The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor of transcription factors that bind to specific DNA response elements as heterodimers with the retinoid X receptor. The peroxisome proliferator-activated receptor-gamma (PPARG) is one of three known subtypes of PPARs. PPAR-gamma plays a key role in activation of adipocyte differentiation and is an important modulator of gene expression in a number of specialized cell types, including adipocytes, where it acts by regulating the transcription of numerous target genes. In addition, PPARG is a molecular target of the synthetic compounds, including thiazolidinediones (TZD) class of drugs, which are insulin sensitizers currently in use for the treatment of type 2 diabetes.
The PPARG gene is located on the short arm of chromosome 3 at 3p25 and spans more than 100 kb of genomic DNA with a coding sequence consisting of 9 exons. Differential promoter usage and alternative splicing of the PPARG gene generates four mRNA species (PPARG 1-4), but just two different receptor proteins, PPARG1 and PPARG2. PPARG1 is encoded by 8 exons and PPARG2 by 7 exons. PPARG1 uses exons A1 and A2, whereas PPARG2 uses exon B; both use exons 1 through 6. The PPARG2 isoform contains 28 additional amino acids at its N terminus and is the most important isoform in adipose tissue, where it is almost exclusively expressed. PPARG1 is more widely expressed; in adipose tissue, lower intestine, and macrophages. Like other nuclear receptors, PPARG protein consists of distinct functional domains including a constitutively active transactivation domain (AF-1), at the N terminus, a centrally located highly conserved DNA binding domain (DBD) composed of two zinc finger motifs, and a C-terminal ligand binding domain (LBD) that contains a powerful ligand-dependent transactivation function (AF-2). Ligand binding stabilizes the active conformation of the PPARG LBD, thereby serving as a molecular switch between activation and repression functions of the receptor.
The substitution of proline to alanine at codon 12 of the PPARG2 gene (Pro12Ala polymorphism) is most widely studied. Functional differences observed for this Ala variant are lower affinity for the response element and lower capacity for activating target genes. This polymorphism has been shown to influence the risk for type 2 diabetes and obesity in various ethnic populations worldwide. Other, very rare mutations in the PPARG gene are associated with extreme insulin resistance, familial partial lipodystrophy, and severe diabetes in humans. Additionally, loss-of function mutations in PPARG have been demonstrated for some human colon cancers and loss of heterozygosity at 3p25, a broad region that includes PPARG, has been seen in many human prostate and pancreatic endocrine tumors.
For the first time in Qatar, Badii et al. (2008) estimated the allele frequency of the Pro12Ala polymorphism of PPARG2 gene among Qataris to investigate the association between this polymorphism and obesity or type 2 diabetes (T2D). The study was based on matched age, sex, and ethnicity of 400 cases (with diabetes) and 450 controls (without diabetes). All subjects were native Qatari and aged 35-60 years. The Pro12Ala polymorphism was found to occur at low frequency (5.5% for diabetic and 5.9% for nondiabetics) as compared to the previous reports in various Caucasians. Badii et al. (2008) found that the association of Pro12Ala allele with higher BMI in non-diabetic controls was more prominent than in diabetic subjects, leading them to suggest that the controls with Pro12Ala may have higher insulin sensitivity and gain weight without developing diabetes. Similar to the observations from previous studies, the systolic blood pressures in Pro12Ala carriers were found to be significantly higher than Pro/Pro homozygous in diabetic subjects. Despite the small number of Pro/Ala carriers in this study, this result led Badii et al. (2008) to suggest that this observed phenomenon might be related to the notion that once diabetes has developed, the protective effect of Ala12 allele may be lost. Badii et al. (2008) failed to find an association between this polymorphism and T2D or obesity, consistent with several previous studies.
