目的: 采用两样本孟德尔随机化研究维生素D与妊娠剧吐之间的因果关联。方法: 基于IEU OpenGWAS project网站,搜寻样本量最大的维生素D的GWAS数据集以及妊娠剧吐的GWAS数据集。从ieu-b-4808库中选取维生素D强相关的SNPs,设置P＜5×10-8且连锁不平衡系数0.001及其区域宽度10 000 kb;从finn-b-O15_EXCESS_VOMIT_PREG中选择妊娠剧吐关联SNPs。合并数据集纳入174个SNPs为工具变量。采用随机效应逆方差加权(IVW)、 MR-Egger、加权中值、加权模型等4种回归模型分析维生素D与妊娠剧吐之间的关联。结果: MR-Egger回归截距项是0.005,相应P值为0.513,提示SNPs没有基因多效性。IVW回归结果发现OR(95%CIs)是0.478(0.303~0.753),P值为0.001;MR-Egger、加权中值、加权模型结果与IVW结果类似。IVW和MR-Egger回归的Cochran’s Q值分别为143.733(P=0.893)和143.303(P=0.888),提示SNPs间没有异质性。结论: 维生素D是妊娠剧吐的保护因素。
Objective: To study the causal relationship between vitamin D and hyperemesis gravidarum by two-sample Mendelian randomization. Methods: Based on the IEU OpenGWAS project website, the GWAS data set of vitamin D with the largest sample size and the GWAS data set of hyperemesis gravidarum were searched. The SNPs strongly associated with vitamin D were selected from the ieu-b-4808 library, and P＜5×10-8 with a linkage disequilibrium coefficient of 0.001 and a region width of 10 000 kb were set. SNPs associated with hyperemesis gravidarum were selected from finn-b-O15_EXCESS_VOMIT_PREG. The combined data set included 174 SNPs as instrumental variables. The association between vitamin D and hyperemesis gravidarum was analyzed by four regression models: random effect inverse variance weighting (IVW), MR-Egger, weighted median, and weighted model. Results: The MR-Egger regression intercept was 0.005, and the corresponding P value was 0.513, suggesting that the SNPs had no gene pleiotropy. IVW regression results showed that OR(95%CIs) was 0.478(0.303-0.753), P value was 0.001; the results of MR-Egger, weighted median and weighted model were similar to those of IVW. The Cochran's Q values of IVW and MR-Egger regression were 143.733(P=0.893) and 143.303(P=0.888), respectively, suggesting that there was no heterogeneity between SNPs. Conclusion: Vitamin D is one of the protective factors of hyperemesis gravidarum in pregnancy.
[1] Jarvis S, Nelson-Piercy C. Management of nausea and vomiting in pregnancy[J]. BMJ, 2011,342:d3606.
[2] Einarson TR, Piwko C, Koren G. Quantifying the global rates of nausea and vomiting of pregnancy: a meta analysis[J]. J Popul Ther Clin Pharmacol, 2013,20(2):e171-e183.
[3] Bailit JL. Hyperemesis gravidarium: Epidemiologic findings from a large cohort[J]. Am J Obstet Gynecol, 2005,193(3):811-814.
[4] Kuru O, Sen S, Akbayır O, et al. Outcomes of pregnancies complicated by hyperemesis gravidarum[J]. Arch Gynecol Obstet, 2012,285(6):1517-1521.
[5] Popa SL, Barsan M, Caziuc A, et al. Life-threatening complications of hyperemesis gravidarum[J]. Exp Ther Med, 2021,21(6):642.
[6] Latva-Pukkila U, Isolauri E, Laitinen K. Dietary and clinical impacts of nausea and vomiting during pregnancy[J]. J Hum Nutr Diet, 2010,23(1):69-77.
[7] Goodwin TM, Poursharif B, Korst LM, et al. Secular trends in the treatment of hyperemesis gravidarum[J]. Am J Perinatol, 2008,25(3):141-147.
[8] Robinson JN, Banerjee R, Thiet MP. Coagulopathy secondary to vitamin K deficiency in hyperemesis gravidarum[J]. Obstet Gynecol, 1998,92(4):673-675.
[9] Ishii K, Komaki H, Ohkuma A, et al. Central nervous system and muscle involvement in an adolescent patient with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency[J]. Brain Dev, 2010,32(8):669-672.
[10] Jwa SC, Ogawa K, Kobayashi M, et al. Validation of a food-frequency questionnaire for assessing vitamin intake of Japanese women in early and late pregnancy with and without nausea and vomiting[J]. J Nutr Sci, 2016,5:e27.
[11] Pagoni P, Dardani C, Leppert B, et al. Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer's disease[J]. Transl Psychiatry, 2022,12(1):422.
[12] Bowden J, Smith GD, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression[J]. Int J Epidemiol, 2015,44(2):512-525.
[13] Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted Median estimator[J]. Genet Epidemiol, 2016,40(4):304-314.
[14] Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method[J]. Eur J Epidemiol, 2017,32(5):377-389.
[15] Nijsten K, Van Der Minnen L, Wiegers HMG, et al. Hyperemesis gravidarum and vitamin K deficiency: a systematic review[J]. Br J Nutr, 2022,128(1):30-42.
[16] Hu YC, Amoah AN, Zhang H, et al. Effect of ginger in the treatment of nausea and vomiting compared with vitamin B6 and placebo during pregnancy: a meta-analysis[J]. J Matern Fetal Neonatal Med, 2022,35(1):187-196.
[17] Da Silveira EA, Moura LANE, Castro MCR, et al. Prevalence of vitamin D and calcium deficiency and insufficiency in women of childbearing age and associated risk factors: a systematic review and meta-analysis[J]. Nutrients, 2022,14(20):4351.
[18] Morales-Suárez-Varela M, Uçar N, Soriano JM, et al. Vitamin D-related risk factors for maternal morbidity and mortality during pregnancy: systematic review and meta-analysis[J]. Nutrients, 2022,14(19):4124.
[19] Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epidemiol, 2013,37(7):658-665.
[20] Kaló Z, Holtorf AP, Alfonso-Cristancho R, et al. Need for multicriteria evaluation of generic drug policies[J]. Value Health, 2015,18(2):346-351.
[21] 申亚男. 基于多个遗传变异的两样本孟德尔随机化法在因果关联研究中的应用[D]. 太原: 山西医科大学, 2018.
[22] 秦雪英, 陈大方, 胡永华. 孟德尔随机化方法在流行病学病因推断中的应用[J]. 中华流行病学杂志, 2006, 27(7): 630-633.
