Vitamin D and Risk of Vascular Disease and Mortality: A Mendelian Randomisation Study Involving 99,012 Chinese and 106,911 European Adults

Abstract

Background: Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) levels are inversely associated with risks of cardiovascular diseases, but it is unclear if these associations are causal, in Chinese or European adults. Objectives: We examined the causal association of 25(OH)D with risk of vascular disease and mortality among both Chinese and Europeans. Methods: We 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 DCHR7 gene and in the CYP2R1 gene were genotyped in 99,012 Chinese adults and 106,911 Danish adults. Results: In Chinese adults, plasma 25(OH)D levels were not significantly associated with cardiovascular disease or cause-specific or all-cause 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 cardiovascular diseases, cause-specific and all-cause mortality. MR analysis did not demonstrate causal associations of genetically increased 25(OH)D levels with incident cardiovascular diseases, and cause-specific mortality in both Chinese and European adults, except for a marginal association for all-cause mortality (HR, 0.98 [95% CI, 0.96, 1.00] and cancer mortality (HR, 0.97 [95% CI, 0.94, 1.01] per 25 nmol/L higher plasma 25[OH]D) in European adults. However, each 25 nmol/L higher genetically increased 25(OH)D level was associated with 0.58 mmol/L lower TC and 0.34 mmol/L lower LDL among Chinese adults. Conclusions: We found no evidence to suggest that genetically increased 25(OH)D was associated with a lower risk of cardiovascular diseases in both Chinese and European adults. Higher genetically increased 25(OH)D levels were inversely associated with all-cause and cancer mortality in Europeans, but not in Chinese adults. These results suggest that the inverse associations of vitamin D with vascular diseases are a marker of some other condition, but are not due to vitamin D and could be the result of confounding. Funding Statement: This work was supported by grants (2016YFC0900500, 2016YFC0900501, 2016YFC0900504) from the National Key R&D Program of China. The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term followup is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), National Natural Science Foundation of China (81390540, 81390544, 81390541), and Chinese Ministry of Science and Technology (2011BAI09B01). The funders had no role in the study design, data collection, data analysis and interpretation, writing of the report, or the decision to submit the article for publication. Declaration of Interests: none declared. Ethics Approval Statement: Ethics approval was obtained from the relevant local, national and international ethics committees.