Strautnieks et al. (1996) carried out linkage analysis study for five consanguineous Saudi families affected with progressive familial intrahepatic cholestasis (PFIC). No significant regions of homozygosity were identified in the six affected children, and the disease locus was excluded from the 18q21-22 region, indicating the existence of locus heterogeneity within the PFIC phenotype. In 1997, Strautnieks et al. performed homozygosity mapping and a genome scan in six consanguineous Saudi pedigrees affected with PFIC. The PFIC2 locus was mapped to chromosome 2q23, with a maximum LOD score of 8.5 between marker loci D2S306 and D2S124.
Zouari Bouassida et al. (2005) conducted a case-controlled study to investigate the potential association of the genetic variation of the PPARgamma2 gene with type 2 diabetes in 242 unrelated Tunisian patients and 246 healthy control subjects. Analysis of the Pro12Ala polymorphism of the PPARgamma2 gene revealed no significant differences in the PPARgamma2 allele frequencies between diabetic patients and control subjects. However the PPARgamma2 Ala12 allele was found significantly associated with a high level of systolic blood pressure in diabetic patients. Stratification of diabetic patients on obese and non obese subjects showed non significant differences in the PPARgamma2 Ala12 frequency between the two groups. Zouari Bouassida et al. (2005) concluded that the PPARgamma2 gene is unlikely to be responsible for type 2 diabetes mellitus or obesity in Tunisian subjects.
Mohamed et al. (2007) examined the association of the PPARgamma Pro12Ala and C1431T gene variants and their haplotypes with the susceptibility to T2DM. The study involved 491 T2DM patients and 400 age- and gender-matched controls. Comparable frequencies of the mutant 12Ala (0.07 vs 0.08, p=0.216) and 1431T (0.12 vs 0.10, p=0.189) alleles, and Pro12Ala (p=0.218) and C1431T (p=0.421) genotypes were seen between patients and in non-diabetic control subjects. While no difference was noted in the distribution of Pro12Ala- C1431T haplotypes and genotypes between patients and controls, the PPARgamma 12Ala, but not 1431T, allele was significantly associated with lower body mass index (BMI) (< or =25.0) among patients. Regression analysis confirmed the association of the Pro12Ala (odds ratio =5.340; 95% confidence interval =1.044-27.311) with normal (BMI<25.0), but not with overweight/obesity among T2DM patients. Mohamed et al. (2007), thus, further confirmed the absence of an association between the PPARgamma gene and type 2 diabetes among Tunisian subjects.
Bouhaha et al. (2008) evaluated the role of the PPARgamma-Pro12Ala and ENPP1-K121Q polymorphisms on type 2 diabetes (T2D) risk in a case-control study in the Tunisian population. The results of Bouhaha et al. (2008) are supportive of a possible link between genetic variation at ENPP1-K121Q and T2D in the Tunisian population after adjustment on gender, age and BMI status (OR=1.55, 95%CI [1.11-2.16], p=0.007). Conversely, the PPARgamma-Pro12Ala variant seems not to have a significant effect on T2D risk in the Tunisian cohort. However, Bouhaha et al. (2008) noted that the minor A-allele would convey protection against obesity in the Tunisian population.
Al-Safar et al. (2015) attempted to investigate the association between TCF7L2 and PPAR-𝛾2 SNPs with Type 2 Diabetes Mellitus (T2DM) in the Emirati population and its relationship with obesity. The authors recruited 272 Emirati T2DM patients along with 216 healthy controls to the case-control study and carried out genotyping for the SNPs rs10885409 (TCF7L2) and rs1801282 (PPAR-𝛾2 Pro12Ala). No association was found between these two SNPs and T2DM in this cohort. PPAR-𝛾2 12Ala was found to be a minor allele with a frequency of 0.04. As the Pro12 allele had a very high incidence in this cohort, the study size was underpowered and the data could not be evaluated for interaction with obesity status. However, it was noted that the TCF7L2 rs10885409 C allele was a T2DM risk factor in non-obese Emirati patients [OR 1.975 (95% CI 1.127-3.461), p=0.017].
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