: T
authors.lastname: Shah
authors.affiliation: University College London Genetics Institute, Department of Genetics, Environment and Evolution, University College London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: White
authors.affiliation: Institute of Psychiatry, Psychology &Neuroscience, King's College London, UK.
authors.forename: Delilah
authors.initials: D
authors.lastname: Zabaneh
authors.affiliation: Department of Primary Care &Population Health, University College London, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jefferis
authors.affiliation: Department of Primary Care &Population Health, University College London, UK.
authors.forename: Goya
authors.initials: G
authors.lastname: Wannamethee
authors.affiliation: Population Health Research Institute, St George's, University of London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Whincup
authors.affiliation: Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Mulick Cassidy
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Gaunt
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Day
authors.affiliation: Centre for Population Health Sciences, The Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, UK.
authors.forename: Stela
authors.initials: S
authors.lastname: McLachlan
authors.affiliation: Centre for Population Health Sciences, The Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Price
authors.affiliation: Institute for Social and Economic Research, University of Essex, UK.|Department of Epidemiology and Public Health, University College London, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.affiliation: Department of Epidemiology and Public Health, University College London, UK.
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.affiliation: Department of Epidemiology and Public Health, University College London, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Brunner
authors.affiliation: Farr Institute of Health Informatics, University College London, UK.|MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: School of Social and Community Medicine, University of Bristol, UK.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.affiliation: Institute of Cardiovascular Science, University College London, UK.
authors.forename: Aroon
authors.initials: A
authors.lastname: Hingorani
authors.affiliation: Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, UK.|Genetics Division, Research and Development, GlaxoSmithKline, UK.
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.affiliation: Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, UK.|Farr Institute of Health Informatics, University College London, UK.
authors.forename: Juan
authors.initials: J
authors.lastname: Pablo Casas
authors.affiliation: Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
mesh_terms: D003327:Coronary Disease / Q000378:metabolism / Q000503:physiopathology*; D055106:Genome-Wide Association Study; D005919:Glomerular Filtration Rate / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D057182:Mendelian Randomization Analysis; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors