A polymorphism in the promoter of UCP2 gene modulates lipid levels in patients with type 2 diabetes

https://doi.org/10.1016/j.ymgme.2004.06.008Get rights and content

Abstract

A G/A single nucleotide polymorphism (SNP) in the position −866 of the UCP2 promoter modulates UCP2 expression in adipose tissue and pancreatic β-cell, and is associated with variations of body mass index (BMI) and insulin secretion in nondiabetic subjects. We investigated associations of this SNP with traits related to obesity, dyslipidemia, and hyperglycemia in patients with type 2 diabetes. The −866 G/A SNP in the UCP2 promoter was genotyped by PCR/RFLP in 681 type 2 diabetic patients. Increased triglyceride (⩾1.70 mM), total cholesterol (⩾6.0 mM) and LDL-cholesterol (⩾3.35 mM) levels were significantly less frequent in homozygous carriers of the G-allele than in homozygous carriers of the A-allele. Odds ratios for the risk of dyslipidemia in GG vs AA carriers were 0.45, 0.57, and 0.50, for triglyceride, total cholesterol and LDL-cholesterol, respectively (all p < 0.007). No genetic effects of this polymorphism on the BMI or on traits related to the severity of hyperglycemia were observed. In conclusion, a common polymorphism in the promoter region of the UCP2 gene modulates triglycerides and cholesterol levels in French Caucasian subjects with type 2 diabetes. The implications of this effect in the evolution of type 2 diabetes and its macrovascular complications deserve to be investigated.

Introduction

Uncoupling proteins are a group of proton carriers from the inner mitochondrial membrane, which comprises UCP1, UCP2, and UCP3 [1]. The role of UCP1 has been clearly demonstrated in brown adipose tissue where it leaks protons into the mitochondrial matrix and dissipates as heat the proton electrochemical gradient needed to generate ATP. As a result, the phosphorylation of ADP into ATP is dissociated from the fuel metabolism, and thermogenesis is increased [1]. The physiological roles of UCP2 and UCP3 are less well established. UCP2 is widely expressed in human tissues, including white adipose tissue, endocrine pancreas, skeletal muscle, liver, brain, kidney, and macrophages [2], [3]. Although UCP2 does not contribute substantially to adaptive thermogenesis in humans, it may play an important role in the regulation of fuel metabolism by direct and indirect actions in the adipose tissue, skeletal muscle, and the endocrine pancreas [4]. In rodents, UCP2 inhibits lipogenesis in the adipose tissue [5] and insulin secretion in pancreatic islets [6].

A common G/A single nucleotide polymorphism (SNP) at the position −866 in the UCP2 promoter region has been associated with modulation of mRNA expression in adipocytes and β-cells. The less frequent A-allele of this SNP was associated with enhanced adipose tissue mRNA expression in vivo and was shown to result in increased transcription of a reporter gene in a human adipocyte cell line [7]. The SNP is located in a region of the promoter containing binding sites for β-cell transcription factors IPF1 and PAX6. Studies in murine β-cell lines showed that PAX6 binds preferentially to and more effectively transactivates the A than the G-allele [8]. Recently, a series of clinical studies showed associations of this polymorphism with several phenotypes related to obesity and glucose homeostasis. A reduction in the prevalence of obesity was observed in A-allele carriers in two independent cohorts of nondiabetic subjects [7]. These results are in keeping with the observation of inverse correlations between UCP2 mRNA expression in human adipose tissue of nondiabetic subjects and the body mass index (BMI), percent of body fat, plasma leptin, insulin, and triglyceride levels [9]. Other studies showed the GG genotype or the G-allele of this SNP to be associated with increased insulin response to glucose [8], [10], [11] and increased insulin sensitivity [7] in nondiabetic individuals. The GG genotype was also associated with a twofold reduction of type 2 diabetes risk in obese subjects [8]. However, contrasting results were observed in other studies. No association with obesity or obesity-related intermediary phenotypes were observed neither in nondiabetic adults [12] nor in extremely obese children and adolescents [13].

These allelic associations of UCP2 were reported in cohorts composed essentially of nondiabetic individuals. In the present study, we investigated the association of the −866 SNP in the UCP2 promoter region with the BMI, dyslipidemia, and traits related to hyperglycemia in a cohort of patients with type 2 diabetes.

