维生素D受体（VDR）基因rs11568820变异与意大利成年受试者的2型糖尿病及胰岛素分泌受损相关，且与儿童心血管代谢风险增加有关。

The vitamin D receptor (VDR) gene rs11568820 variant is associated with type 2 diabetes and impaired insulin secretion in Italian adult subjects, and associates with increased cardio-metabolic risk in children.

作者信息

Sentinelli F, Bertoccini L, Barchetta I, Capoccia D, Incani M, Pani M G, Loche S, Angelico F, Arca M, Morini S, Manconi E, Lenzi A, Cossu E, Leonetti F, Baroni M G, Cavallo M G

机构信息

Department of Experimental Medicine, Sapienza University of Rome, Italy.

Internal Medicine Unit, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy.

出版信息

Nutr Metab Cardiovasc Dis. 2016 May;26(5):407-13. doi: 10.1016/j.numecd.2016.02.004. Epub 2016 Feb 19.

DOI:10.1016/j.numecd.2016.02.004

PMID:27052925

Abstract

BACKGROUND AND AIMS

1α,25-dihydroxyvitamin-D3, the biologically active vitamin D, plays a central role in several metabolic pathways through the binding to the vitamin D receptor (VDR). VDR has been shown to be involved in cardiovascular diseases, cancer, autoimmunity and type 2 diabetes mellitus (T2DM). Several polymorphisms in the VDR gene have been described. Among these, the rs11568820 G-to-A nucleotide substitution was found to be functional, modulating the transcription of the VDR gene. Objective of this study was to perform an association study between rs11568820 polymorphism and T2DM in a cohort of Italian adults with T2DM and in non-diabetic controls. To add further insight into the role of VDR gene we explored whether this association begins early in life in overweight/obese children, or becomes manifest only in adulthood.

METHODS AND RESULTS

As many as 1788 adults and 878 children were genotyped for the rs11568820 polymorphism. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose and insulin levels. Indices of insulin-resistance and secretion were also calculated. The AA genotype was significantly more frequent in adults with T2DM compared to controls (7.5% vs. 4.6%, P = 0.037), and conferred a higher risk of T2DM (ORHom = 1.69C.I. = [1.13-2.53], P = 0.011). In the adult cohort, rs11568820 was also associated with reduced indices of β-cell insulin secretion. In children, the AA genotype was associated with 2 h high-normal glucose, a marker of cardio-metabolic risk.

CONCLUSIONS

Our study demonstrates for the first time that VDR gene AA carriers have higher risk of T2DM and impaired insulin secretion. In children, the association between AA homozygous and high-normal 2h glucose suggests that mild alterations associated with this genotype may appear early in life.

摘要

背景与目的

1α,25 - 二羟基维生素D3作为具有生物活性的维生素D，通过与维生素D受体（VDR）结合，在多种代谢途径中发挥核心作用。VDR已被证明与心血管疾病、癌症、自身免疫以及2型糖尿病（T2DM）有关。VDR基因存在多种多态性。其中，rs11568820的G到A核苷酸替换被发现具有功能性，可调节VDR基因的转录。本研究的目的是在一组患有T2DM的意大利成年人及非糖尿病对照人群中，开展rs11568820多态性与T2DM的关联研究。为了进一步深入了解VDR基因的作用，我们探究了这种关联是在超重/肥胖儿童的生命早期就已开始，还是仅在成年期才显现出来。

方法与结果

对多达1788名成年人和878名儿童进行了rs11568820多态性的基因分型。所有参与者均接受口服葡萄糖耐量试验（OGTT），并测量血糖和胰岛素水平。还计算了胰岛素抵抗和分泌指标。与对照组相比，T2DM成年患者中AA基因型的频率显著更高（7.5%对4.6%，P = 0.037），且患T2DM的风险更高（ORHom = 1.69，置信区间 = [1.13 - 2.53]，P = 0.011）。在成年人群体中，rs11568820还与β细胞胰岛素分泌指标降低有关。在儿童中，AA基因型与2小时血糖略高于正常水平相关，这是一种心血管代谢风险标志物。