PPARG gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma. The protein encoded by PPARG gene is PPAR-gamma and is a regulator of adipocyte differentiation. Additionally, PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. [From RefSeq]
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].