A CpG-SNP Located within the <b><i>ARPC3</i></b> Gene Promoter Is Associated with Hypertriglyceridemia in Severely Obese Patients

Abstract

Aims: To test the potential association of cytosine-phosphate-guanine dinucleotides (CpG)-single-nucleotide polymorphisms (SNPs) located within actin-related protein 2/3 complex subunit 3 (ARPC3), a gene recently linked to adipogenesis and lipid accumulation, with metabolic syndrome (MetS) features in severely obese patients. Methods: Prioritized SNPs within the ARPC3 locus were genotyped and tested for associations with MetS features in a cohort of 1,749 obese patients with and without MetS. Association testing with CpG methylation levels was performed in a methylation sub-cohort of 16 obese men. Results: A significant association was found between the CpG-SNP rs3759384 (C>T) and plasma triglyceride (TG) levels (false discovery rate-corrected p = 3.5 × 10^-2), with 0.6% of the phenotypic variance explained by the CpG-SNP, and with TT homozygotes showing the highest plasma TG levels (1.89 mmol/l). The carriers of the rs3759384 T allele also showed a significant decrease in methylation levels of the ARPC3 promoter-associated CpG site cg10738648 in both visceral adipose tissue and blood. ARPC3 expression levels showed a strong correlation with plasma TG levels (r = 0.70; p = 0.02). Conclusions: The increased plasma TG levels found in homozygous rs3759384 T allele carriers argue for a relevant role of this CpG-SNP in lipid management among obese individuals, which may be driven by an epigenetic-mediated mechanism.

DNA methylation in human diseases

“…Changes in genotype-dependent DNA methylation have been observed in the promoter of the actin-related protein 2/3 complex subunit 3, a gene related to lipogenesis and lipid accumulation, and this was proposed to be a risk factor for obesity-related disorders. 63 Moreover, studies have shown the correlation between DNA methylation and many metabolic traits such as high-density levels of lipoprotein cholesterol, 64 , 65 , 66 LDL, 67 and triglycerides. 67 …”

DNA methylation in human lipid metabolism and related diseases

“…Methylation of CpG sites within exon 3 of APOA5 was positively correlated with triglyceride concentration and with a lipoprotein profile associated with atherogenic dyslipidemia [ 53 ]. Another candidate gene study reported decreased methylation levels of the actin-related protein 2/3 complex subunit 3 ( ARPC3 ) promoter-associated CpG site cg10738648 in both visceral adipose tissue and blood for carriers of the rs3759384 T allele in obese patients with hypertriglyceridemia, and showed ARPC3 expression to be correlated with plasma triglyceride levels [ 55 ]. Finally, lower TNNT1 DNA methylation levels were found to be independently associated with lower HDL-C levels and a TNNT1 polymorphism in patients with and without familial hypercholesterolemia [ 29 ].…”

Omics Approaches in Adipose Tissue and Skeletal Muscle Addressing the Role of Extracellular Matrix in Obesity and Metabolic Dysfunction

“…In addition, the carriers of the rs3759384 T allele also showed a significant decrease in methylation levels of the ARPC3 promoter-associated CpG site cg10738648 in VAT. Therefore, ARPC3, which is involved in cytoskeleton organization during adipose tissue expansion, might have an impact on the development of metabolic syndrome, acting through the regulation of DNA methylation in VAT [137]. Wang et al (2018) described that the rho guanine nucleotide exchange factor 1 (ARHGEF1) gene is hypermethylated in VAT from diabetic individuals compared with healthy controls.…”