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Clinical Trial
. 2005 Nov 1;2(12):e345.
doi: 10.1371/journal.pmed.0020345.

Genetic prediction of future type 2 diabetes

Valeriya Lyssenko  1 , Peter Almgren, Dragi Anevski, Marju Orho-Melander, Marketa Sjögren, Carola Saloranta, Tiinamaija Tuomi, Leif Groop; Botnia Study Group
Affiliations
Clinical Trial

Genetic prediction of future type 2 diabetes

Valeriya Lyssenko et al. PLoS Med. .

Abstract

Background: Type 2 diabetes (T2D) is a multifactorial disease in which environmental triggers interact with genetic variants in the predisposition to the disease. A number of common variants have been associated with T2D but our knowledge of their ability to predict T2D prospectively is limited.

Methods and findings: By using a Cox proportional hazard model, common variants in the PPARG (P12A), CAPN10 (SNP43 and 44), KCNJ11 (E23K), UCP2 (-866G>A), and IRS1 (G972R) genes were studied for their ability to predict T2D in 2,293 individuals participating in the Botnia study in Finland. After a median follow-up of 6 y, 132 (6%) persons developed T2D. The hazard ratio for risk of developing T2D was 1.7 (95% confidence interval [CI] 1.1-2.7) for the PPARG PP genotype, 1.5 (95% CI 1.0-2.2) for the CAPN10 SNP44 TT genotype, and 2.6 (95% CI 1.5-4.5) for the combination of PPARG and CAPN10 risk genotypes. In individuals with fasting plasma glucose > or = 5.6 mmol/l and body mass index > or = 30 kg/m(2), the hazard ratio increased to 21.2 (95% CI 8.7-51.4) for the combination of the PPARG PP and CAPN10 SNP43/44 GG/TT genotypes as compared to those with the low-risk genotypes with normal fasting plasma glucose and body mass index < 30 kg/m(2).

Conclusion: We demonstrate in a large prospective study that variants in the PPARG and CAPN10 genes predict future T2D. Genetic testing might become a future approach to identify individuals at risk of developing T2D.

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Conflict of interest statement

Competing Interests: LG is a member of the editorial board of PLoS Medicine.

Figures

Figure 1
Figure 1. Unadjusted Kaplan–Meier Diabetes-Free Survival Probability Curves
Curves for different carriers of PPARG P12A (PP versus PA/AA), CAPN10 SNP44 (TT versus TC/CC), UCP2 −866 G/A (GG versus GA/AA), and the combination of PPARG and CAPN10 SNP43/44 (PP/GG/TT versus other). y-Axis shows probability of diabetes-free survival time. x-Axis shows follow-up time in years. The HR of developing T2D in different genotype carriers obtained from Cox proportional hazards regression stratified on sex and adjusted for age, BMI, and family history of diabetes with robust variance estimate is shown (see also Table 3).
Figure 2
Figure 2. The Effects of Risk Genotypes of the PPARG P12A Polymorphism (PP), the Combination of CAPN10 SNP43/44 (GG/TT), and the Combination of PPARG and CAPN10 SNP43/44 (PP/GG/TT) Together with FPG and BMI for the Risk of Developing T2D
y-Axis denotes incident diabetes estimated as the proportion (percent) of participants who developed diabetes during the follow-up period in the groups with each risk factor defined as risk genotype, elevated FPG (≥5.6 mmol/l), and high BMI (≥30 kg/m2). The absolute number of individuals who developed diabetes in the groups with each risk factor is given within the bars (in parentheses) and in Table S2. The incidence of T2D was significantly increased in carriers of the risk PP genotype, GG/TT genotypes, and PP/GG/TT genotypes with elevated FPG and high BMI as compared with individuals carrying low risk genotypes without risk factors (χ2 test, p < 0.001).
Figure 3
Figure 3. The Effect of Insulin Resistance Together with the Risk Genotype of the PPARG P12A Polymorphism on Risk of Developing T2D
y-Axis denotes HR and its 95% CI. x-Axis denotes increase in insulin resistance estimated as HOMAIR.
See this image and copyright information in PMC

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