Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK
Department of Population Health Sciences, Bristol Medical School, Bristol, UK.
BMJ. 2018 Jun 20;361:k2167. doi: 10.1136/bmj.k2167.
To use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia.
One and two sample mendelian randomisation analyses.
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).
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.
Single nucleotide polymorphisms in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables.
Gestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy.
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.
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.
利用孟德尔随机化研究 25-羟维生素 D 浓度是否对妊娠期高血压或子痫前期有因果影响。
单样本和双样本孟德尔随机化分析。
两个欧洲妊娠队列（雅芳纵向父母与子女研究和世代研究），以及两个病例对照研究（嵌套于挪威母亲和儿童队列研究的亚组和英国子痫前期遗传学研究）。
单样本孟德尔随机化分析中 7389 名女性（751 名患有妊娠期高血压，135 名患有子痫前期），双样本孟德尔随机化分析中 3388 名子痫前期病例和 6059 名对照。
与维生素 D 合成（rs10741657 和 rs12785878）和代谢（rs6013897 和 rs2282679）相关的基因中的单核苷酸多态性被用作工具变量。
根据国际妊娠高血压学会的标准，定义妊娠期高血压和子痫前期。
在常规多变量分析中，25-羟维生素 D 水平每降低 10%，子痫前期的相对风险为 1.03（95%置信区间 1.00 至 1.07），25-羟维生素 D 水平<25 nmol/L 与≥75 nmol/L 相比为 2.04（1.02 至 4.07）。未发现与妊娠期高血压相关的关联。使用总遗传风险评分作为工具的单样本孟德尔随机化分析未提供 25-羟维生素 D 对妊娠期高血压或子痫前期风险的线性影响的有力证据：每降低 10%的比值比分别为 0.90（95%置信区间 0.78 至 1.03）和 1.19（0.92 至 1.52）。双样本孟德尔随机化估计对子痫前期的比值比为每降低 10%的 25-羟维生素 D 水平为 0.98（0.89 至 1.07），25-羟维生素 D 水平<75 nmol/L 的对数（优势）每增加一个单位为 0.96（0.80 至 1.15），25-羟维生素 D 水平<50 nmol/L 的对数（优势）每增加一个单位为 0.93（0.73 至 1.19）。
没有强有力的证据支持维生素 D 状态对妊娠期高血压或子痫前期有因果影响。需要进行具有更多子痫前期女性或更多遗传工具的孟德尔随机化研究，这些工具可以增加工具解释的 25-羟维生素 D 水平的比例。
