Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes

Doney, Alex S.F.; Fischer, B.; Cecil, Joanne E.; Boylan, Katherine E.; McGuigan, Fiona; Ralston, SH; Morris, Andrew D.; Palmer, Colin N.A.

doi:10.1007/s00125-003-1323-1

Cited by 119 publications

(92 citation statements)

References 11 publications

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“…For example, the Taiwanese study was able to detect the increased myocardial infarction risk associated with the T1431 allele in individuals Ͻ50 years old, 18 and interestingly, the Ala12 variant has been shown recently to be enriched in very elderly Italians. 23 These findings, together with our findings that healthy middle-aged control populations have a higher Ala12 frequency relative to children, 17 support our hypothesis that common variation at PPARG has pleiotropic consequences for general morbidity and mortality. It is likely that the stronger association observed in the group with no previous cardiovascular events before enrollment reflects the effects of an increased number of cardiovascular protective drugs prescribed to individuals with previous cardiovascular events.…”

Section: Discussionsupporting

confidence: 76%

“…11,21 The mean age of the population at enrollment was 64.4 years (SD 11.6) and the mean duration of diabetes 7.9 years (SD 6.8). The mean follow-up time for all events was 36.6 months (SD 15.0).…”

Section: Resultsmentioning

confidence: 99%

“…19 These findings corroborate previous observations that the Ala12 and the linked T1431 are associated with opposing phenotypes. 11,16,17 Because the T allele is silent, it is likely that these observed associations are attributable to its LD with a further common variant with functional consequences at the PPARG locus. This may Kaplan-Meier plot illustrating time to all events including allcause death by PPARG genotype in the individuals enrolled in Go-DARTS at Ͻ70 years of age.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we have demonstrated that the strength of the association of the Ala allele with a reduced risk of type 2 diabetes may be modulated by the presence of LD with the T allele. 17 Interestingly, in contrast to the balanced frequency and strong LD observed in the white population, T1431 occurs much more frequently than Ala12 in Asian and Oji-Cree populations, and reports from these populations have suggested a role of T1431 in increased risk of cardiovascular disease. 9,18,19 Because the T allele of C1431T and the Ala allele of Pro12Ala appear to be consistently associated with opposing metabolic traits, we hypothesized this may also be observed for the development of cardiovascular disease in a large group of individuals with type 2 diabetes.…”

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confidence: 99%

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Cardiovascular Risk in Type 2 Diabetes Is Associated With Variation at the PPARG Locus

Doney

Fischer

Leese

et al. 2004

ATVB

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Objective-The Pro12Ala polymorphism of PPARG modulates risk of developing type 2 diabetes. The Ala allele has also been associated with a reduced risk of cardiovascular events. We have shown previously that the linked T allele of the C1431T polymorphism influences Ala12-associated diabetes risk and that the 2 polymorphisms have opposing associations with body weight. We therefore investigated the association of these 2 variants with cardiovascular events in people with type 2 diabetes. T he peroxisome proliferator-activated receptor-␥ (PPAR␥) has a key role in the molecular pathophysiology of obesity and type 2 diabetes. 1 It is directly involved in adipogenesis 2 and liver and muscle responses to glucose, 3,4 as well as some aspects of pancreatic ␤-cell function. 5 It is also the molecular target of the thiazolidinedione class of insulin sensitizing drugs. 6 Genetic variation at the PPARG locus may modulate individual susceptibility to type 2 diabetes mellitus and related traits associated with premature cardiovascular disease. [7][8][9] Notably, the Ala allele of the Pro12Ala polymorphism has been associated with greater insulin sensitivity, 7,9 reduced risk of type 2 diabetes, 10 reduced body mass index (BMI), 11 lower blood pressure, 12 and reduced risk of myocardial infarction. 13 Furthermore, the action of this variant may be subject to interaction with diet and exercise. 14, 15 We demonstrated previously that a further silent variant in exon 6 of PPARG, C1431T, which is in strong linkage disequilibrium (LD) with the Pro12Ala variant, has an opposing association with body mass in several populations with and without type 2 diabetes. 11 We found the Ala12 variant to be associated with a reduced BMI, whereas the T allele was associated with an increased BMI. Similar findings have been reported recently in a study of polycystic ovary syndrome, 16 and several reports have suggested that the T1431 allele is associated with higher leptin levels in obese women. 8,16 Although the relationship between T1431, leptin, and BMI is as yet undefined. Furthermore, we have demonstrated that the strength of the association of the Ala allele with a reduced risk of type 2 diabetes may be modulated by the presence of LD with the T allele. 17 Interestingly, in contrast to the balanced frequency and strong LD observed in the white population, T1431 occurs much more frequently than Ala12 in Asian and Oji-Cree populations, and reports from these populations have suggested a role of T1431 in increased risk of cardiovascular disease. 9,18,19 Because the T allele of C1431T and the Ala allele of Pro12Ala appear to be consistently associated with opposing metabolic traits, we hypothesized this may also be observed for the development of cardiovascular disease in a large group of individuals with type 2 diabetes. Materials and MethodsAll individuals with diabetes mellitus in the population of Tayside, Scotland, have been identified previously through record linkage techniques with a sensitivity of 97%. 20 Health Service data protectio...

