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

Abstract

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...

The Pro12Ala and C–681G variants of the PPARG locus are associated with opposing growth phenotypes in young schoolchildren

“…It is possible that the impact of this variant on BMI may become apparent later in life. As yet no functional mechanism has been given to this variant, although we consistently find diabetes-related traits associating in adults with this variant in opposition to the Ala12 variant [13,36].…”

Health effects of trans-fatty acids: experimental and observational evidence

“…Few studies have evaluated relationships between TFA consumption and cancer incidence, and significant associations have generally not been observed (World Cancer Research Fund, 2007), although in the 20-year follow-up of the Nurses' Health Study, TFA intake during the premenopausal years was associated with incidence of postmenopausal breast cancer (Kim et al, 2006). TFA was associated with higher risk of dementia in one prospective study (Doney et al, 2004), suggestive of a potentially adverse effect on cerebrovascular disease. However, in a prospective study of male health professionals (He et al, 2003), TFA intake was not significantly associated with incidence of clinical stroke.…”

Rates of glycaemic deterioration in a real-world population with type 2 diabetes

“…An observational cohort study was performed using comprehensive electronic medical records from individuals in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS) database, which has previously been described elsewhere [12,13]. In short, this contains detailed information on all encashed prescriptions from 1994 onwards in Tayside, Scotland, as well as all biochemistry and BMI measures.…”