Abstract
BackgroundAssociations between BMI and DNA methylation of hypoxia-inducible factor 3-alpha (HIF3A) in both blood cells and subcutaneous adipose tissue (SAT) have been reported. In this study, we investigated associations between BMI and HIF3A DNA methylation in the blood and SAT from the same individuals, and whether HIF3A gene expression in SAT and skeletal muscle biopsies showed associations with BMI and insulin resistance. Furthermore, we aimed to investigate gender specificity and heritability of these traits.MethodsWe studied 137 first-degree relatives of type 2 diabetes (T2D) patients from 48 families, from whom we had SAT and muscle biopsies. DNA methylation of four CpG sites in the HIF3A promoter was analyzed in the blood and SAT by pyrosequencing, and HIF3A gene expression was analyzed in SAT and muscle by qPCR. An index of whole-body insulin sensitivity was estimated from oral glucose tolerance tests.ResultsBMI was associated with HIF3A methylation at one CpG site in the blood, and there was a positive association between the blood and SAT methylation levels at a different CpG site within the individuals. The SAT methylation level did not correlate with HIF3A gene expression. Interestingly, HIF3A expression in SAT, but not in muscle, associated negatively with BMI and whole-body insulin resistance. We found a significant effect of familiality on HIF3A methylation levels in the blood and HIF3A expression levels in skeletal muscle.ConclusionsOur findings are in line with the previously reported link between BMI and DNA methylation of HIF3A in the blood. The tissue-specific results of HIF3A gene expression indicate that SAT is the more functional tissue in which a low expression may adversely affect whole-body insulin sensitivity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0258-6) contains supplementary material, which is available to authorized users.
Highlights
Associations between BMI and DNA methylation of hypoxia-inducible factor 3-alpha (HIF3A) in both blood cells and subcutaneous adipose tissue (SAT) have been reported
HIF3A DNA methylation in the blood and SAT DNA methylation levels on CpG sites 1 and 3 were lower compared to CpG sites 2 and 4 in the blood and SAT
No significant associations between BMI and HIF3A methylation were detected in women or men separately, and we found no associations between whole-body insulin sensitivity and the level of HIF3A DNA methylation in the blood for any of the four examined methylation sites
Summary
Associations between BMI and DNA methylation of hypoxia-inducible factor 3-alpha (HIF3A) in both blood cells and subcutaneous adipose tissue (SAT) have been reported. We investigated associations between BMI and HIF3A DNA methylation in the blood and SAT from the same individuals, and whether HIF3A gene expression in SAT and skeletal muscle biopsies showed associations with BMI and insulin resistance. We aimed to investigate gender specificity and heritability of these traits. It has been shown that adipose tissue-specific Hif3a knockout mice. One mechanism whereby environmental factors can contribute to T2D is epigenetics. Epigenetics is the study of heritable changes in DNA that affect gene transcription irrespective of the DNA sequence, such as methylation of DNA cytosine residues (mainly CpG sites) [7]. Twin studies indicated that both environmental and heritable factors affect
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