In the present study of the Balinese population, we examined the association of two commonly observed UCP2 gene polymorphisms, the G(−866)A in the promoter region (rs659366) and the Ala55Val in exon 4 (rs660339), with obesity, high FPG and high serum lipids. Uncoupling protein 2 has been reported to play an important role in the regulation of human energy metabolism, through its functions of proton gradient dissipation, and uncoupling of respiration from oxidative phosphorylation that consequently converted ATP to heat. Thus, variations in the UCP2 gene was proposed as potential modulator of energy balance.
Urban lifestyle affected BMI
This study provided evidence concerning the role of UCP 2 gene polymorphisms in influencing the increasing prevalence of obesity. Moreover, this study has the advantage of being conducted in a relatively homogeneous population in terms of genetic backgrounds, considering Bali is a small island, and intermarriage between Balinese with individuals from other ethnic groups is still relatively uncommon. Also, as a population that has undergone swift lifestyle changes for the last 20 years due to rapid developments in the tourism industry, the traditional Balinese has become more sedentary [28, 32, 33]. The effect of these lifestyle changes is reflected by the high prevalence of obesity in the urban as compared to the rural Balinese. Furthermore, BMI was higher in the urban subjects (both male and female) of the non-obese group, showing that lifestyle changes influenced the increasing BMI.
In spite of the fact that this study has a power limitation for the genetic analyses due to the relatively small sample size, in particular in the sub-group analyses, we found that the MAFs for both G(−866)A and Ala55Val SNPs of the UCP2 genes were rather high, showing that these polymorphisms were relatively frequent in this population.
UCP2 G(−866)A influenced the increased of BMI
In the Balinese population studied, we observed that urban subjects with A/A genotype of the SNP G(−866)A has higher BMI than rural subjects with the same genotype, suggesting the important role of the environment. Several studies have reported that the A-allele or AA genotype is associated with obesity [22, 45]. In a study conducted in Korean women undergoing a very low-calorie program, the A/A genotype of this SNP lost less weight than carriers of the G-allele . Two other studies reported that in obese children with the A/A genotype the resting energy expenditure was increased , and in Pima Indians the SNP was associated with increased 24-hour energy expenditure . A recent study reported a strong effect of sibutramine on weight and body fat percentage loss in the combined UCP2 A/A + G/A of the SNP G(−866)A in a Taiwanese population . Interesting to note that in their placebo group, the A/A genotype showed the least weight and fat percentage loss, which was in agreement with a study conducted in Korean women , indicating that the effect of the UCP2 G(−866)A polymorphism might be universal, at least for Asian.
Even though marginal, there was also an association of the Balinese with C/T genotype of the Ala55Val SNP with high BMI when influenced by the urban environment, but we failed to detect the same association with subjects possessing the homozygous risk alleles T/T, which indicates that the interaction of UCP2 genotypes and environment is not straightforward.
Although we did not observe any significant association with other traits, a previous study has reported that subjects with the (−866)A/A genotype had significantly reduced LDL particle size, a significant predictor of the development for coronary artery disease, than those with the (−866)G/G genotype . Several studies have confirmed the association of either G(−866)A and/or Ala55Val variants with T2DM [18, 23, 25, 27, 31]. In the obese state, the risk would be increased due to insulin resistance, which may accompany obesity and impairment of glucose-stimulated insulin secretion attributable to UCP2 at-risk genotype . Excess of fat storage in the obesity state may lead to local insulin resistance, and might stimulate a chronic, sub-acute state of inflammation. A study reported an association of the high-sensitivity C reactive protein (hs-CRP), a biomarker of inflammation that is also a powerful risk marker for cardiovascular disease, with the G(−866)A polymorphism, thus suggesting the role of UCP2 gene in the regulation of the inflammatory response . The lack of association of individual UCP2 SNPs and disease traits in the Balinese population might be due to the influence of other genetic or environmental factors that were not studied in this research, such as the MTNR1B gene polymorphism that has been reported to be associated with type 2 diabetes mellitus and lipid levels in Han Chinese population .
UCP2 haplotypes interacted with environment
The G(−866)A and Ala55Val SNPs were in strong linkage disequilibrium. Therefore, the effect of one SNP cannot be separated from the other. To address the influence of combined UCP2 variants on high BMI, high levels of FPG, TG, LDL-C, and TC, as well as low level of HDL-C, we generated UCP2 haplotypes and tested the association between haplotypes and disease traits. Again, we did not find significant association between haplotypes and traits, unless influenced by the urban environment. The AT ((−866)A-55Val) haplotype showed an association with high BMI in urban, in both additive and dominant models. A trend of high FPG was observed in carriers of AC ((−866)A-55Ala) haplotype. We also noticed a tendencies of high TG, and low HDL-C in urban subjects carrying the AC ((−866)A-55Ala) haplotype, although not significant for haplotype-environment interaction in both models, which might be due to the low frequency of this haplotype in the population studied.
In our study, the level of FPG and TC in the Balinese increased with age, and male subjects have more tendency for high BMI than female subjects. A study conducted in non-diabetic Chinese reported a 0.15 mmol/L increase in FPG for every decade of increase in age . In a previous study to determine the effects of sex and ovarian hormones carried out in mice, it was reported that male mice had a greater susceptibility of body weight gain than female mice .
In this study, we did not find significant association between UCP2 gene polymorphisms and disease traits. However, we were able to demonstrate that in an urban environment, the A/A genotype of the G(−866)A SNP and the AT haplotype were associated with high BMI, and consequently resulted in high prevalence of obesity. Discrepancies between our results and others might be due not only to different ethnic groups and genetic makeup, but also to the influence of various lifestyle and environmental exposures, as well as the responses to these exposures. Thus, the role of the UCP2 variants as obesity and/or diabetes risk factor might be overshadowed by environmental influence in some populations. Nonetheless, this study and others have emphasized the important role of UCP2 in metabolism, and therefore further investigations are needed to confirm its specific role.