Section snippets

Subjects

We studied a group of 681 unrelated Caucasian patients with type 2 diabetes mellitus, clinically followed by us (JT and DDL), and consecutively recruited at the diabetes department of Hôspital Necker, Paris, France. Clinical and biological data were obtained from their medical records and correspond to the most recent standardized complete clinical follow-up taken before inclusion in the research protocol. Routine biochemistry measurements (glucose, HbA1c, creatinine, and lipid levels) were

Results

Table 1 shows the clinical profile of diabetic patients according to UCP2 genotype. The BMI, the prevalence of arterial hypertension, the age at diagnosis of diabetes and traits related to the severity of hyperglycemia (fasting plasma glucose and HbA1c levels) were similar in the three groups of patients. Treatment of diabetes was similar in carriers of the three genotypes. However, in insulin users, there was a trend towards an earlier requirement of insulin after diagnosis of diabetes in

Discussion

In the present investigation, we have shown that a frequent and functional A/G SNP at position −866 in the promoter region of UCP2 is associated with the plasma levels of triglycerides, total cholesterol, and LDL cholesterol in type 2 diabetic subjects. Multiple factors are involved in the dyslipidemia associated with type 2 diabetes, including effects of insulin on liver apoprotein production, on actions of cholesteryl ester transfer protein, on the regulation of lipoprotein lipase and

Acknowledgments

This work was supported by grants from INSERM/Merck, Sharp Dhome, and Chibret for research in Clinical Investigation Centers (INSERM CIC 9303 NEM), the FRM (Fondation pour la Recherche Médicale), France, and CAPES, Brazil. We thank Pr. Marc Delpech and Dr. Dominique Récan (Banque de Cellules, Hôpital Cochin) for their help with DNA banking.

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  • UCP2–866G/A Polymorphism is Associated with Prediabetes and Type 2 Diabetes

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    Earlier studies (42,43) found no association between this polymorphism and lipid levels. In contrast, Reis AF, et al. (44) showed that the G allele of UCP2 −866G/A was associated with increased TG and TC levels, and increased the risk of hyperlipidemia. To the best of our knowledge, this is the first report on the association of the UCP2 −886G/A polymorphism with pre-DM rather than T2DM alone.

  • The -866G/A polymorphism in the promoter of the UCP2 gene is associated with risk for type 2 diabetes and with decreased insulin levels

    2019, Gene
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    In accordance with our report, other authors also found that the G-866A polymorphism is not associated with lipid levels (Mancini et al., 2003; Sesti et al., 2003; D'Adamo et al., 2004; Bulotta et al., 2005). On the contrary, Reis et al. (2004) reported that “G” allele in the UCP2 promoter region was associated with elevated level of triglycerides, total cholesterol and increased risk of dyslipidemia. Further, a study among Korean women emphasizes that the person carrying “A” allele had decreased level of HDL than the “G” allele (Cha et al., 2007).

  • No association between peroxisome proliferator-activated receptor and uncoupling protein gene polymorphisms and obesity in Malaysian university students

    2010, Obesity Research and Clinical Practice
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    For UCP2, the genotype distribution pattern for the −866G/A SNP in this study is dissimilar to the studies in Singaporeans [33] and French Caucasians [21], where they had the lowest AA genotype prevalence instead of GG. Also, the 0.56 frequency of the A allele among Malaysian Chinese is higher than 0.38 frequency among Singaporean Chinese [33], and also other Caucasian populations [21,34]. In the present study, the non-association of this SNP with obesity and its related indicators is in agreement with another study done by Dalgaard et al. [34] which revealed that it was not associated with obesity or obesity-related intermediary phenotypes in Danish subjects.

  • Association of UCP2 and UCP3 gene polymorphisms with serum high-density lipoprotein cholesterol among Korean women

    2007, Metabolism: Clinical and Experimental
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    In East Asian populations, however, metabolic risk is moderate at a BMI of 25 and becomes severe at a BMI of 30 [44]. In this study, we determined that the frequency (0.48) of the risky A allele of −866G>A in the Korean population is similar to that of the Japanese population (0.46-0.47) [43,45], both of which are significantly higher than the frequencies (0.36-0.38) determined in white population studies [14,36,46]. The higher frequency of the risky allele in the East Asian population may contribute, at least in part, to the higher susceptibility to metabolic disorders compared with white populations.

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