Peroxisome Proliferator-Activated Receptor- 2 P12A Polymorphism and Risk of Coronary Heart Disease in US Men and Women

Department of Nutrition , Harvard University, Cambridge, Massachusetts, United States
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 09/2005; 25(8):1654-8. DOI: 10.1161/01.ATV.0000171993.78135.7e
Source: PubMed


Activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma) improves insulin sensitivity and exerts antiatherogenic effects. A common alanine for proline substitution at codon 12 in the PPARG2 gene is related to lower receptor activity. Studies suggest that the A12 allele is associated with reduced risk of type 2 diabetes; however, data on the risk of coronary heart disease (CHD) are scarce and controversial.
We examined the relationship between PPARG2 P12A and CHD risk in women (Nurses' Health Study) and men (Health Professionals Follow-Up Study) in nested case control settings. Among participants free of cardiovascular disease at baseline, 249 women and 266 men developed nonfatal myocardial infarction (MI) or fatal CHD during 8 and 6 years of follow-up, respectively. Using risk-set sampling, controls were selected 2:1 matched on age, smoking, and date of blood draw. The relative risk (RR) of nonfatal MI or fatal CHD of carriers compared with noncarriers of the A12 allele was 1.17 (95% CI, 0.82 to 1.68) among women and 1.44 (95% CI, 1.00 to 2.07) among men (pooled RR, 1.30 [95% CI, 1.00 to 1.67]). We found a significantly increased risk associated with the A12 allele among individuals with a body mass index > or =25 kg/m2 (women: RR, 1.88; 95% CI, 1.01 to 3.50; men: RR, 1.55; 95% CI, 0.92 to 2.60; pooled: RR, 1.68; 95% CI, 1.13 to 2.50) but not among those <25 kg/m2 (pooled RR, 0.86; 95% CI, 0.37 to 1.97; P heterogeneity overweight versus nonoverweight 0.16).
These data do not support the hypothesis that the A12 allele is associated with a decreased risk of CHD. The potential interaction between PPARG2 P12A, overweight, and increased CHD risk needs further evaluation.

