Updated Genetic Score Based on 34 Confirmed Type 2 Diabetes Loci Is Associated With Diabetes Incidence and Regression to Normoglycemia in the Diabetes Prevention Program

Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Diabetes (Impact Factor: 8.1). 03/2011; 60(4):1340-8. DOI: 10.2337/db10-1119
Source: PubMed


Over 30 loci have been associated with risk of type 2 diabetes at genome-wide statistical significance. Genetic risk scores (GRSs) developed from these loci predict diabetes in the general population. We tested if a GRS based on an updated list of 34 type 2 diabetes-associated loci predicted progression to diabetes or regression toward normal glucose regulation (NGR) in the Diabetes Prevention Program (DPP).
We genotyped 34 type 2 diabetes-associated variants in 2,843 DPP participants at high risk of type 2 diabetes from five ethnic groups representative of the U.S. population, who had been randomized to placebo, metformin, or lifestyle intervention. We built a GRS by weighting each risk allele by its reported effect size on type 2 diabetes risk and summing these values. We tested its ability to predict diabetes incidence or regression to NGR in models adjusted for age, sex, ethnicity, waist circumference, and treatment assignment.
In multivariate-adjusted models, the GRS was significantly associated with increased risk of progression to diabetes (hazard ratio [HR] = 1.02 per risk allele [95% CI 1.00-1.05]; P = 0.03) and a lower probability of regression to NGR (HR = 0.95 per risk allele [95% CI 0.93-0.98]; P < 0.0001). At baseline, a higher GRS was associated with a lower insulinogenic index (P < 0.001), confirming an impairment in β-cell function. We detected no significant interaction between GRS and treatment, but the lifestyle intervention was effective in the highest quartile of GRS (P < 0.0001).
A high GRS is associated with increased risk of developing diabetes and lower probability of returning to NGR in high-risk individuals, but a lifestyle intervention attenuates this risk.

Download full-text


Available from: Leigh Perreault,
  • Source
    • "The SLC30A8 gene encodes a pancreatic islet-specific Zn transporter involved in insulin biosynthesis, maturation, and storage of pancreatic beta cells and is associated with decreased insulin secretion [9]. In addition, as expected [10,11], while most SNPs were not associated with T2D in any one racial/ethnic group, genetic risk scores calculated using all 15 previously-associated SNPs were associated with T2D for each racial/ethnic group. Some data are available on GRS and T2D risk in European-ancestry populations and results were similar to ours. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Both environmental and genetic factors impact type 2 diabetes (T2D). To identify such modifiers, we genotyped 15 T2D-associated variants from genome-wide association studies (GWAS) in 6,414 non-Hispanic whites, 3,073 non-Hispanic blacks, and 3,633 Mexican American participants from the National Health and Nutrition Examination Surveys (NHANES) and evaluated interactions between these variants and carbohydrate intake and fiber intake. Results We calculated a genetic risk score (GRS) with the 15 SNPs. The odds ratio for T2D with each GRS point was 1.10 (95% CI: 1.05-1.14) for non-Hispanic whites, 1.07 (95% CI: 1.02-1.13) for non-Hispanic blacks, and 1.11 (95% CI: 1.06-1.17) for Mexican Americans. We identified two gene-carbohydrate interactions (P < 0.05) in non-Hispanic whites (with CDKAL1 rs471253 and FTO rs8050136), two in non-Hispanic blacks (with IGFBP2 rs4402960 and THADA rs7578597), and two in Mexican Americans (with NOTCH2 rs1092398 and TSPAN8-LGRS rs7961581). We found three gene-fiber interactions in non-Hispanic whites (with ADAMT59 rs4607103, CDKN2A/2B rs1801282, and FTO rs8050136), two in non-Hispanic blacks (with ADAMT59 rs4607103 and THADA rs7578597), and two in Mexican Americans (with THADA rs7578597 and TSPAN8-LGRS rs796158) at the P < 0.05 level. Interactions between the GRS and nutrients failed to reach significance in all the racial/ethnic groups. Conclusion Our results suggest that dietary carbohydrates and fiber may modify T2D-associated variants, highlighting the importance of dietary nutrients in predicting T2D risk.
    BMC Genetics 06/2014; 15(1):69. DOI:10.1186/1471-2156-15-69 · 2.40 Impact Factor
  • Source
    • "For example, one recent study found that a set of 40 SNPs associated with T2D could predict the risk of younger people for T2D but not for older people [52]. Another study published around the same time found that 34 confirmed that T2D loci were sufficient to predict increased risk for developing the disease [53]. A more recent study has also demonstrated that T2D risk could be predicted using a set of 46 known associated variants [54]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context.
    International Journal of Endocrinology 02/2014; 2014(17):769671. DOI:10.1155/2014/769671 · 1.95 Impact Factor
  • Source
    • "Whereas recent prospective studies in populations of varying age, metabolic status, and ethnicity have shown that genetic risk is associated with incidence of type 2 diabetes (3–8), very few studies have investigated the effect of genetic variants on changes in quantitative glycemic traits over time in large study samples (3,9–11). How changes in BMI and lifestyle may interact with genetic factors to modify glucose homeostasis over time has, moreover, been even less investigated (6,12). Since the effects of common single variants are generally modest and of limited clinical significance, it is more likely that risk assessment of a combination of variants will be useful to identify subgroups at increased risk of type 2 diabetes that would require more aggressive intervention and monitoring. "
    [Show abstract] [Hide abstract]
    ABSTRACT: More than 40 genetic risk variants for type 2 diabetes have been validated. We aimed to test if a genetic risk score associates with the incidence of type 2 diabetes and with 5-year changes in glycemic traits and if the effects were modulated by changes in BMI and lifestyle.The Inter99 study population was genotyped for 46 variants and a genetic risk score was constructed. During a median follow-up of 11 years 327 of 5,850 individuals developed diabetes. Physical examinations and oral glucose tolerance tests were performed at baseline and after 5 years (n=3,727).The risk of incident type 2 diabetes was increased with a hazard ratio of 1.06 [95%CI 1.03-1.08] per risk allele. While the population in general improved their glucose regulation during the 5-year follow-up period, each additional allele in the genetic risk score was associated with a relative increase in fasting, 30-min and 120-min plasma glucose values and a relative decrease in measures of beta-cell function over the 5-year period, whereas indices of insulin sensitivity were unaffected. The effect of the genetic risk score on 5-year changes in fasting plasma glucose was stronger in individuals who increased their BMI.In conclusion, a genetic risk score based on 46 variants associated strongly with incident type 2 diabetes and 5-year changes in plasma glucose and beta-cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose.
    Diabetes 07/2013; 62(10). DOI:10.2337/db13-0362 · 8.10 Impact Factor
Show more