近日，国家交叉中心李启寨副研究员与美国国家癌症研究所的科研人员合作，在25羟基维他命D循环水平的全基因组关联分析取得阶段性成果。该成果发表在《人类分子遗传学》期刊。
羟基维他命循环水平的全基因组关联分析
他们对2396个病例和2105个对照的基因组上的593253个突变位点进行了25羟基维他命D循环水平的关联分析，统计分析结果如图1所示。他们发现位于4号染色体的突变位点rs22582679与25羟基维他命D的循环水平有关联 (p-value=2×10-30); 而且他们还发现另外三个突变位点: rs3829251 (p-value=8.8×10-7)，rs6599638 (p-value=3.3×10-7)，rs2060793 (p-value=1.4×10-5)也有可能与25羟基维他命D的循环水平也有关联。
此前，基于双胞胎数据，研究者们发现了与维他命D的循环水平相关联的遗传因素，但是由于数据量少，没有得出确定性的结论。而李启寨副研究员的这一研究结果将为人们开发有效药物治疗与25羟基维他命D相关的疾病提供靶点。
维他命D的功能非常多，它能调节人体内的钙平衡，促进钙和磷的吸收代谢，促进细胞正常生长，增强免疫系统，保持荷尔蒙平衡等。维他命D在人体内的主要循环形式的25羟基维他命D[25(OH)D]与人类的许多复杂疾病相关，比如，佝偻病、骨质疏松症和多发性硬化症等。维他命D的受体响应元直接或间接地影响细胞周期和增殖，分化和凋亡。与维他命D关联的常见遗传变异可能是科学家们识别维他命D缺乏风险的重要手段。（生物谷 Bioon.com)
doi:10.1093/hmg/ddq155
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Genome-wide association study of circulating vitamin D levels
Jiyoung Ahn1,†, Kai Yu2,†, Rachael Stolzenberg-Solomon2, K. Claire Simon3, Marjorie L. McCullough6, Lisa Gallicchio7, Eric J. Jacobs6, Alberto Ascherio3,4,8, Kathy Helzlsouer7, Kevin B. Jacobs2, Qizhai Li9, Stephanie J. Weinstein2, Mark Purdue2, Jarmo Virtamo10, Ronald Horst11, William Wheeler12, Stephen Chanock2, David J. Hunter3,4,5, Richard B. Hayes1, Peter Kraft4,5 and Demetrius Albanes2
The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH)D concentrations: rs2282679 (P = 2.0 × 10−30), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P = 4.1 × 10−22) and rs1155563 (P = 3.8 × 10−25). Suggestive signals for association with 25(OH)D were also observed for SNPs in or near three other genes involved in vitamin D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P = 8.8 × 10−7], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P = 3.3 × 10−7); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D3 to an active vitamin D receptor ligand; P = 1.4 × 10−5). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations with 25(OH)D through meta-analysis with the GWAS data for GC (P = 1.8 × 10−49), NADSYN1/DHCR7 (P = 3.4 × 10−9) and CYP2R1 (P = 2.9 × 10−17), but not C10orf88 (P = 2.4 × 10−5).
