Evidence for an association with type 2 diabetes mellitus at the PPARG locus in a South Indian population
Introduction
Diabetes is a major clinical and public health problem within certain racial and ethnic groups where both new cases of diabetes and the risk of associated complications are increasing at an alarming rate [1]. Indians are one such ethnic group who is considered to be a high-risk population for diabetes. Studies have shown that type 2 diabetes mellitus occurs at least 2 decades earlier in migrant Indians compared with the host population of those countries [2], [3]. It is also well established that Asian Indians have greater insulin resistance [4] and waist -hip ratio [5], [6], and increased susceptibility to diabetes [7], [8], [9] and to premature coronary artery disease [10], [11] compared with Europeans. This is indicative of a strong genetic predisposition to type 2 diabetes mellitus and its related traits in Asian Indians.
Peroxisome proliferator–activated receptor–γ2 (PPARG2) plays a significant role in regulating adipose cell differentiation and insulin action [12], [13]. In addition to its role in adipogenesis, PPARG2 has a role in insulin signaling [14], insulin resistance [15], and development of type 2 diabetes mellitus [15] and is the target for the thiazolidinedione group of drugs. The relative potency of most thiazolidinediones to bind and activate PPARG2 in vitro correlates perfectly with their antidiabetic potency in vivo, suggesting that PPARG2 mediates their antidiabetic effect [16]. Because of its key role in adipogenesis and the expression of genes that favor energy storage, it has been called the ultimate thrifty gene[17].
In the present study, we screened the promoter and the coding regions of the PPARG2 gene for novel variations and evaluated the association of the identified variants with type 2 diabetes mellitus and its metabolic abnormalities. Nine variants were identified, of which the highly prevalent CCA-to-GCA (Pro12Ala), the silent CAC478CAT (His478His), and the promoter −1279G/A variants were considered for an extensive study on a large population based on location (promoter and coding region) and frequency. We have already shown in our earlier study that the Pro12Ala variant is not associated with type 2 diabetes mellitus in Asian Indians [18]. Recently, we have shown that Pro12Ala, His478His, and −1279G/A variants were not associated with metabolic syndrome in our population [19]. In this study, we examined the association of the 3 variants with type 2 diabetes mellitus and the combined effect of Pro12Ala with the other 2 variants in association with type 2 diabetes mellitus in a South Indian population.
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Study population
A total of 2000 unrelated subjects were randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), an ongoing epidemiologic study conducted on a representative population of 26 001 individuals (aged ≥20 years) in Chennai (formerly Madras), the fourth largest city in India, with a population approximately of about 4.2 million. The methodology of the study has been described elsewhere [20]. In phase 1 of CURES, individuals were screened by a systematic sampling technique. In phase
Results
The diabetic subjects (52 ± 11 years) were older compared with the NGT subjects (46 ± 12 years, P = .0001). Compared with the NGT subjects, the diabetic subjects had significantly higher BMI (diabetes, 26.1 ± 4.2 kg/m2 vs NGT, 24.0 ± 4.7 kg/m2; P = .003), waist circumference (diabetes, 92.3 ± 9.4 cm vs NGT, 87.2 ± 11.4 cm; P = .002), total cholesterol (diabetes, 201 ± 42 mg/dL; NGT, 176 ± 37 mg/dL; P < .0001), and serum triglycerides (diabetes, 180 ± 130 mg/dL; NGT, 112 ± 65 mg/dL; P < .0001).
Discussion
The important finding of this study is that the 3 variants of the PPARG2 gene are not independently associated with type 2 diabetes mellitus; but as 2 loci (Pro12Ala and −1279G/A) and as a haplotype (A-Ala-T), they show a protective effect against the development of diabetes. This is one of the first reports investigating the association of these 3 variants with type 2 diabetes mellitus in Asian Indians.
The frequency of the A allele of the −1279G/A variant in the NGT and type 2 diabetes
Acknowledgment
The study was supported by a grant from the Department of Biotechnology, New Delhi. We thank the Chennai Wellingdon Corporate Foundation for their support for the CURES field studies (CURES-63).
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Polymorphisms in the IRS-1 and PPAR-γ genes and their association with polycystic ovary syndrome among South Indian women
2012, GeneCitation Excerpt :Our study also suggests similar pattern of relationship of the PPAR‐γ with the specific quantitative clinical traits representing the insulin resistant phenotypes in PCOS. Further, the allele and the genotype frequencies reported in our study are comparable to similar data on T2DM cases from Southern India (Vimaleswaran et al., 2010). While we could find association of both the PPAR-γ variants with PCOS, Vimaleswaran et al. (2010) did not find any association of the Pro12Ala with T2DM.
Genotype risk score of common susceptible variants for prediction of type 2 diabetes mellitus in Japanese: The Shimanami Health Promoting Program (J-SHIPP study): Development of type 2 diabetes mellitus and genotype risk score
2011, Metabolism: Clinical and ExperimentalCitation Excerpt :Here, to clarify the prognostic significance of these T2DM-associated variants, we conducted a longitudinal genetic epidemiological study in a community-dwelling general population. Furthermore, we also investigated the cross-validity and prognostic significance of the additionally identified susceptible genes, including MTNR1B, TSPAN8, CDC123, ADAMTS9, THADA, JAZF1, PANK1, HK1, WFS1, and TCF2 [14-21], as well as KCNQ1, which was identified by a Japanese GWAS [22]. All T2DM subjects (n = 506) were in- or outpatients evaluated by diabetes specialists at Ehime University Hospital and Ehime Prefectural Hospital in Japan.
Association between PPARγ rs1801282 polymorphism with diabetic nephropathy and type-2 diabetes mellitus susceptibility in south India and a meta-analysis
2020, NefrologiaCitation Excerpt :After removing the duplicate studies, case reports, studies on cell lines, 236 records remained. According to the quality assessment criteria, followed by HWE analysis, nine studies T2DM = 6365, controls = 5322 participants26–33 were eligible for this meta-analysis. The characteristics (author name, year of publication, country, ethnicity, DNA source, a sample size of cases-controls and genotyping methods) of each study included in the meta-analysis were defined in supplementary Table 2.
PPARG (Pro12Ala) genetic variant and risk of T2DM: a systematic review and meta-analysis
2020, Scientific Reports
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These authors contributed equally to the work.