Objective To use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia. Design One and two sample mendelian randomisation analyses. Setting Two European pregnancy cohorts (Avon Longitudinal Study of Parents and Children, and Generation R Study), and two case-control studies (subgroup nested within the Norwegian Mother and Child Cohort Study, and the UK Genetics of Pre-eclampsia Study). Participants 7389 women in a one sample mendelian randomisation analysis (751 with gestational hypertension and 135 with pre-eclampsia), and 3388 pre-eclampsia cases and 6059 controls in a two sample mendelian randomisation analysis. Exposures Single nucleotide polymorphisms in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables. Main outcome measures 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 relative risk for pre-eclampsia was 1.03 (95% confidence interval 1.00 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, and 2.04 (1.02 to 4.07) for 25-hydroxyvitamin D levels <25 nmol/L compared with ≥75 nmol/L. No association was found for gestational hypertension. The one sample mendelian randomisation analysis using the total genetic risk score as an instrument did not provide strong evidence of a linear effect of 25-hydroxyvitamin D on the risk of gestational hypertension or pre-eclampsia: Odds ratio 0.90 (95% confidence interval 0.78 to 1.03) and 1.19 (0.92 to 1.52) per 10% decrease, respectively. The two sample mendelian randomisation estimate gave an odds ratio for pre-eclampsia of 0.98 (0.89 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, an odds ratio of 0.96 (0.80 to 1.15) per unit increase in the log(odds) of 25-hydroxyvitamin D level <75 nmol/L, and an odds ratio of 0.93 (0.73 to 1.19) per unit increase in the log(odds) of 25-hydroxyvitamin D levels <50 nmol/L. Conclusions No strong evidence was found to support a causal effect of vitamin D status on gestational hypertension or pre-eclampsia. Future mendelian randomisation studies with a larger number of women with pre-eclampsia or more genetic instruments that would increase the proportion of 25-hydroxyvitamin D levels explained by the instrument are needed.

Additional Metadata
Persistent URL dx.doi.org/10.1136/bmj.k2167, hdl.handle.net/1765/109024
Journal BMJ (Online)
Citation
Magnus, M.C. (Maria C.), Miliku, K, Bauer, A. (Anna), Engel, S.M. (Stephanie M.), Felix, J.F. (Janine F.), Jaddoe, V.W.V, … Fraser, A. (Abigail). (2018). Vitamin D and risk of pregnancy related hypertensive disorders: Mendelian randomisation study. BMJ (Online), 361. doi:10.1136/bmj.k2167


See Also
review
Vitamin D and Risk of Pregnancy-Related Hypertensive Disorders: Mendelian Randomization Study
Magnus, M.C. (Maria C.), K. Miliku (Kozeta), Bauer, A. (Anna), Engel, S.M. (Stephanie M.), Felix, J.F. (Janine F.), V.W.V. Jaddoe (Vincent), Lawlor, D.A. (Debbie A.), S.J. London (Stephanie J.), P. Magnus (Per), McGinnis, R. (Ralph), et al. W. Nystad (Wenche), Page, C.M. (Christian M.), F. Rivadeneira Ramirez (Fernando), Stene, L.C. (Lars C.), Tapia, G. (German), Williams, N. (Nicholas), C. Bonilla (Carolina) and Fraser, A. (Abigail)