Sibling-based association study of the PPARγ2 Pro12Ala polymorphism and metabolic variables in Chinese and Japanese hypertension families: a SAPPHIRe study

Abstract

The peroxisome proliferator activated receptor (PPAR) gamma2 is a transcription factor that has been shown to be involved in adipocyte differentiation, adipogenesis, and insulin sensitivity. To address the role of PPARgamma2 in glucose homeostasis and insulin sensitivity, among many other objectives, we conducted a sibling-controlled association study in a multicenter program - the Stanford Asian-Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe). Approximately 2525 subjects in 734 Chinese and Japanese families have been recruited from six field centers for SAPPHIRe. In total, 1702 subjects including parents and siblings from 449 families have been genotyped for PPARgamma2, of which 328 families were Chinese and 121 Japanese. Only 88 subjects of the 1525 siblings screened for the P12A polymorphism were found to be carriers of the A variant, the most common variant of the PPARgamma2 gene. A variant frequencies of the siblings were 4.27% in Chinese and 2.72% in Japanese. A sibling-controlled association study was performed through genetically discordant sibships (i.e., P/P genotype vs. P/A + A/A genotypes). Specifically, we examined whether there were differences in metabolic variables between the discordant siblings within families. In total, 88 subjects carrying either 1 or 2 A alleles had at least one sibling who was discordant for the P12A polymorphism, yielding a total of 180 individuals from 47 families for analyses, among which 92 siblings were homozygous for wild-type P allele. Siblings with the A variant tended to have lower levels of fasting plasma glucose (OG-10), and lower glucose levels at 60 min following oral glucose loading after adjusting for age, gender, and body mass index. Using a mixed model treating family as a random effect, we found that P12A polymorphism of the PPARgamma2 gene contributes significantly to the variance in fasting plasma glucose, glucose level at 60 min, and insulin-resistance homeostasis model assessment. Our results suggest that within families siblings with the A variant in the PPARgamma2 gene may be more likely to have better glucose tolerance and insulin sensitivity independent of obesity in Chinese and Japanese populations.

The Peroxisome Proliferator-Activated Receptor-γ2 Pro12Ala Polymorphism

“…A power calculation based on these data revealed a required sample size of ϳ2,000 to achieve significance. In a Chinese/Japanese sib-pair study, which by design controlled relatively well for genetic background and childhood environment, a greater estimated insulin sensitivity (homeostasis model analysis) was observed in carriers of the Ala allele (28). Interestingly, a more pronounced effect of the Pro12Ala polymorphism on insulin sensitivity was observed before the background of the common Gly972Arg polymorphism in insulin receptor substrate-1 (29).…”

“…Cross-sectional studies with small to moderate sample sizes yielded inconsistent results by demonstrating either no difference (21,23,28,38,39) or a modestly greater BMI in carriers of the Ala allele (10,40,41). Two sufficiently large studies (Ͼ1,000 nondiabetic subjects) found a lower BMI in Finns (11) and no difference in Japanese (15).…”

Genetic epistasis of adiponectin and PPAR?2 genotypes in modulation of insulin sensitivity: a family-based association study

“…Previously we reported the association of the PPARγ 2 Ala12 variant with betType 2 diabetes mellitus (T2DM) has daunted many countries in the developed or developing world [1]. Insensitivity to insulin stimulation is generally accepted ter glucose tolerance and insulin sensitivity among subjects from Japanese and Chinese hypertension families in the Stanford Asia Pacific Program in Hypertension and Insulin Resistance (Sapphire) study [9]. Due to its family-based study design utilizing the comparisons between siblings, the genetic association study in Sapphire was expected to have better control in early childhood environmental factors and genetic background than a population-based genetic association study [9,10,11].…”

Pro12Ala polymorphism in PPAR-γ2 and dementia in Chinese nonagenarians/centenarians

“…Therefore, it is reasonable to believe that mortality in the nonagenarian/centenarian Adjusted multiple logistic regression was used to adjust for covariates OR odds ratio, Unadjusted Wald Chi-square test with df=1 was used, Model 1 adjustment made with covariates which might be associated with cognitive function at baseline (P<0.05 shown in Table 1), Model 2 adjustment made with covariates which might be associated with Pro12Ala (P<0.05 shown in Table 2), Model 3 adjustment made with all the covariates group may alter the association between dementia and Pro12Ala Polymorphism in PPAR-γ2. In addition, the prevalence of Ala12 allele varied greatly in different ethnic populations, with the prevalence rate being much lower in Asians than in Caucasians (Chuang et al 2001;Tai et al 2004). Therefore, ethnicity might also be an influencing factor.…”

“…In addition, the prevalence of Ala12 allele varied greatly among different ethnic populations, with the prevalence being much lower in Asians than in Caucasians (Chuang et al 2001;Tai et al 2004). The relationship between Pro12Ala polymorphism in PPAR-γ2 and dementia in the very-elderly population might be different from that in old people aged 60 years and above, and the allele frequency of Ala12 in PPAR-γ2 varies greatly in different ethnic populations.…”