The rs2341471-G/G genotype of activating transcription factor 6 (ATF6) is the risk factor of type 2 diabetes in subjects with obesity or overweight

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Elena Klyosova, Iuliia Azarova, Irina Petrukhina, Ramis Khabibulin, Alexey Polonikov
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Abstract

Numerous studies have demonstrated that the onset of type 2 diabetes (T2D) is linked to the reduction in ß-cell mass caused by apoptosis, a process initiated by endoplasmic reticulum (ER) stress. The aim of this study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the ATF6 gene (activating transcription factor 6), a key sensor of ER stress, and T2D susceptibility. The study involved 3229 unrelated individuals, including 1569 patients with T2D and 1660 healthy controls from Central Russia. Four functionally significant intronic SNPs, namely rs931778, rs90559, rs2341471, and rs7517862, were genotyped using the MassARRAY-4 system. The rs2341471-G/G genotype of ATF6 was found to be associated with an increased risk of T2D (OR = 1.61, 95% CI 1.37–1.90, PFDR < 0.0001). However, a BMI-stratified analysis showed that this genotype and haplotypes CGGA and TAGA are associated with T2D risk exclusively in subjects with obesity or overweight (PFDR < 0.05). Despite these patients being found to have higher consumption of high-carbohydrate and high-calorie diets compared to normal-weight individuals (P < 0.0001), the influence of the rs7517862 polymorphism on T2D risk was observed independently of these dietary habits. Functional SNP annotation revealed the following: (1) the rs2341471-G allele is associated with increased ATF6 expression; (2) the SNP is located in a region exhibiting enhancer activity epigenetically regulated in pancreatic islets; (3) the rs2341471-G was predicted to create binding sites for 18 activating transcription factors that are part of gene-regulatory networks controlling glucose metabolism and maintaining proteostasis. The present study revealed, for the first time, a strong association between the rs2341471-G/G ATF6 genotype and an increased risk of type 2 diabetes in people with obesity or overweight, regardless of known dietary risk factors. Further research is needed to support the potential of silencing the ATF6 gene as a means for the treatment and prevention of type 2 diabetes.
活化转录因子 6(ATF6)的 rs2341471-G/G 基因型是肥胖或超重人群罹患 2 型糖尿病的风险因素。
背景:大量研究表明,2型糖尿病(T2D)的发病与内质网(ER)应激引起的细胞凋亡导致的ß细胞数量减少有关。本研究的目的是调查ER应激的关键传感器ATF6基因(激活转录因子6)的单核苷酸多态性(SNPs)与T2D易感性之间的关联:研究涉及 3229 名无血缘关系的个体,包括 1569 名 T2D 患者和 1660 名来自俄罗斯中部的健康对照者。使用 MassARRAY-4 系统对四个功能显著的内含子 SNPs(即 rs931778、rs90559、rs2341471 和 rs7517862)进行了基因分型:结果:发现 ATF6 的 rs2341471-G/G 基因型与 T2D 风险的增加有关(OR = 1.61,95% CI 1.37-1.90,PFDR FDR 结论:本研究首次发现 ATF6 的 rs2341471-G/G 基因型与 T2D 风险的增加有关:本研究首次揭示了 rs2341471-G/G ATF6 基因型与肥胖或超重人群罹患 2 型糖尿病风险增加之间的密切联系,而与已知的饮食风险因素无关。要证明沉默 ATF6 基因作为治疗和预防 2 型糖尿病的一种手段的潜力,还需要进一步的研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Obesity
International Journal of Obesity 医学-内分泌学与代谢
CiteScore
10.00
自引率
2.00%
发文量
221
审稿时长
3 months
期刊介绍: The International Journal of Obesity is a multi-disciplinary forum for research describing basic, clinical and applied studies in biochemistry, physiology, genetics and nutrition, molecular, metabolic, psychological and epidemiological aspects of obesity and related disorders. We publish a range of content types including original research articles, technical reports, reviews, correspondence and brief communications that elaborate on significant advances in the field and cover topical issues.
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