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

Maria Magnus, Kozeta Miliku, Anna Bauer, Stephanie Engel, Janine F Felix, Vincent W V Jaddoe, Debbie Lawlor, Stephanie London, Per Magnus, Ralph McGinnis, Wenche Nystad, Christian Page, Fernando Rivadeneira, Lars Stene, German Tapia, Nicholas Williams, Carolina Bonilla, Abigail Fraser

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Abstract

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.
Original languageEnglish
Article numberk2167
Number of pages9
JournalBMJ
Volume361
DOIs
Publication statusPublished - 20 Jun 2018

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  • Projects

    NIHR BRC Reproductive

    Lawlor, D. A.

    1/04/1731/03/22

    Project: Research

    Cite this

    Magnus, M., Miliku, K., Bauer, A., Engel, S., Felix, J. F., Jaddoe, V. W. V., Lawlor, D., London, S., Magnus, P., McGinnis, R., Nystad, W., Page, C., Rivadeneira, F., Stene, L., Tapia, G., Williams, N., Bonilla, C., & Fraser, A. (2018). Vitamin D and risk of pregnancy related hypertensive disorders: mendelian randomisation study. BMJ, 361, [k2167]. https://doi.org/10.1136/bmj.k2167u