Vitamin D and risk of pregnancy related hypertensive disorders: mendelian randomisation study

Objective: To use Mendelian randomization to investigate whether 25-hydroxyvitamin D (25(OH)D) has a causal effect on gestational hypertension and/or pre-eclampsia. Design: We conducted both a one-sample (7,389 women from two European pregnancy-cohorts, 751 gestational hypertension cases and 135 pre-eclampsia cases) and a two-sample (3,388 pre-eclampsia cases and 6,059 controls from two case-control studies) Mendelian randomization analysis. Setting: Europe. Participants: Women participating in the Avon Longitudinal Study of Parents and Children, Generation R, the Norwegian Mother and Child Cohort Study, and the UK Genetics of pre-eclampsia study. Exposures: Single nucleotide polymorphisms (SNPs) in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables. Main Outcome Measure: gestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy. Results: In the conventional multivariable analysis, the RR for pre-eclampsia was 1.03 (95% Confidence Interval: 1.00 to 1.07) per 10% decrease in 25(OH)D, and 2.04 (1.02 to 4.07) when comparing 25(OH)D levels <25 nmol/L to ≥75 nmol/L. There was no association with gestational hypertension. The one-sample Mendelian randomization analysis using the total genetic risk score as an instrument did not provide strong evidence of a linear effect of 25(OH)D on the risk of gestational hypertension or pre-eclampsia: OR 0.90 (0.78 to 1.03) and 1.19 (0.92 to 1.52) per 10% decrease, respectively. The two-sample Mendelian randomization estimate yielded an OR for pre-eclampsia of 0.98 (0.89 to 1.07) per 10% decrease in 25(OH)D; an OR of 0.96 (0.80 to 1.15) per unit increase in the log(odds) of 25(OH)D levels <75 nmol/L; and an OR of 0.93 (0.73 to 1.19) per unit increase in the log(odds) of 25(OH)D levels <50 nmol/L. Conclusions: In conclusion, Mendelian randomization analyses using the largest available sample yielded no strong evidence to support a causal effect of vitamin D status on gestational hypertension or pre-eclampsia. Future Mendelian randomization studies with a larger number of pre-eclampsia cases and/or more genetic instruments that would increase the proportion of 25(OH)D explained by the instrument are needed.