HIF3A DNA Methylation Is Associated with Childhood Obesity and ALT

Abstract

Gene polymorphisms associated so far with body mass index (BMI) can explain only 1.18–1.45% of observed variation in BMI. Recent studies suggest that epigenetic modifications, especially DNA methylation, could contribute to explain part of the missing heritability, and two epigenetic genome-wide analysis studies (EWAS) have reported that Hypoxia Inducible Factor 3 Alpha Subunit (HIF3A) methylation was associated with BMI or BMI change. We therefore assessed whether the HIF3A methylation is associated with obesity and other obesity-related phenotypes in Chinese children. The subjects included 110 severe obese cases aged 7–17y and 110 normal-weight controls matched by age and gender for measurement of blood DNA methylation levels at the HIF3A gene locus using the Sequenom’s MassARRAY system. We observed significantly higher methylation levels in obese children than in controls at positions 46801642 and 46801699 in HIF3A gene (P<0.05), and found positive associations between methylation and alanine aminotransferase (ALT) levels adjusted by gender, age and BMI at the position 46801699 (r = 0.226, P = 0.007). These results suggest that HIF3A DNA methylation is associated with childhood obesity, and has a BMI-independent association with ALT. The results provide evidence for identifying epigenetic factors of elivated ALT and may be useful for risk assessment and personalized medicine of liver diseases such as non-alcoholic fatty liver disease (NAFLD).

Genetics and epigenetics in obesity

“…was linked to higher BMI and this relationship was present in both subcutaneous adipose tissue (SAT) and whole blood which was successfully replicated by others [76][77][78][79]. Other studies identified significant correlations of multiple genes (either involved in insulin and glucose metabolism, adipogenesis or early development) with BMI or other clinical variables related to obesity and adipose tissue distribution (e.g.…”

Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

“…Human lifestyle and nutritional status were also believed to affect DNA methylation levels (Niculescu, 2012). High fructose or fat intake could induce DNA methylation, suggesting DNA methylation is involved in the metabolism of human body (Ohashi et al, 2015;Wang et al, 2015). According to the liver is the human body's largest metabolism organ, there is increasing evidence that DNA methylation also participated in pathological process of various liver diseases.…”

Epigenetics and DOHaD: from basics to birth and beyond

“…HIF3A, SREBP1, CPT1A, ABCG1, TXNIP, PHOS-PHO1) in multiple cohorts and in different ethnicities. [23][24][25][26][27][28][29][30] A recent EWAS, the largest of its kind to date (n = 10,261), showed that body mass index (BMI) as a measure of obesity, is associated with widespread changes in DNA methylation in genes involved in metabolic and inflammatory pathways. 31 In most human studies the methylation changes are measured when the obese or diabetic phenotype is already present, and it is therefore difficult to establish whether the observed DNA methylation changes are on the causal pathway to develop the disease or whether they are a consequence of the phenotype.…”