Obesity-related CpG Methylation (cg07814318) of Kruppel-like Factor-13 (KLF13) Gene with Childhood Obesity and its cis-Methylation Quantitative Loci

Abstract

The cg07814318 hypermethylation of Kruppel-like factor 13 (KLF13) gene has been reported for its relevancy with Body Mass Index (BMI) from European origin. We explored the cg07814318 methylation and its cis-meQTL (cis-methylation quantitative loci) of KLF13 from a childhood obesity cohort. The cg07814318 methylation in blood was significantly associated with obesity and correlated with several obesity-related physical and biochemical traits. We examined the same loci from purified three human cell types (n = 47), i.e., pre-adipocytes, adipocytes and islets. The cg07814318 methylation pattern in pre-adipocytes and islets were significant higher in cells from subjects with a higher BMI compared with control subjects. By exome sequencing of KLF13 gene in blood with the same cohort, we found nine SNPs (single nucleotide polymorphisms) within its gene body, and two SNPs (rs11537749 and rs12595641) were as cis-meQTL of cg07814318. There was the 2.01% methylation change of cg07814318 between homozygous dominant and recessive genotypes, especially, in rs12595641. The sequencing variations within KLF13 genes could drive dynamic modifications of obesity-related CpG methylation. Differential DNA methylation patterns in the KLF13 gene determined from separate blood samples showed that this criterion could be used as a surrogate for representing overall epigenetic changes in cells related to obesity.

Insights into the multifactorial causation of obesity by integrated genetic and epigenetic analysis

“…We observed a strong correlation between prenatal pesticide exposure, paraoxonase 1 polymorphism rs662:T > C, and adverse epigenetic reprogramming of neuroendocrine pathways; children carrying the C allele and prenatally exposed to pesticides showed DNA methylation changes of genes involved in cardiometabolic health with higher body fat content and serum leptin levels as outcome (childhood obesity) 90 . Moreover, Koh et al 123 disclosed an association of obesity‐related physical and biochemical traits with cg07814318 Kruppel‐like Factor‐13 methylation depending on sequencing variations within this gene. Those findings indicate the relationship between genetic variants and DNA methylation (meQTL) for specific obesity candidate genes.…”

“…The epigenetic profile is not only influenced by environmental exposure, but likewise seems to be modulated by genetic variants 120 . Evidence is available that SNPs can affect methylation in nearby ( cis ) or distant ( trans ) CpGs, thus supporting the genotype‐epigenotype effect on complex traits 113, 115, 121–124 . Such variants are defined as methylation quantitative trait loci (meQTLs) and could offer some clarification for the unsolved previously identified GWAS polymorphisms.…”

Transcriptional and Epigenetic Regulation of Krüppel-Like Transcription Factors

“…Another example of KLF13 methylation is the methylation of the obesity-related variant of KLF13: cg07814318. The methylation of this particular SNP appears to be related to increased childhood obesity [155]. These studies suggest that methylation of promoters could be one possible mechanism of regulation of KLFs in development or disease.…”

Positive correlation of cg16672562 methylation with obesity-related traits in childhood obesity, and its independence with underlying HIF3A (hypoxia-inducible factor 3a) genetic background

“…The study subjects, who ranged in age from 12 to 15 years, were selected from the KoCAS, which followed a cohort of Korean students using annual questionnaires and investigations at four elementary schools in Gwacheon from the time of the students’ entry into the school (IRB approval number, 2014-08EXP-05-P-A). The overall objective of the cohort study was to identify early risk factors for obesity and associated metabolic diseases in Korean children[ 13 ]. We defined “extreme obesity” as a BMI of ≥ 1.2 times the 95 th percentile value for the relevant age group or a BMI of ≥ 30 kg/m 2 , according to the recently proposed definition by the Centers for Disease Control and Prevention.…”