Elsevier

Metabolism

Volume 59, Issue 4, April 2010, Pages 457-462
Metabolism

Evidence for an association with type 2 diabetes mellitus at the PPARG locus in a South Indian population

https://doi.org/10.1016/j.metabol.2009.07.034Get rights and content

Abstract

Peroxisome proliferator–activated receptor–γ2 (PPARG2) is a nuclear hormone receptor of ligand-dependent transcription factor involved in adipogenesis and a molecular target of the insulin sensitizers thiazolidinediones. We addressed the question of whether the 3 variants (−1279G/A, Pro12Ala, and His478His) in the PPARG2 gene are associated with type 2 diabetes mellitus and its related traits in a South Indian population. The study subjects (1000 type 2 diabetes mellitus and 1000 normal–glucose-tolerant subjects) were chosen randomly from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The variants were screened by single-stranded conformational variant, direct sequencing, and restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotypic frequencies. The −1279G/A, Pro12Ala, and His478His variants of the PPARG2 gene were not associated with type 2 diabetes mellitus. However, the 2-loci analyses showed that, in the presence of Pro/Pro genotype of the Pro12Ala variant, the −1279G/A promoter variant showed increased susceptibility to type 2 diabetes mellitus (odds ratio, 2.092; 95% confidence interval, 1.22-3.59; P = .008), whereas in the presence of 12Ala allele, the −1279G/A showed a protective effect against type 2 diabetes mellitus (odds ratio, 0.270; 95% confidence interval, 0.15-0.49; P < .0001). The 3-loci haplotype analysis showed that the A-Ala-T (−1279G/A-Pro12Ala-His478His) haplotype was associated with a reduced risk of type 2 diabetes mellitus (P < .0001). Although our data indicate that the PPARG2 gene variants, independently, have no association with type 2 diabetes mellitus, the 2-loci genotype analysis involving −1279G/A and Pro12Ala variants and the 3-loci haplotype analysis have shown a significant association with type 2 diabetes mellitus in this 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.

Section snippets

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).

References (31)

  • MckeigueP.M. et al.

    Coronary artery disease in South Asian overseas: a review

    J Clin Epidemiol

    (1989)
  • MckeigueP.M.

    Coronary heart disease in Indians, Pakistanis and Bangladeshis: aetiology and possibilities for prevention

    Br Heart J

    (1992)
  • SempleR.K. et al.

    PPARG and human metabolic disease

    J Clin Invest

    (2006)
  • RadhaV. et al.

    The genetics of diabetes mellitus

    Indian J Med Res

    (2003)
  • BalasubramanyamM. et al.

    Current concepts of PPAR-gamma signaling in diabetes mellitus

    Curr Sci

    (2000)
  • Cited by (0)

    1

    These authors contributed equally to the work.

    View full text