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    • "We sequentially removed the single study every time to ascertain the cause of heterogeneity. As a result, 2 independent studies (Zee et al. [44] and Pischon [HPFS] et al. [22]) accounted for the major sources of heterogeneity. The overall heterogeneity of the Pro12Ala polymorphism no longer existed when these 2 studies were ruled out respectively in the total analysis under the four genetic models (Pheterogeneity>0.10) and the total effect estimation remained negative. "
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    ABSTRACT: Contradictory results have been reported regarding the association between Pro12Ala polymorphism of PPARγ2 and coronary artery disease (CAD). We sought to estimate the inconsistent results by performing a comprehensive meta-analysis. Studies in English or Chinese publications were identified by screening MEDLINE, Embase, CNKI, Wanfang and CBM. 22 studies including 8948 cases and 14427 controls were selected. A random-effects model was applied to combine the divergent outcomes of the individual studies, while addressing between-study heterogeneity and publication bias. The Pro12Ala polymorphism of control population followed Hardy-Weinberg equilibrium for all studies (P>0.05). Overall, a marginal increased risk of CAD under the recessive genetic model (AlaAla vs ProAla+ProPro: P = 0.04, OR = 1.31, 95%CI 1.01-1.69, P(heterogeneity) = 0.67, I(2) = 0%) and the homozygote comparison (AlaAla vs ProPro: P = 0.04,OR = 1.30, 95%CI 1.01-1.68, P(heterogeneity) = 0.68, I(2) = 0%) was observed. In the subgroup analysis by ethnicity, carriers of AlaAla homozygotes had a significant increased risk for CAD among Caucasians (AlaAla vs ProAla+ProPro: P = 0.01, OR = 1.45, 95%CI 1.08-1.96, P(heterogeneity) = 0.48, I(2) = 0%; AlaAla vs ProPro: P = 0.02,OR = 1.44, 95%CI 1.07-1.93, P(heterogeneity) = 0.46, I(2) = 0%). After dividing into population source, the CAD risk magnitude of hospital-based studies was distinctly strengthened under the recessive model (P = 0.03,OR = 1.85,95%CI 1.07-3.19, P(heterogeneity) = 0.87,I(2) = 0%) and the homozygote comparison (P = 0.03,OR = 1.83, 95%CI 1.06-3.16, P(heterogeneity) = 0.88, I(2) = 0%). There was no observable publication bias as reflected by funnel plot and Egger's linear regression test (t = -0.12, P = 0.91). Our results demonstrated that the PPARγ2 Pro12Ala polymorphism might be risk-conferring locus for the progression of CAD among Caucasians, but not among Asians.
    Full-text · Article · Dec 2012 · PLoS ONE
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    • "As reported by Temelkova-Kuktshiev et al. [15], the decreased risk of atherosclerosis was observed only in Ala12 homozygotes, not among Pro-Ala heterozygotes . Two previous studies failed to identify any association between PPARγ2Ala12 and atherosclerosis [17] [18], but both the cases and controls in these studies had significant risk factors (either T2D or obesity) that may have rendered the risk associated with the Pro12 Ala polymorphism less discernable. Although PPARγ2 Pro12Ala has been widely reported to affect risk of T2D [10] [11] [12], PPARγ2 allele and genotype frequencies were not significantly different in T2D+ CAD patients vs. controls or in CAD patients with vs. without T2D. "
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    ABSTRACT: Several studies suggest that the peroxisome proliferator-activated receptor gamma (PPARγ) is involved in atherogenesis. The Pro12Ala polymorphism in the gene encoding PPARγ (PPARγ2 gene) influences the risk for type 2 diabetes. Two population-based studies have shown that the Ala allele is associated with reduced carotid intimal-medial thickness (IMT). However, studies focusing on acute clinical events have yielded conflicting results. Our aim was to evaluate the role of the Pro12Ala PPARγ2 polymorphism on the risk of coronary artery disease (CAD) in an Italian population with a case-controlled genetic association study in which 478 CAD patients and 218 controls were genotyped for the Pro12Ala polymorphism. CAD was diagnosed by angiography. We found that homozygotes for the Ala12 allele had a significantly reduced risk of CAD after adjusting for diabetes, sex, age, body mass index (BMI), smoking, lipids and hypertension (OR = 0.007; 95% C.I. = 0.00–0.32 p < 0.011). In this casecontrol study, homozygosity for the Ala allele at codon 12 of the PPAR 2 gene resulted in reduced risk of CAD. This is consistent with reports from previous studies focusing on atherosclerosis and myocardial infarction.
    Full-text · Article · Jan 2010 · Disease markers
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    • "Diabetes and overweight are risk factors for coronary heart disease and ACS, and therefore the PPARγ2 Pro12Ala variant could be associated with lower risk of coronary heart disease and ACS. Indeed, variant allele carriers of PPARγ2 Pro12Ala have been reported to be at lower risk of myocardial infarction in some studies [8,9], but this was not confirmed in two prospective cohorts, where variant allele carriers were at higher risk of coronary heart disease than homozygous common allele carriers [10,11]. The varying results may be explained by a low number of cases and thus limited statistical power but may also be explained by different distributions of potential effect modifiers in the study populations. "
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    ABSTRACT: Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the western world. Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the regulation of the energy balance, adipocyte differentiation and lipid biosynthesis. The aim was to investigate if the polymorphism PPARgamma2 Pro12Ala, which encodes a less efficient transcription factor, was associated with risk of acute coronary disease and if there were interactions between this polymorphism and factors that modify PPARgamma activity, such as alcohol intake, smoking, and use of non-steroidal anti-inflammatory medicine. A case-cohort study including 1031 ACS cases and a sub-cohort of 1703 persons was nested within the population-based prospective study Diet, Cancer and Health of 57,053 individuals. Homozygous male variant allele carriers of PPARgamma2 Pro12Ala were at higher risk of ACS (HR = 2.12, 95% CI: 1.00-4.48) than homozygous carriers of the Pro-allele. Among men, there was a statistically significant interaction between genotypes and alcohol intake such that homozygous variant allele carriers with a low alcohol intake were at higher risk of ACS (HR = 25.3, CI: 16.5-38.7) compared to homozygous common allele carriers (p for interaction < 0.0001). Overall, the association was only observed among homozygous variant allele carriers. Thus, all the observed associations were obtained in subgroups including small numbers of cases. It is therefore possible that the observed associations were due to chance. In the present study, there were no consistent associations between PPARgamma Pro12Ala and risk of ACS, and no consistent interaction with alcohol, BMI, NSAID or smoking in relation to ACS.
    Full-text · Article · Jun 2009 · BMC Medical Genetics
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