Moy Kristin A, Mondul Alison M, Zhang Han, Weinstein Stephanie J, Wheeler William, Chung Charles C, Männistö Satu, Yu Kai, Chanock Stephen J, Albanes Demetrius
From the Nutritional Epidemiology Branch (KAM, AMM, SJW, and DA), Biostatistics Branch (HZ and KY), Cancer Genomics Research Laboratory (CCC), and Office of the Director (SJC), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; Information Management Services Inc, Silver Spring, MD (WW); and the Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (SM).
Am J Clin Nutr. 2014 Jun;99(6):1424-31. doi: 10.3945/ajcn.113.080309. Epub 2014 Apr 16.
Vitamin D status may influence a spectrum of health outcomes, including osteoporosis, arthritis, cardiovascular disease, and cancer. Vitamin D-binding protein (DBP) is the primary carrier of vitamin D in the circulation and regulates the bioavailability of 25-hydroxyvitamin D. Epidemiologic studies have shown direct DBP-risk relations and modification by DBP of vitamin D-disease associations.
We aimed to characterize common genetic variants that influence the DBP biochemical phenotype.
We conducted a genome-wide association study (GWAS) of 1380 men through linear regression of single-nucleotide polymorphisms (SNPs) in the Illumina HumanHap500/550/610 array on fasting serum DBP, assuming an additive genetic model, with adjustment for age at blood collection.
We identified 2 independent SNPs located in the gene encoding DBP, GC, that were highly associated with serum DBP: rs7041 (P = 1.42 × 10⁻²⁴⁶) and rs705117 (P = 4.7 × 10⁻⁹¹). For both SNPs, mean serum DBP decreased with increasing copies of the minor allele: mean DBP concentrations (nmol/L) were 7335, 5149, and 3152 for 0, 1, and 2 copies of rs7041 (T), respectively, and 6339, 4280, and 2341, respectively, for rs705117 (G). DBP was also associated with rs12144344 (P = 5.9 × 10⁻⁷) in ST6GALNAC3.
In this GWAS analysis, to our knowledge the first to examine this biochemical phenotype, 2 variants in GC--one exonic and one intronic--were associated with serum DBP concentrations at the genome-wide level of significance. Understanding the genetic contributions to circulating DBP may provide greater insights into the vitamin D binding, transport, and other functions of DBP and the effect of vitamin D status on health outcomes.
维生素D状态可能会影响一系列健康结局，包括骨质疏松症、关节炎、心血管疾病和癌症。维生素D结合蛋白（DBP）是循环中维生素D的主要载体，并调节25-羟基维生素D的生物利用度。流行病学研究已显示DBP与风险之间的直接关系以及DBP对维生素D与疾病关联的修饰作用。
我们旨在鉴定影响DBP生化表型的常见基因变异。
我们通过对Illumina HumanHap500/550/610芯片中的单核苷酸多态性（SNP）进行线性回归，对1380名男性进行了全基因组关联研究（GWAS），以空腹血清DBP为指标，采用加性遗传模型，并对采血时的年龄进行了校正。
我们在编码DBP的基因GC中鉴定出2个独立的SNP，它们与血清DBP高度相关：rs7041（P = 1.42×10⁻²⁴⁶）和rs705117（P = 4.7×10⁻⁹¹）。对于这两个SNP，随着次要等位基因拷贝数的增加，平均血清DBP均降低：rs7041（T）等位基因0、1和2拷贝时的平均DBP浓度（nmol/L）分别为7335、5149和3152，rs705117（G）等位基因时分别为6339、4280和2341。DBP还与ST6GALNAC3中的rs12144344相关（P = 5.9×10⁻⁷）。
在这项GWAS分析中，据我们所知这是首次对这种生化表型进行研究。GC基因中的2个变异——一个在外显子中，一个在内含子中——在全基因组水平上与血清DBP浓度相关。了解循环中DBP的遗传贡献可能有助于更深入地了解DBP的维生素D结合、转运及其他功能，以及维生素D状态对健康结局的影响。
