The prevalence of overweight and obesity has risen sharply worldwide over the past few decades, and China reaching a rate of 28.1% of overweight and 5.2% of obesity in 2015(24). The majority of the studies have emphasized the influence of SNP in obesity, especially the polymorphisms of PPARγ2 gene Pro12Ala and C161-T. At present, however, there is no report on the correlation between PPARγ2 gene polymorphism and obesity of Han nationality in the cold region of Yunnan Plateau. To our knowledge, this is the first study to date to investigate whether the main effects of PPARγ2 gene Pro12Ala and C161-T polymorphisms are associated with the risk of obesity in Han ethnic groups in the cold region of Yunnan Plateau.
The PPARγ2 Pro12Ala polymorphism has been widely implicated in affecting the risk of obesity (25),although genetic evidence of its effect on obesity is inconsistent. In this study, single locus analysis did not show a significant main effect of PPARγ2 Prol2Ala (in genotypic test, or odds ratio analysis) on the risk of obesity in the whole sample population. Our results were consistent with those of several other studies. A previous study by Vaccaro suggested no significant association between PPARγ Prol2Ala polymorphism and obesity in Italian subjects(26). In addition, Oh EY also presented their own opinion that PPARγ2 Prol2Ala may not be a determinant of obesity among Koreans(27). Clement and Ghoussaini et al also showed that the PPARγ2 Prol2Ala polymorphism was unlikely to influence obesity in French subjects(14, 28). In contrast to our study and the aforementioned studies, the G allele of PPARγ2 Pro12Ala has been suggested to be significantly associated with obesity in populations of diverse ethnicities, including Indians, Caucasians in the United States, Finns, Spanish, and Iranians(10, 29–32). The potential reasons for differences between these studies and our results may be the use of diverse phenotype assessments, insufficient sample size, ethnic differences, effects of gender, different study designs, and a lack of adjustment for confounders. The distribution of Pro12Ala polymorphism also varies among different populations. According to the HAPMAP database, the Ala allele frequency ranged between 2.7% and 4.1% in Han population, 0 to 4.4% in Africans, 4.6–16% in European population, 5.3% in Koreans, and 13% in Pakistani population. The previous studies of our research group in Yunnan Province have showed that the G allele frequency of Pro12Ala was 3.17% in Blang people, 2.27% in Wa people, 1.44% in Hani people and 4.66% in Naxi people (data unpublished). In this study, the frequency of G allele in the extreme overweight and control 1 was 3.87% and 5.11%, and in the obese and control 2 was 5.37% and 5.58%, which was close to the Korean, Hui and Naxi ethnic groups, but much lower than that in Pakistan. It may be influenced by ethnic and environmental factors, thus showing variations between different regions.
Several studies indicated that the distribution of C161-T polymorphism may varies greatly among different countries and ethnical populations. Based on our results, the T allele distribution in the extreme overweight and control 1 was 24.82% and 21.83%, and in the obese and control 2 was 24.11% and 24.95%. Our previous studies in Yunnan Province have found that the T allele frequency of C161-T was 24.50% in Blang nationality, 27.20% in Wa people, 17.35% in Hani people and 18.87% in Naxi people respectively(data unpublished). The carrying rate of T mutation gene in Blang nationality and other domestic studies was basically the same as that in this study (19, 33), however, compared with foreign studies, our results were significantly higher than that of other ethnic groups (16.30% in Caucasians and 13.30% in Japanese women), which may be caused by ethnic differences(34, 35). At present, there are few studies on PPARγ2 gene C161-T polymorphism at home and abroad, and some of them are related to chronic diseases such as obesity, diabetes, coronary heart disease and so on. A study has shown that the C161-T variant affects leptin, BMI and blood lipid levels(34). Grygiel-Gorniak et al. reported that the presence of the T allele of the PPARγ2 C161-T promoted higher BMI and visceral fat deposition(36). Studies have shown that PPARγ2 gene C161-T has the largest CC type BMI, waist circumference and hip circumference, and the smallest TT genotype (37). There are also studies suggesting the opposite conclusion. The Chia PP et al. suggest that C161-T polymorphism is not associated with obesity(38). In our previous studies, we found that the association between C161-T polymorphism and obesity was not found in Yunnan Blang, Wa and Hani nationalities (data unpublished). In our study, no statistical significance was found between the genotype of C161-T polymorphism frequency distribution and the extreme overweight or obesity. We speculated that this might be partly due to the differences in the haplotypes of PPARγ among different ethnic groups, and Pro12Ala and C161-T were associated with other SNPs in PPARγ gene. Therefore, other variants around PPARγ Pro12Ala and C161-T may influence the prevalence of overweight or obesity.
Our study showed that the combined genotypes "CC + TT" of PPARγ2 Pro12Ala and C161-T were associated with an increased risk of extreme overweight (OR = 4.04; 95%CI = 1.33–12.33; P = 0.014), using "CC + CC" combination genotype as reference category. As far as we know, the present study is the first analysis of the Pro12Ala and C161-T polymorphisms in the PPARγ2 gene and obesity.
The study population in the present analysis were all from Yongsheng, Lijiang county of Yunnan province, where belongs to the typical plateau slants cold regions. Special geographical environment may produce certain effect to our study results. As a major regulator of adipocyte development, PPARγ regulates adipogenesis and adipogenesis pathways in white adipocytes (39), and is required for the differentiation and control of the thermogenesis program in brown or beige adipocytes (40). Exposure to low temperatures modulates the expression of heat shock protein (HSP) in humans and animals, and it has been reported that the HSP20-FBXO4-ubiquitin dependent pathway plays a role in mediating adipocytic function by inhibiting PPARγ activity of β-adrenergic signaling(41). On this basis, we speculated other possibilities for the results of this study, that is whether the high expression of HSP under cold exposure inhibits the activity of PPARγ and reduces its regulatory function on adipocytes, thus covering the possible association between PPARγ gene polymorphism and obesity, because the study objects are located in a cold region. Of course, this hypothesis needs to be explored in further experimental studies.
One limitation of the study is that the sample was too small to draw firm conclusions. Secondly, the results of our study may not be generalized to other populations, and it is necessary to conduct ethno-matching studies to understand whether such results exist in Han subjects from non-cold areas of the Yunnan Plateau (42). Due to the multifactorial inheritance of obesity, more research must be done to elucidate the role of different genes and SNPs. In future work, it is necessary to conduct large-scale trials to answer the correlation between this SNP and obesity and obesity-related metabolic characteristics.