Interactions Between Peroxisome Proliferator–Activated Receptor Gene Polymorphism and Birth Length Influence Risk for Type 2 Diabetes

Type 2 diabetes has previously been shown to be associated with a small body size at birth, which is considered an indicator of the intrauterine environment. This inverse association has been observed between both birth weight and birth length (1,2). The peroxisome proliferator–activated receptor (PPAR) γ2 gene is associated with glucose and lipid metabolism and is therefore a major candidate gene for type 2 diabetes (3,4). We have previously reported that the effects of the Pro12Pro genotype of the PPAR γ2 gene on insulin sensitivity depends on birth size (5). In subjects whose birth weight was <3,500 g, the Pro12Pro genotype was associated with insulin resistance. In the present study, we have assessed the association between the PPAR γ2 gene polymorphism and birth length on manifest type 2 diabetes.

Of the measures of body size at birth, birth length predicts type 2 diabetes most strongly in this cohort (2,6). A total of 476 elderly subjects (mean age 70 ± 3 years) with data on birth size and who attended a clinical study, including a 75-g oral glucose tolerance test, participated in the present study. The PPAR γ genotype was unrelated to either birth weight or birth length. The Pro12Pro genotype was associated with higher fasting insulin concentrations than the Pro12Ala/Ala12Ala genotype (71 vs. 62 pmol/l, P = 0.02). This association was strongest in people who were short at birth (P = 0.02 for interaction between genotype and birth length). Ninety-four subjects in the cohort had type 2 diabetes. We examined the combined effects of the PPAR γ2 gene polymorphism and birth length on the occurrence of the disease. The Pro12Pro genotype was weakly associated with a higher incidence of type 2 diabetes (P = 0.08). However, this association was confined to people who were ≤49 cm in length at birth, among whom the cumulative incidence of type 2 diabetes was 24.5%, compared with those >49 cm in length at birth, whose cumulative incidence was 14.3% (P = 0.02). There were no interactions between genotype and adult body size on the incidence of type 2 diabetes.

The PPAR γ2 gene, which is known to be linked to insulin sensitivity, has only weak effects on the occurrence of type 2 diabetes. When the analysis was confined to people who had short body length at birth, the gene had somewhat stronger effects on disease rates. We suggest that this is a manifestation of gene-environmental interaction, whereby the genotype has different effects according to intrauterine growth, for which birth length serves as a marker. Our findings are consistent with the hypothesis that type 2 diabetes originates through an adverse environment during development, which influences gene expression and later disease risk.