TY - JOUR

T1 - Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease

T2 - Observational and Mendelian Randomization Analyses

AU - Gaziano, Liam

AU - Sun, Luanluan

AU - Arnold, Matthew

AU - Bell, Steven

AU - Cho, Kelly

AU - Kaptoge, Stephen K.

AU - Song, Rebecca J.

AU - Burgess, Stephen

AU - Posner, Daniel C.

AU - Mosconi, Katja

AU - Robinson-Cohen, Cassianne

AU - Mason, Amy M.

AU - Bolton, Thomas R.

AU - Tao, Ran

AU - Allara, Elias

AU - Schubert, Petra

AU - Chen, Lingyan

AU - Staley, James R.

AU - Staplin, Natalie

AU - Altay, Servet

AU - Amiano, Pilar

AU - Arndt, Volker

AU - Ärnlöv, Johan

AU - Barr, Elizabeth L.M.

AU - Björkelund, Cecilia

AU - Boer, Jolanda M.A.

AU - Brenner, Hermann

AU - Casiglia, Edoardo

AU - Chiodini, Paolo

AU - Cooper, Jackie A.

AU - Coresh, Josef

AU - Cushman, Mary

AU - Dankner, Rachel

AU - Davidson, Karina W.

AU - De Jongh, Renate T.

AU - Donfrancesco, Chiara

AU - Engström, Gunnar

AU - Freisling, Heinz

AU - De La Cámara, Agustín Gómez

AU - Gudnason, Vilmundur

AU - Hankey, Graeme J.

AU - Hansson, Per Olof

AU - Heath, Alicia K.

AU - Hoorn, Ewout J.

AU - Kyrø, Cecilie

AU - Nordestgaard, Børge G.

AU - Tjønneland, Anne

AU - Tybjaerg-Hansen, Anne

AU - Afzal, Shoaib

AU - Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Program

N1 - Publisher Copyright: © 2022 The Authors.

PY - 2022

Y1 - 2022

N2 - Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

AB - Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

KW - cardiovascular diseases

KW - coronary disease

KW - kidney diseases

KW - stroke

U2 - 10.1161/CIRCULATIONAHA.122.060700

DO - 10.1161/CIRCULATIONAHA.122.060700

M3 - Journal article

C2 - 36314129

AN - SCOPUS:85143192673

VL - 146

SP - 1507

EP - 1517

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 20

ER -