An epigenetic map of age-associated autosomal loci in northern European families at high risk for the metabolic syndrome.

Omar Ali,Jack W Kent,Melanie A Carless,Diana Cerjak,Yi Zhang,Roland James,John Blangero

doi:10.1186/s13148-015-0048-6

Abstract

BackgroundThe prevalence of chronic diseases such as cancer, type 2 diabetes, metabolic syndrome (MetS), and cardiovascular disease increases with age in all populations. Epigenetic features are hypothesized to play important roles in the pathophysiology of age-associated diseases, but a map of these markers is lacking. We searched for genome-wide age-associated methylation signatures in peripheral blood of individuals at high risks for MetS by profiling 485,000 CpG sites in 192 individuals of Northern European ancestry using the Illumina HM450 array. Subjects (ages 6–85 years) were part of seven extended families, and 73% of adults and 32% of children were overweight or obese.ResultsWe found 22,122 genome-wide significant age-associated CpG sites (Pα=0.05 = 3.65 × 10−7 after correction for multiple testing) of which 14,155 are positively associated with age while 7,967 are negatively associated. By applying a positional density-based clustering algorithm, we generated a map of epigenetic ‘hot-spots’ of age-associated genomic segments, which include 290 age-associated differentially methylated CpG clusters (aDMCs), of which 207 are positively associated with age. Gene/pathway enrichment analyses were performed on these clusters using FatiGO. Genes localized to both the positively (n = 241) and negatively (n = 16) age-associated clusters are significantly enriched in specific KEGG pathways and GO terms. The most significantly enriched pathways are the hedgehog signaling pathway (adjusted P = 3.96 × 10−3) and maturity-onset diabetes of the young (MODY) (adjusted P = 6.26 × 10−3) in the positive aDMCs and type I diabetes mellitus (adjusted P = 3.69 × 10−7) in the negative aDMCs. We also identified several epigenetic loci whose age-associated change rates differ between subjects diagnosed with MetS and those without.ConclusionWe conclude that in a family cohort at high risk for MetS, age-associated epigenetic features enrich in biological pathways important for determining the fate of fat cells and for insulin production. We also observe that several genes known to be related to MetS show differential epigenetic response to age in individuals with and without MetS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0048-6) contains supplementary material, which is available to authorized users.

Highlights

The prevalence of chronic diseases such as cancer, type 2 diabetes, metabolic syndrome (MetS), and cardiovascular disease increases with age in all populations
As the subjects were selected from families that are part of a previous genetic study on the metabolic risk complications of obesity [47], the cohort is enriched for obesity and MetS traits (Table 1) with 73% of the adults being overweight or obese (based on body mass index (BMI)), 52% with waist circumference above MetS thresholds (>102 cm in men; >88 cm in women), 31.9% with evidence of insulin resistance (based on homeostatic model of assessment (HOMA) > 3.5) [48,49], 20.3% with hypertriglyceridemia (>150 mg/dl), and 65.7% with high-density lipoprotein (HDL) below MetS thresholds (
It has been shown that genetic effects determine the majority of transgenerational similarity in DNA methylation in humans [23], and by using extended pedigrees, we may have more power to detect age-affected epigenetic signals as compared to designs using unrelated subjects because these families will have less of the epigenetic variation that can be caused by differences in the genetic makeup of unrelated individuals (Additional file 2)

Summary

Introduction

The prevalence of chronic diseases such as cancer, type 2 diabetes, metabolic syndrome (MetS), and cardiovascular disease increases with age in all populations. We identified several epigenetic loci whose age-associated change rates differ between subjects diagnosed with MetS and those without Chronic diseases such as cancer, type 2 diabetes (T2D), metabolic syndrome (MetS), cardiovascular disease, and dementia constitute the most common health problems seen in developed societies (and increasingly, in developing societies), and their prevalence increases with age in Epigenetic mechanisms mediate the interaction between gene and environment throughout the lifespan; while the underlying genetic sequence does not change, environmental influences can alter epigenetic marks and alter gene expression and induce long-term changes. There is evidence from both human and animal sources that prenatal nutritional deprivation can permanently alter DNA methylation at multiple loci, and these changes play a role in the observed alteration of future risk of chronic diseases like obesity, insulin resistance, and diabetes [26,27,28,29,30,31,32]. Several studies have looked at the effect of aging on genomewide DNA methylation in adults, and these studies show that age-dependent methylation changes are found in a variety of tissues and correlate well enough with age that the methylation status of selected loci can be used to predict the age of a subject [35,39,40,41]

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