Genotype score in addition to common risk factors for prediction of type 2 diabetes

Abstract

Background: Multiple genetic loci have been convincingly associated with the risk of type 2 diabetes mellitus. We tested the hypothesis that knowledge of these loci allows better prediction of risk than knowledge of common phenotypic risk factors alone.

Methods: We genotyped single-nucleotide polymorphisms (SNPs) at 18 loci associated with diabetes in 2377 participants of the Framingham Offspring Study. We created a genotype score from the number of risk alleles and used logistic regression to generate C statistics indicating the extent to which the genotype score can discriminate the risk of diabetes when used alone and in addition to clinical risk factors.

Results: There were 255 new cases of diabetes during 28 years of follow-up. The mean (+/-SD) genotype score was 17.7+/-2.7 among subjects in whom diabetes developed and 17.1+/-2.6 among those in whom diabetes did not develop (P<0.001). The sex-adjusted odds ratio for diabetes was 1.12 per risk allele (95% confidence interval, 1.07 to 1.17). The C statistic was 0.534 without the genotype score and 0.581 with the score (P=0.01). In a model adjusted for sex and self-reported family history of diabetes, the C statistic was 0.595 without the genotype score and 0.615 with the score (P=0.11). In a model adjusted for age, sex, family history, body-mass index, fasting glucose level, systolic blood pressure, high-density lipoprotein cholesterol level, and triglyceride level, the C statistic was 0.900 without the genotype score and 0.901 with the score (P=0.49). The genotype score resulted in the appropriate risk reclassification of, at most, 4% of the subjects.

Conclusions: A genotype score based on 18 risk alleles predicted new cases of diabetes in the community but provided only a slightly better prediction of risk than knowledge of common risk factors alone.

Figure 1. Distribution of Genotype Score and Cumulative Incidence of Type 2 Diabetes According to Genotype Score among Participants in the Framingham Offspring Study

The panels were drawn on the basis of 2434 participants with complete genotypic data. (Data on 2377 participants with complete genotypic and phenotypic data were included in the remainder of the analysis reported in this article.) Panel A shows the distribution of participants in the Framingham Offspring Study according to genotype score, stratified according to persons in whom diabetes developed over a period of 28 years of follow-up and those in whom diabetes did not develop. The minimum genotype score was 7, and the maximum was 27. The P value is for the difference in the mean genotype score between the two groups, accounting for the presence of related persons in the sample. Panel B shows the 28-year cumulative incidence of type 2 diabetes grouped according to whether the genotype score was low (≤15, 41 cases of diabetes among 605 participants at risk), medium (16 to 20, 169 cases among 1562 at risk), or high (≥21, 45 cases among 267 at risk). Overall, among the 2434 participants at risk, 24.9% had a low genotype score, 64.2% had a medium score, and 11.0% had a high score. The P value is for the difference in cumulative incidence across genotype-score groups, accounting for the presence of related persons in the sample. I bars indicate standard errors.