Elena Klyosova, Iuliia Azarova, Irina Petrukhina, Ramis Khabibulin, Alexey Polonikov
{"title":"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","authors":"Elena Klyosova, Iuliia Azarova, Irina Petrukhina, Ramis Khabibulin, Alexey Polonikov","doi":"10.1038/s41366-024-01604-5","DOIUrl":null,"url":null,"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.","PeriodicalId":14183,"journal":{"name":"International Journal of Obesity","volume":"48 11","pages":"1638-1649"},"PeriodicalIF":4.2000,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Obesity","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41366-024-01604-5","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
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.
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.