Vitamin D and cause-specific vascular disease and mortality: a Mendelian randomisation study involving 99,012 Chinese and 106,911 European adults

On Behalf Of The China Kadoorie Biobank Collaborative Group ,Tao Huang,Ningyu Chen,Zheng Bian,Liming Li,Yu Guo,Ruqin Gao,Ling Yang,Zhengming Chen,Jun Lv,Yiping Chen,Børge G Nordestgaard,Canqing Yu,Iona Y Millwood,Robin G Walters,Junshi Chen,Shoaib Afzal,Christina Ellervik,Robert Clarke

doi:10.1186/s12916-019-1401-y

Abstract

BackgroundRandomised control trials and genetic analyses have demonstrated that vitamin D or 25-hydroxyvitamin D (25[OH]D) levels may not play a causal role in the development of cardiovascular disease. However, it is unclear if 25(OH)D is causally associated with cause-specific vascular disease and lipids. Therefore, we examined the causal association of 25(OH)D with myocardial infarction, stroke, ischaemic heart disease, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and lipid levels among both Chinese and Europeans.MethodsWe used a Mendelian randomisation (MR) design in the China Kadoorie Biobank, the Copenhagen City Heart Study, and the Copenhagen General Population Study. The 25(OH)D-related genetic variants in the CYP2R1 and DCHR7 genes were genotyped in 99,012 Chinese adults and 106,911 Danish adults.ResultsIn Chinese adults, plasma 25(OH)D levels were not significantly associated with cause-specific vascular disease or mortality, with the exception of intracerebral haemorrhage (HR, 1.09 [95% CI, 1.01,1.18] per 25 nmol/L higher plasma 25(OH)D). In Europeans, plasma 25(OH)D levels were inversely associated with all types of vascular diseases and mortality. However, MR analysis did not demonstrate causal associations of genetically increased 25(OH)D levels with cause-specific vascular diseases, or mortality in both Chinese and European adults. In addition, each 25 nmol/L higher 25(OH)D was observationally associated with lower total cholesterol and low-density lipoprotein cholesterol levels, but higher high-density lipoprotein cholesterol levels. Likewise, MR analysis showed that 25(OH)D levels were not causally associated with lipids in both Chinese and European adults after Bonferroni correction.ConclusionsWe found no evidence to support that genetically increased 25(OH)D was associated with a lower risk of ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and lipid levels in both Chinese and European adults. These results suggest that the inverse associations of vitamin D with vascular disease could be the result of confounding.

Highlights

Randomised control trials and genetic analyses have demonstrated that vitamin D or 25-hydroxyvitamin D (25[OH]D) levels may not play a causal role in the development of cardiovascular disease
Outcomes The present study examined major coronary events, major vascular events [I60 and I64], intracerebral haemorrhage (I61), ischaemic stroke (I63), and cardiovascular death (I00-I99) as the primary outcomes in the China Kadoorie Biobank (CKB)
[95% CI, 0.98,1.07]), major coronary events (HR, 0.98 [95% CI, 0.89,1.07]), myocardial infarction (HR, 0.99 [95% CI, 0.89,1.12]), stroke (HR, 1.04 [95% CI, 0.99,1.10]), ischaemic stroke (HR, 0.99[95% CI, 0.93,1.07]), subarachnoid haemorrhage (HR, 1.24 [95% CI, 0.83,1.85]), and ischaemic heart disease (HR, 0.98 [95% CI, 0.89,1.07]) after adjustment for age, sex, smoking status, alcohol intake, season, region, systolic blood pressure (SBP), and physical activity

Summary

Introduction

Randomised control trials and genetic analyses have demonstrated that vitamin D or 25-hydroxyvitamin D (25[OH]D) levels may not play a causal role in the development of cardiovascular disease It is unclear if 25(OH)D is causally associated with cause-specific vascular disease and lipids. We examined the causal association of 25(OH)D with myocardial infarction, stroke, ischaemic heart disease, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and lipid levels among both Chinese and Europeans. The causal associations between 25(OH)D and cause-specific vascular disease such as stroke, ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and lipid levels have not been examined among European and Chinese adults. This question has important public health relevance, as about half of the population have vitamin D deficiency and regularly take vitamin D supplements [16], but without proper scientific evidence for any beneficial effect on many disease outcomes

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