In a community-based sample followed for 28 years, we found that a genotype score for type 2 diabetes, based on 18 loci, was associated with a very modest but significant 12% increase in the relative risk of diabetes per risk allele. Adjustment for family history and common risk factors did not diminish the size or significance of this association. Irrespective of clinical variables, people with the highest genotype scores as compared with those with the lowest scores had a risk that was increased by a factor of 2.6. Although the individual risk alleles were common, only a small percentage of people had at least one risk allele at half or more of the loci. It might be expected that a score based on common variants would not be an efficient discriminator of risk, owing to weak effects for individual alleles.34
However, we found that a combination of risk alleles was a strong risk factor with modest discriminatory ability when sex alone was considered, especially among younger persons. This finding might be useful for genetic screening at birth or in youth, before obvious risk factors have developed.
When familial diabetes or clinical risk factors that are typically documented at a periodic examination in adulthood were considered, the genotype score did not improve risk discrimination. A possible explanation for this finding is that some alleles might increase the risk through these intermediate traits or that phenotypic risk factors are overwhelmingly stronger determinants of the near-term risk of diabetes than are known genetic influences. Findings were similar with use of a score in which loci were weighted according to previous evidence of their association with diabetes. The results suggest that “personalized medicine” that is made possible by the expanded understanding of genetics is not yet as useful for the prediction of the risk of diabetes in adults as it is for other potential applications such as pharmacogenetic analyses of drug toxicity or response.
A few other studies have examined the use of combinations of SNPs to predict the risk of diabetes. In the Botnia study, people with risk alleles in both the gene encoding for the peroxisome proliferator-activated receptor gamma (PPARG
) and the gene encoding for the cystein protease calpain 10 (CAPN10
), as compared with people who had no risk alleles, had a risk that was increased by a factor of 2.6,14
but the use of risk alleles as predictors did not result in a better C statistic for diabetes (0.68) than did the use of fasting glucose level and body-mass index.18
In a study from the United Kingdom, subjects with all six risk alleles in the gene encoding for potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11
, and the transcription factor 7-like gene (TCF7L2
) (1% of the sample), in comparison with subjects who had no risk alleles, had a risk that was increased by a factor of 5 to 7; the C statistic with the three loci as predictors was 0.58.15
In the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study, carriers of at least 4 risk alleles in the genes encoding for glucokinase (GCK
), interleukin 6 (IL6
), and TCF7L2
, as compared with those who had one risk allele or none, had a risk that was increased by a factor of 2.5.17
The C statistic with these three variants as predictors was 0.56, and the C statistic with these loci plus age, sex, and body-mass index as predictors was 0.82. The Genetics of Diabetes Audit and Research Tayside (GoDARTS) study examined 18 risk loci.35
Carriers of more than 24 risk alleles (1.2% of the sample), as compared with carriers of 10 to 12 risk alleles, had a prevalence ratio of 4.2. The C statistic with all variants combined as predictors was 0.60; the C statistic with age, body-mass index, and sex as predictors was 0.78; and the C statistic with variants and risk factors as predictors was 0.80. Our data extend these studies to show that individual per-allele effects are small; that people with more risk alleles are at greater risk than those with fewer, no matter how many or which genes are considered; that groups with an apparently greatly increased genetic risk can be identified but are not commonly found; and that the marginal ability of genotype scores to discriminate risk is small, with minimal effect after consideration of even a few common risk factors.
We found that the presence or absence of parental diabetes and the genotype score were independently associated with the risk of diabetes. This suggests that family history as a risk factor for diabetes conveys more than heritable genetic information; it probably includes nongenetic familial behaviors and norms. The lower relative risks for diabetes associated with observed parental diabetes as compared with those associated with self-reported family history (approximately 1.8 vs. approximately 2.2) support the contention that family history contains more risk information than is implied by inheritance of the diabetes phenotype alone.
One of the limitations of our study is that the 18 SNPs we included are probably insufficient to account for the familial risk of diabetes. They account for a minority of diabetes heritability, and the SNP array platforms from which they were chosen capture only approximately 80% of common variants in Europeans. In addition, we have not considered structural variants that might confer a risk of diabetes. It is possible that the addition of rare risk alleles with large effects, or a much larger number of common risk alleles with small individual effects, could improve discrimination.36
Indeed, as many as 500 loci may underlie the genetic risk of type 2 diabetes.16
Also, we did not study interactions among genes or between genes and the environment that might alter the genetic risk in exposed persons. As more diabetes risk variants become known, their incorporation into the genotype score may explain more of the genetic risk implied by parental diabetes.
Our study has other limitations. There were few significant associations between individual risk alleles and diabetes in the Framingham Offspring Study cohort, but this finding was expected, given that alleles of small effect were tested in a community-based sample of modest size, and the aggregate set of 18 SNPs was predictive of new cases of diabetes. The participants in the Framingham Offspring Study are essentially all of European ancestry; allelic variation may require that different SNPs be used to generate a genotype score in different ancestry groups.37
Our genotype score gave all alleles the same weight; this may not be a true reflection of the biologic basis of type 2 diabetes. We considered the marginal value of the genotype score after accounting for only phenotypic risk factors, without consideration of behavioral risk factors for diabetes.38
We expect that accounting for unhealthful behaviors associated with the risk of diabetes would only further diminish the discriminatory capacity of a genotype score. However, persons with relatively less healthful lifestyle behaviors might be more susceptible to genetic risk than those with more healthful behaviors.39
Whether the genotype score would have value in predicting the risk of diabetes in specific subgroups that have an elevated risk on the basis of poor health habits remains to be tested.
In summary, a genotype score based on 18 risk alleles predicted new cases of diabetes in the community but did not result in a substantially better prediction of risk than the knowledge of common phenotypic risk factors alone. Although genetic information appeared to be useful when only factors known in youth were considered, genetic information in the context of risk factors measured in adulthood did not help to refine the prediction of diabetes risk. Our findings underscore the view that identification of adverse phenotypic characteristics remains the cornerstone of approaches to predicting the risk of type 2 diabetes.19