CAD is the most common cause of death among diabetic patients. Adult diabetic patients have an increased risk of mortality due to heart disease and stroke from 2-4 times more than those without diabetes [22]. Dyslipidemia, obesity, and hypertension are the leading cause of elevating the risk for CVD observed in T2DM patients [1, 23]. The identification of genetic markers implicated in dyslipidaemia and oxidative stress, such as the PPARγ gene, is one possible approach to determine an individual risk profile.
PPARγ is express in all significant cells of the vasculature: vascular smooth muscle cells, human endothelial cells, and macrophages [24, 25]. Furthermore, PPARγ has a significant role in lipoprotein metabolism, vascular homeostasis, and glucose homeostasis [14, 26]. Therefore PPARγ is a potential candidate gene for the link between diabetes mellitus and CAD in patients with diabetes mellitus, and its variation has been reported associated with several metabolic syndromes such as T2DM, cardiovascular diseases (CVD) and hyperlipidemia [12]. Although some studies have been conducted to investigate the association between the PPARγ2 Pro12Ala polymorphism and CAD risk, the results obtained from these studies have remained conflicting [10, 14, 27-30]. Therefore, we carried out this work to further explore the association between the PPARγ2 Pro12Ala polymorphism and the risks of CAD.
The idea of this study was based on determining a genetic marker for early detection or prediction of CAD in diabetic patients and in the current study based on Iranian population, we found that the common variant of PPARγ2, rs1801282 (c.34C>G, Pro12Ala), is significantly associated with higher CAD risk. Our findings are in agreement with various studies that carried out in different populations and ethnic groups. Hasan et al. (2017) reported that PPARγ Pro12Ala polymorphism was associated significantly with the development of CAD in T2DM Egyptian subjects [12]. They are also suggested that the SNP at the Pro12Ala was associated with BMI, weight, DBP, SBP, and LDL in patients suffering from CAD with or without T2DM. However, our report demonstrates that there is no significant difference between this polymorphism and physiologic variables in both patient and control groups. Wu, Z et al. (2012) performed a meta-analysis and indicated that the Pro12Ala polymorphism might be a risk-conferring locus for the progression of CAD in the Caucasians population, but not among Asians and other population [10]. In an American study, Pischon et al. (2005) demonstrated that the Ala12 allele had a significantly increased risk for CAD and that these results were more significant in overweight (but not normal weight) subjects, suggesting that the involvement of PPARγ Pro12Ala polymorphism in the vasculature might occur in association with obesity [19]. These results suggest a high possibility of involvement of Pro12Ala polymorphism in the occurrence and risk for CAD in patients with T2DM.
On the other hand, Rhee et al. (2007) suggested that this polymorphism had no significant association with CAD in Korean subjects, the similar results were also found in Galgani et al. (2010), Bluher et al. (2002) and Youssef SM et al. (2013) studies in Italian, Germany, Tunisia populations, respectively [24, 27, 29, 31].
The reason for the difference between these studies can be explained by a relatively small size of samples in some enrolled studies, ethnic factors, the limited statistical power of single studies, different distributions of potential effect modifiers in the study populations, and genetic heterogeneity in disease identification strategy.
In summary, our study indicates that Pro12Ala polymorphism in exon B of PPARγ showed a significant association with higher CAD risk in Iranian patients with T2DM. As a result, it could be concluded that this polymorphism could be an essential indicator for an increased risk of CAD in diabetic patients. More prospective registered studies with a larger sample size will help to confirm or refute this association.