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Tobacco smoking is associated with DNA methylation of diabetes susceptibility genes.

ABSTRACT: Tobacco smoking, a risk factor for diabetes, is an established modifier of DNA methylation. We hypothesised that tobacco smoking modifies DNA methylation of genes previously identified for diabetes.We annotated CpG sites available on the Illumina Human Methylation 450K array to diabetes genes previously identified by genome-wide association studies (GWAS), and investigated them for an association with smoking by comparing current to never smokers. The discovery study consisted of 630 individuals (Bonferroni-corrected p?=?1.4?×?10(-5)), and we sought replication in an independent sample of 674 individuals. The replicated sites were tested for association with nearby genetic variants and gene expression and fasting glucose and insulin levels.We annotated 3,620 CpG sites to the genes identified in the GWAS on type 2 diabetes. Comparing current smokers to never smokers, we found 12 differentially methylated CpG sites, of which five replicated: cg23161492 within ANPEP (p?=?1.3?×?10(-12)); cg26963277 (p?=?1.2?×?10(-9)), cg01744331 (p?=?8.0?×?10(-6)) and cg16556677 (p?=?1.2?×?10(-5)) within KCNQ1 and cg03450842 (p?=?3.1?×?10(-8)) within ZMIZ1. The effect of smoking on DNA methylation at the replicated CpG sites attenuated after smoking cessation. Increased DNA methylation at cg23161492 was associated with decreased gene expression levels of ANPEP (p?=?8.9?×?10(-5)). rs231356-T, which was associated with hypomethylation of cg26963277 (KCNQ1), was associated with a higher odds of diabetes (OR 1.06, p?=?1.3?×?10(-5)). Additionally, hypomethylation of cg26963277 was associated with lower fasting insulin levels (p?=?0.04).Tobacco smoking is associated with differential DNA methylation of the diabetes risk genes ANPEP, KCNQ1 and ZMIZ1. Our study highlights potential biological mechanisms connecting tobacco smoking to excess risk of type 2 diabetes.

SUBMITTER: Ligthart S

PROVIDER: S-EPMC4826423 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Tobacco smoking is associated with DNA methylation of diabetes susceptibility genes.

Ligthart Symen S Steenaard Rebecca V RV Peters Marjolein J MJ van Meurs Joyce B J JB Sijbrands Eric J G EJ Uitterlinden André G AG Bonder Marc J MJ Hofman Albert A Franco Oscar H OH Dehghan Abbas A

Diabetologia 20160129 5

<h4>Aims/hypothesis</h4>Tobacco smoking, a risk factor for diabetes, is an established modifier of DNA methylation. We hypothesised that tobacco smoking modifies DNA methylation of genes previously identified for diabetes.<h4>Methods</h4>We annotated CpG sites available on the Illumina Human Methylation 450K array to diabetes genes previously identified by genome-wide association studies (GWAS), and investigated them for an association with smoking by comparing current to never smokers. The disc ...[more]

PMID: 26825526

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Project description:Smoking is one of the leading preventable causes of morbidity and mortality worldwide, prompting interest in its association with DNA methylation-based measures of biological aging. Considerable progress has been made in developing DNA methylation-based measures that correspond to self-reported smoking status. In addition, assessment of DNA methylation-based aging has been expanded to better capture individual differences in risk for morbidity and mortality. Untested to date, however, is whether smoking is similarly related to older and newer indices of DNA methylation-based aging, and whether DNA methylation-based indices of smoking can be used in lieu of self-reported smoking to examine effects on DNA methylation-based aging measures. In the current investigation we examine mediation of the impact of self-reported cigarette consumption on accelerated, intrinsic DNA methylation-based aging using indices designed to predict chronological aging, phenotypic aging, and mortality risk, as well as a newly developed DNA methylation-based measure of telomere length. Using a sample of 500 African American middle aged smokers and non-smokers, we found that a) self-reported cigarette consumption was associated with accelerated intrinsic DNA methylation-based aging on some but not all DNA methylation-based aging indices, b) for those aging outcomes associated with self-reported cigarette consumption, DNA methylation-based indicators of smoking typically accounted for greater variance than did self-reported cigarette consumption, and c) self-reported cigarette consumption effects on DNA methylation-based aging indices typically were fully mediated by DNA methylation-based indicators of smoking (e.g., PACKYRS from GrimAge; or cg05575921 CpG site). Results suggest that when DNA methylation-based indices of smoking are substituted for self-reported assessments of smoking, they will typically fully reflect the varied impact of cigarette smoking on intrinsic, accelerated DNA methylation-based aging.

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Tobacco smoking is associated with DNA methylation of diabetes susceptibility genes.

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Tobacco smoking is associated with DNA methylation of diabetes susceptibility genes.

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