Abstract
Single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor γ (PPARG) gene have been associated with cardiovascular risk factors, particularly obesity and diabetes. We assessed the relationship between 4 PPARG SNPs (C-681G, C-689T, Pro12Ala, and C1431T) and coronary heart disease (CHD) in the PRIME (249 cases/494 controls, only men) and ADVANCE (1,076 cases/805 controls, men or women) studies. In PRIME, homozygote individuals for the minor allele of the PPARG C-689T, Pro12Ala, and C1431T SNPs tended to have a higher risk of CHD than homozygote individuals for the frequent allele (adjusted OR [95% CI] = 3.43 [0.96–12.27], P = .058, 3.41 [0.95–12.22], P = .060 and 5.10 [0.99–26.37], P = .050, resp.). No such association could be detected in ADVANCE. Haplotype distributions were similar in cases and control in both studies. A meta-analysis on the Pro12Ala SNP, based on our data and 11 other published association studies (6,898 CHD cases/11,287 controls), revealed that there was no evidence for a significant association under the dominant model (OR = 0.99 [0.92–1.07], P = .82). However, there was a borderline association under the recessive model (OR = 1.29 [0.99–1.67], P = .06) that became significant when considering men only (OR = 1.73 [1.20–2.48], P = .003). In conclusion, the PPARG Ala12Ala genotype might be associated with a higher CHD risk in men but further confirmation studies are needed.
Highlights
The peroxisome proliferator-activated receptor γ (PPARG) is a nuclear hormone receptor that dimerizes with the retinoid X receptor (RXR) to regulate target genes involved in adipocyte differentiation and insulin sensitization [1]
Major cardiovascular risk factors such as smoking, history of hypertension, history of dyslipidemia, history of diabetes, and systolic and diastolic blood pressure levels differed between cases and controls in both PRIME and ADVANCE studies (Table 1)
In PRIME, homozygote individuals for the minor allele of the PPARG C-689T, Pro12Ala, and C1431T SNPs tended to have a higher risk of coronary heart disease (CHD) than homozygote individuals for the frequent allele (OR [95% CI] = 3.34 [0.98–11.45], P = .054, odds ratio (OR) = 3.32 [0.97–11.39], P = .056 and OR = 5.93 [1.19–29.45], P = .029, resp.)
Summary
The peroxisome proliferator-activated receptor γ (PPARG) is a nuclear hormone receptor that dimerizes with the retinoid X receptor (RXR) to regulate target genes involved in adipocyte differentiation and insulin sensitization [1]. Activation of PPARG with thiazolidinediones is used to stimulate insulin sensitivity in the treatment of type 2 diabetes. PPARG plays a role in macrophage, malignant breast epithelial, colon cancer cell differentiation, and lipid homeostasis [2] and has been shown to control the expression of proinflammatory genes in vascular cell models [3]. This suggests that PPARG may contribute to the pathogenesis of the atherosclerotic plaque physiology at a very early stage. The Pro12Ala substitution in the specific exon B of PPARG2 isoform, which contributes to a lower PPARG2
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