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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cardiovascular Risk in Type 2 Diabetes Is Associated With Variation at the PPARG Locus

Doney

Fischer

Leese

et al. 2004

ATVB

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“…In some studies, it has been shown to modulate the Pro12Ala effect on both T2D and body mass index (BMI). [19][20][21] Interaction effects between fat intake and PPARG polymorphisms on BMI and other related parameters have been documented, but the results have not always been concordant. [22][23][24][25][26] Our aim was to study potential interactions between Pro12Ala and 1431C4T polymorphisms and dietary fat intake on T2D and BMI, in a prospective cohort drawn from a French general population, the D.E.S.I.R.…”

Section: Introductionmentioning

confidence: 99%

Dietary fat intake and polymorphisms at the PPARG locus modulate BMI and type 2 diabetes risk in the D.E.S.I.R. prospective study

et al. 2011

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Context: Fat-rich diets are involved in many disorders such as obesity and type 2 diabetes (T2D). The Pro12Ala variant of peroxisome proliferator-activated receptor-g (PPARg) is known to modulate body mass index (BMI) and T2D risk. Objective: Our aim was to study the interaction effect between PPARg gene (PPARG) polymorphisms Pro12Ala and 1431C4T and fat intake on incident T2D and BMI in a 9-year prospective cohort drawn from the French general population, the D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study (n ¼ 4676). Methods: Nutritional intake was assessed by a food frequency self-questionnaire completed by each participant. Statistical analyses included logistic regression, analysis of covariance and haplotype analysis, with adjustment for confounding variables. Results: A high fat consumption (the third sex-specific tertile of fat intake, as a percentage of energy intake) was associated with an increased T2D risk among ProPro and CC homozygotes (P interaction ¼ 0.05, odds ratio (OR) (95% confidence interval (95% CI)) ¼ 1.73 (1.19-2.52) P ¼ 0.004 and OR ¼ 1.85 (1.27-2.71) P ¼ 0.001, respectively) but not in Ala and T carriers. There was a significant interaction effect between Pro12Ala and 1431C4T on BMI (P interaction ¼ 0.004); Ala was associated with lower BMI in CC homozygotes and with higher BMI in T carriers while the opposite was found for ProPro. There was also an interaction effect between Pro12Ala and dietary fat intake on BMI (P interaction ¼ 0.02); AlaAla individuals had a higher BMI than Pro carriers among high fat consumers (27.1 ± 1.0 versus 24.9 ± 0.1 for AlaAla and Pro þ , respectively). There was no interaction effect between the 1431C4T single-nucleotide polymorphism and fat intake on BMI. Conclusion: Our results indicate strong genetic and nutritional interaction effects on BMI and T2D risk at the PPARG locus in a general population.

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Textbook of Pharmacoepidemiology

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Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes

Cited by 119 publications

References 11 publications

Cardiovascular Risk in Type 2 Diabetes Is Associated With Variation at the PPARG Locus

Cardiovascular Risk in Type 2 Diabetes Is Associated With Variation at the PPARG Locus

Dietary fat intake and polymorphisms at the PPARG locus modulate BMI and type 2 diabetes risk in the D.E.S.I.R. prospective study

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