No evidence that genetically reduced 25-hydroxyvitamin D is associated with increased risk of ischaemic heart disease or myocardial infarction: a Mendelian randomization study

TY - JOUR

T1 - No evidence that genetically reduced 25-hydroxyvitamin D is associated with increased risk of ischaemic heart disease or myocardial infarction

T2 - a Mendelian randomization study

AU - Brøndum-Jacobsen, Peter

AU - Benn, Marianne

AU - Afzal, Shoaib

AU - Nordestgaard, Børge G

N1 - © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

PY - 2015/5/27

Y1 - 2015/5/27

N2 - Background: Low plasma 25-hydroxyvitamin D [p-25(OH)D] is associated with increased risk of ischaemic heart disease and with the subgroup myocardial infarction. However, whether this association is causal or due to confounding or reverse causation is presently unknown. We tested the hypothesis that genetically reduced plasma 25(OH)D is associated with increased risk of ischaemic heart disease and myocardial infarction. Methods: We used a Mendelian randomization design in the Copenhagen City Heart Study, the Copenhagen General Population Study, and the Copenhagen Ischaemic Heart Disease Study. Two 25(OH)D reducing genetic variants in the DCHR7 gene (rs7944926 and rs11234027) and two in the CYP2R1 gene (rs10741657 and rs12794714) were genotyped in 92 416 participants of Danish descent, of whom 14 455 developed ischaemic heart disease (ICD-8:410-414; ICD-10:I20-I25) and 7061 myocardial infarction (ICD-8:410: ICD-10:I21-I22) from 1977 through 2011. P-25(OH)D was measured in 36 089 participants. APOE genotype was included as a positive control for risk of ischaemic heart disease. Results: The multivariable adjusted hazard ratios for lowest vs highest quartile of 25(OH)D were 1.82 [95% confidence interval (CI): 1.42-2.32] for ischaemic heart disease. Each allele increase in a combined allele score was associated with a 1.9-nmol/l decrease in p-25(OH)D (P=7×10-55; R2=0.9%). The genetic variants were, however, not associated with increased risk of ischaemic heart disease. In instrumental variable analysis, the odds ratio for ischaemic heart disease for a genetically 25-nmol/l decrease in p-25(OH)D was 0.98 (95% CI: 0.76-1.26), with a corresponding observational hazard ratio by Cox regression of 1.07 (1.01-1.13). Similarly, with myocardial infarction as the outcome, observational analyses suggested an increased risk with lower 25(OH)D, whereas genetic analyses suggested no causal effect. For APOE genotype, the odds ratio for ischaemic heart disease for a 1-mmol/l genetic increase in plasma total cholesterol concentrations was 1.23 (1.08-1.41), with a corresponding observational hazard ratio of 1.08 (1.04-1.14). Conclusion: We found no evidence to suggest that genetically reduced p-25(OH)D is associated with increased risk of ischaemic heart disease or myocardial infarction.

AB - Background: Low plasma 25-hydroxyvitamin D [p-25(OH)D] is associated with increased risk of ischaemic heart disease and with the subgroup myocardial infarction. However, whether this association is causal or due to confounding or reverse causation is presently unknown. We tested the hypothesis that genetically reduced plasma 25(OH)D is associated with increased risk of ischaemic heart disease and myocardial infarction. Methods: We used a Mendelian randomization design in the Copenhagen City Heart Study, the Copenhagen General Population Study, and the Copenhagen Ischaemic Heart Disease Study. Two 25(OH)D reducing genetic variants in the DCHR7 gene (rs7944926 and rs11234027) and two in the CYP2R1 gene (rs10741657 and rs12794714) were genotyped in 92 416 participants of Danish descent, of whom 14 455 developed ischaemic heart disease (ICD-8:410-414; ICD-10:I20-I25) and 7061 myocardial infarction (ICD-8:410: ICD-10:I21-I22) from 1977 through 2011. P-25(OH)D was measured in 36 089 participants. APOE genotype was included as a positive control for risk of ischaemic heart disease. Results: The multivariable adjusted hazard ratios for lowest vs highest quartile of 25(OH)D were 1.82 [95% confidence interval (CI): 1.42-2.32] for ischaemic heart disease. Each allele increase in a combined allele score was associated with a 1.9-nmol/l decrease in p-25(OH)D (P=7×10-55; R2=0.9%). The genetic variants were, however, not associated with increased risk of ischaemic heart disease. In instrumental variable analysis, the odds ratio for ischaemic heart disease for a genetically 25-nmol/l decrease in p-25(OH)D was 0.98 (95% CI: 0.76-1.26), with a corresponding observational hazard ratio by Cox regression of 1.07 (1.01-1.13). Similarly, with myocardial infarction as the outcome, observational analyses suggested an increased risk with lower 25(OH)D, whereas genetic analyses suggested no causal effect. For APOE genotype, the odds ratio for ischaemic heart disease for a 1-mmol/l genetic increase in plasma total cholesterol concentrations was 1.23 (1.08-1.41), with a corresponding observational hazard ratio of 1.08 (1.04-1.14). Conclusion: We found no evidence to suggest that genetically reduced p-25(OH)D is associated with increased risk of ischaemic heart disease or myocardial infarction.

KW - Adult

KW - Denmark

KW - Female

KW - Genotype

KW - Humans

KW - Male

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Myocardial Infarction

KW - Myocardial Ischemia

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Risk Factors

KW - Vitamin D

U2 - 10.1093/ije/dyv078

DO - 10.1093/ije/dyv078

M3 - Journal article

C2 - 25981321

SN - 0300-5771

VL - 44

SP - 651

EP - 661

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 2

ER -