Baca Katharyn M, Govil Manika, Zmuda Joseph M, Simhan Hyagriv N, Marazita Mary L, Bodnar Lisa M
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Eur J Obstet Gynecol Reprod Biol. 2018 Jan;220:61-68. doi: 10.1016/j.ejogrb.2017.11.013. Epub 2017 Nov 16.
Several candidate genes and genome wide association studies have reported significant associations between vitamin D metabolism genes and 25-hydroxyvitamin D. Few studies have examined these relationships in pregnancy.
We evaluated the relationship between maternal allelic variants in three vitamin D metabolism genes and 25-hydroxyvitamin D (25(OH)D) concentration in pregnancy.
In two case-control studies, samples were drawn from women who delivered at Magee Womens Hospital in Pittsburgh, PA from 1999 to 2010 and twelve recruiting sites across the United States from 1959 to 65. For 882 Black and 1796 White pregnant women from these studies, 25(OH)D concentration was measured and single nucleotide polymorphisms (SNPs) were genotyped 50 kilobases up- and down-stream in three genes (VDR, GC, and CYP27B1). Using multivariable linear regression, we estimated the associations between allelic variation of each locus and log-transformed 25(OH)D concentration separately by race and study group. Meta-analysis was used to estimate the association across the four groups for each SNP.
Minor alleles of several variants in VDR, GC, and CYP27B1 were associated with differences in log-transformed 25(OH)D concentration compared to the corresponding major alleles [beta, 95% confidence intervals (CI)]. The meta-analysis confirmed the associations for differences in log-transformed 25(OH)D by allelic loci for one intron VDR variant [rs2853559 0.08 (0.02, 0.13), p<0.01] and a variant in the GC flanking region [rs13150174: 0.04 (0.02, 0.07), p<0.01], and a GC missense mutation [rs7041 0.05 (0.01, 0.09), p<0.01]. The meta-analysis also revealed possible associations for SNPs in linkage disequilibrium with variants in the VDR 3-prime untranslated region, another GC missense variant (rs4588), and a variant of the 3-prime untranslated region of CYP27B1.
We observed associations between VDR, GC, and CYP27B1 variants and maternal 25-hydroxyvitamin D concentration. Our results provide additional support for a possible role of genetic variation in vitamin D metabolism genes on vitamin D status during pregnancy.
多项候选基因及全基因组关联研究报告了维生素D代谢基因与25-羟维生素D之间存在显著关联。很少有研究在孕期中探究这些关系。
我们评估了三种维生素D代谢基因中母亲的等位基因变异与孕期25-羟维生素D（25(OH)D）浓度之间的关系。
在两项病例对照研究中，样本取自1999年至2010年在宾夕法尼亚州匹兹堡市梅杰妇女医院分娩的女性，以及1959年至1965年美国各地的12个招募点。在这些研究中的882名黑人孕妇和1796名白人孕妇中，测量了25(OH)D浓度，并对三个基因（维生素D受体（VDR）、维生素D结合蛋白（GC）和细胞色素P450 27B1（CYP27B1））上下游50千碱基内的单核苷酸多态性（SNP）进行基因分型。使用多变量线性回归，我们分别按种族和研究组估计了每个基因座的等位基因变异与对数转换后的25(OH)D浓度之间的关联。采用荟萃分析来估计每个SNP在四组中的关联。
与相应的主要等位基因相比，VDR、GC和CYP27B1中几个变异的次要等位基因与对数转换后的25(OH)D浓度差异相关[β，95%置信区间（CI）]。荟萃分析证实了一个VDR内含子变异[rs2853559 0.08（0.02，0.13），p<0.01]、GC侧翼区域的一个变异[rs13150174：0.04（0.02，0.07），p<0.01]以及一个GC错义突变[rs7041 0.05（0.01，0.09），p<0.01]的等位基因座与对数转换后的25(OH)D差异之间的关联。荟萃分析还揭示了与VDR 3'非翻译区变异、另一个GC错义变异（rs4588）以及CYP27B1 3'非翻译区变异处于连锁不平衡状态的SNP可能存在的关联。
我们观察到VDR、GC和CYP27B1变异与母亲的25-羟维生素D浓度之间存在关联。我们的结果为维生素D代谢基因的遗传变异对孕期维生素D状态可能发挥的作用提供了更多支持。
