Epidemiological studies have demonstrated that glucose intolerance, hypertension, and abdominal obesity often coexist in the same individuals increasing the risk for coronary heath disease (CHD). In 1988, Reaven focused on this cluster of cardiovascular risk factors, named it as "syndrome X", and proposed insulin resistance as the possible common etiological factor . The relationship between insulin resistance and metabolic risk factors is not fully understood and appears complex. Most persons with insulin resistance have abdominal obesity, and dysfunctional adipose tissue might be the common link in determining this cluster of risk factors, currently named as metabolic syndrome (MetS).
Among the clinical criteria proposed for the diagnosis of MetS, the one provided by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) is easily applicable, and identifies patients with different combinations of hypertension, atherogenic dyslipidemia, impaired glucose homeostasis, and visceral obesity . It is difficult to dissect the possible contribution of each MetS component to CHD risk; however, there is little doubt that in individuals with MetS the CHD risk is increased, and that insulin resistance enhances the risk of developing type 2 diabetes.
The pathogenesis of MetS has been associated with the effect of a genetic predisposition  in combination with environmental factors. Considering the central role of adipose tissue in MetS, different adipocyte related genes have been studied as possible candidates in MetS, including peroxisome proliferator-activated receptor-γ (PPARγ), and renin-angiotensin system related genes. PPARγ transcriptionally regulates the expression of genes involved in cell metabolism; endogenous ligands are thought to bind PPARγ and promote downstream gene target transcription [4, 5]. From human PPARγ gene two distinct isoforms of mRNA and protein, PPARγ1 and PPARγ2, are spliced . PPARγ 1 is abundantly expressed in different tissues including adipose tissue and macrophages , whereas PPARγ 2 expression is restricted only to adipose tissue. In vivo and in vitro studies demonstrated that PPARγ has a critical role in regulating adipocyte differentiation and lipid accumulation [8, 9]; furthermore, its has been implicated in the regulation of lipid homeostasis and insulin sensitivity . Not surprisingly, PPARγ has been identified as the target for thiazolidinediones , drugs that improve insulin sensitivity . The role of PPARγ in affecting insulin action has been confirmed by several genetic studies on PPARγ gene polymorphisms; among these, the Pro12Ala mutation in PPARγ 2 (Pro12Ala) is the most common . The Ala12 variant has been associated with decreased body mass index (BMI) [13–16], increased BMI [17, 18], and increased risk of obesity . Different meta-analysis on Pro12Ala mutation and type 2 diabetes indicates that Ala12 carriers have a reduced risk of diabetes compared to Pro12 carriers [20, 21]; nevertheless, the association between Pro12Ala and type 2 diabetes seems to be modulated by genetic and environmental factors, dietary lipids , and intrauterine condition .
Recently, the Angiotensin Converting Enzyme (ACE) gene also received substantial attention as possible candidate for diabetes , hypertension , cardiovascular disease , and diabetic nephropathy . Recent data suggest that the Renin Angiotensin System might be involved in the pathophysiology of obesity and associated hypertension ; therefore, ACE gene might be a good candidate for MetS. The most common ACE gene polymorphism is the insertion-deletion (I/D) located in intron 16; the D allele has been associated with higher levels of circulating ACE [29, 30]. Moreover PPARs modulate the renin-angiotensin-aldosterone system (RAAS), by transcriptional control of renin, angiotensinogen, angiotensin converting enzyme (ACE) and angiotensin II receptor 1 (AT-R1) , linking biologically the Renin Angiotensin System with the PPARs. Despite data on the association between ACE gene and MetS or hypertension are not conclusive, it appears interesting to evaluate the possible interaction of these two common polymorphisms.
In the present study we investigated, in a cohort of Italian adult individuals, the possible association between PPARγ2 Pro12Ala and ACE I/D polymorphisms and MetS components; furthermore, we searched for a possible interaction between these two common genetic variants.