遗传因素可能影响个体25-羟基维生素D[25(OH)D]的浓度,维生素D暴露的生物标志物以前与几种慢性疾病的风险降低有关。我们对血清25(OH)D(使用液相色谱-串联质谱法评估)和386,449个单核苷酸多态性(SNP)进行了全基因组关联研究。我们的样本包括从姐妹研究中随机选择的1,829名参与者,一群有一个姐姐患有乳腺癌但自己从未患过乳腺癌的女性。19,741个SNP与25(OH)D相关(p<0.05)。我们在1,534名后来患上乳腺癌的参与者的独立样本中重新评估了这些命中。汇集后,32个SNP具有全基因组显著关联(p<5×10-8)。这些位于GC或附近,维生素D结合蛋白,或CYP2R1,一种细胞色素P450酶,将维生素D羟基化形成25(OH)D。最受欢迎的是rs4588,这是一种错义的GC多态性,与每个次要等位基因拷贝的25(OH)D减少3.5ng/mL相关(95%置信区间[CI]:-4.1,-3.0;p=4.5×10-38)。CYP2R1附近最强的SNP是rs12794714,这是一个同义变体(p=3.8×10-12;β=1.8ng/mL每个次要等位基因25(OH)D减少[CI:-2.2,-1.3])。基线3-10年后从一些参与者收集的样本中血清25(OH)D浓度(811例,780个非病例)也与两个基因座密切相关。这些发现增强了我们对25(OH)D的遗传影响以及维生素D结合蛋白和细胞色素P450酶在确定测量水平中的可能作用的理解。这些结果可能有助于鉴定遗传上易患维生素D不足的个体。
Genetic factors likely influence individuals\' concentrations of 25-hydroxyvitamin D [25(OH)D], a biomarker of vitamin D exposure previously linked to reduced risk of several chronic diseases. We conducted a genome-wide association
study of serum 25(OH)D (assessed using liquid chromatography-tandem mass spectrometry) and 386,449 single nucleotide polymorphisms (SNPs). Our sample consisted of 1,829 participants randomly selected from the Sister
Study, a cohort of women who had a sister with breast cancer but had never had breast cancer themselves. 19,741 SNPs were associated with 25(OH)D (p < 0.05). We re-assessed these hits in an independent sample of 1,534 participants who later developed breast cancer. After pooling, 32 SNPs had genome-wide significant associations (p < 5 × 10-8). These were located in or near GC, the vitamin D binding protein, or
CYP2R1, a cytochrome P450 enzyme that hydroxylates vitamin D to form 25(OH)D. The top hit was rs4588, a missense GC polymorphism associated with a 3.5 ng/mL decrease in 25(OH)D per copy of the minor allele (95% confidence interval [CI]: -4.1, -3.0; p = 4.5 × 10-38). The strongest SNP near
CYP2R1 was rs12794714, a synonymous variant (p = 3.8 × 10-12; β = 1.8 ng/mL decrease in 25(OH)D per minor allele [CI: -2.2, -1.3]). Serum 25(OH)D concentrations from samples collected from some participants 3-10 years after baseline (811 cases, 780 non-cases) were also strongly associated with both loci. These findings augment our understanding of genetic influences on 25(OH)D and the possible role of vitamin D binding proteins and cytochrome P450 enzymes in determining measured levels. These results may help to identify individuals genetically predisposed to vitamin D insufficiency.