JAMA：基因突变或改变低水平维生素D和机体副作用之间的关系

刊登在11月14日国际杂志JAMA上的一篇研究报告中，来自华盛顿大学研究者通过研究揭示了，维生素D代谢基因的特定突变，或许可以改变低血清25-羟维生素D浓度和健康状况之间的关系，包括个体的髋部骨折、心脏病发作以及癌症、死亡等。

维生素D的状况可以通过测定血清25-羟维生素D的浓度来判定，低水平的血清25-羟维生素D和许多慢性病的高风险发病相关，可以促使进行临床试验来测试是否维生素D的补充可以降低疾病发生的风险。

本项研究中，研究者调查了是否血清25-羟维生素D和特定疾病之间已知的关系可以通过血清25-羟维生素D代谢基因的突变来发生变化，研究者对来自1514名参与者的141个单核苷酸多态性（SNP）进行了检测，结果显示，包括维生素D受体基因在内的一个SNP可以明显改变低血清25-羟维生素D和主要健康状况如心脏病发作、癌症等疾病之间的关联。研究者表示，携带有特定的25-羟维生素D代谢基因型的个体或许对低水平维生素D敏感，又或者是受到其保护来抵御副作用的产生。

研究者表示，这只是首次研究来鉴别是什么影响机体的25-羟维生素D的代谢基因，这就为后期我们理解维生素D受体的遗传突变带来了帮助，后期研究中研究者会进行深入研究来确定维生素D代谢基因如何突变使得不同个体对维生素D的缺失产生敏感反应。

编译自：Genetic Variation May Modify Associations Between Low Vitamin D Levels and Adverse Health Outcomes

doi:10.1001/jama.2012.17304
PMC:
PMID:

Genetic Variants and Associations of 25-Hydroxyvitamin D Concentrations With Major Clinical Outcomes

Gregory P. Levin, PhD; Cassianne Robinson-Cohen, PhD; Ian H. de Boer, MD, MS; Denise K. Houston, PhD; Kurt Lohman, MS; Yongmei Liu, PhD; Stephen B. Kritchevsky, PhD; Jane A. Cauley, DrPh; Toshiko Tanaka, PhD; Luigi Ferrucci, MD, PhD; Stefania Bandinelli, MD; Kushang V. Patel, PhD, MPH; Emil Hagström, MD, PhD; Karl Michaëlsson, MD, PhD; Håkan Melhus, MD, PhD; Thomas Wang, MD; Myles Wolf, MD, MMSc; Bruce M. Psaty, MD, PhD; David Siscovick, MD, MPH; Bryan Kestenbaum, MD, MS

Context Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D. Objective To investigate whether common variation within genes encoding the vitamin D–binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes. Design, Setting, and Participants Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies. Main Outcome Measure Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up. Results Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism. Conclusion Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.