DNA methylation level of the gene encoding thioredoxin-interacting protein in peripheral blood cells is associated with metabolic syndrome in the Japanese general population

Abstract

Metabolic syndrome (MetS) is cluster of metabolic diseases, including abdominal obesity, hyperglycemia, high blood pressure, and dyslipidemia, that directly escalate the risk of type 2 diabetes, heart disease, and stroke. Thioredoxininteracting protein (TXNIP) is a binding protein for thioredoxin, a molecule that is a key inhibitor of cellular oxidation, and thus regulates the cellular redox state. Epigenetic alteration of the TXNIP-encoding locus has been associated with components of MetS. In the present study, we sought to determine whether the level of TXNIP methylation in blood is associated with MetS in the general Japanese population. DNA was extracted from the peripheral blood cells of 37 subjects with and 392 subjects without MetS. The level of TXNIP methylation at cg19693031 was assessed by the bisulfitepyrosequencing method. We observed that TXNIP methylation levels were lower in MetS subjects (median 74.9%, range 71.7-78.4%) than in non-MetS subjects (median 77.7%, range 74.4-80.5%; p = 0.0024). Calculation of the confounding factor-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for hypomethylation revealed that subjects with MetS exhibited significantly higher ORs for hypomethylation than did those without MetS (OR, 2.92; 95% CI, 1.33-6.62; p = 0.009). Our findings indicated that lower levels of TXNIP methylation are associated with MetS in the general Japanese population. Altered levels of DNA methylation in TXNIP at cg19693031 might play an important role in the pathogenesis of MetS.

Blood DNA methylation at TXNIP and glycemic changes in response to weight-loss diet interventions: the POUNDS lost trial

“…Regional DNAm was analyzed continuously; for presentation purpose, we grouped it into tertiles, similar as previous publications by us and others. 22 – 24 All statistical analyses were performed using SAS version 9.4 (SAS Institute). All-p values were 2-sided, and a p-value <0.05 was considered statistically significant.…”

Genome- and epigenome-wide association studies identify susceptibility of CpG sites and regions for metabolic syndrome in a Korean population

“…The hypomethylation of TXNIP (cg19693031) has previously been reported to be associated with MetS in Japanese and European populations. [ 6 , 8 ] Similarly, other DNA methylation sites, including cg26974062 and cg02988828, have shown associations with maternal hyperglycemia and T2D as cg19693031 [ 44 ]. In contrast to cg19693031, the relationship between cg26974062 and cg02988828 and their association with these conditions has not been extensively studied or firmly established.…”

“…[ 1 , 2 ] Both obesity [ 3 , 4 ] and hypertension [ 5 ], as components of MetS, have also been reported to be regulated by epigenetic mechanisms. Recently, various EWAS conducted among European, African American, and East Asian populations have identified certain CpG sites near TXNIP, ABCG1, SREBF1, IGF2BP1 and GFPT2 that are associated with MetS [ 6 – 8 ]. While numerous studies have revealed methylation sites linked to MetS, the causal relationship between these epigenetic modifications and the onset of the disease remains an area requiring more extensive investigation.…”

Association between DNA methylation levels of <i>thioredoxin-interacting protein (TXNIP)</i> and changes in glycemic traits: a longitudinal population-based study

“…We previously measured DNAm levels at the same cytosine-phosphate-guanine (CpG) site of the TXNIP gene as described elsewhere [13][14][15][16]. This CpG site (chr 1: 145,441,552 bp, GRCh37.p13) is located within a 3'untranslated region (3'-UTR) of the TXNIP gene and has been investigated extensively in previous studies [9][10][11].…”