👤 Dana Dabelea

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component-clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in Show less

To examine whether BMI-associated genetic risk variants modify the association of intrauterine diabetes exposure with childhood BMI z-scores, we assessed the interaction between 95 BMI-associated genetic variants and in utero exposure to maternal diabetes among 459 children in the Exploring Perinatal Outcomes among Children historical prospective cohort study (n = 86 exposed; 373 unexposed) in relation to age- and sex-standardized childhood BMI z-scores (mean age = 10.3 years, standard deviation = 1.5 years). For the genetic variants showing a nominally significant interaction, we assessed the relationship in an additional 621 children in Project Viva, which is an independent longitudinal cohort study, and used meta-analysis to combine the results for the two studies. Seven of the ninety-five genetic variants tested exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to the offspring BMI z-score in EPOCH. Five of the seven variants exhibited a consistent direction of interaction effect across both EPOCH and Project Viva. While none achieved statistical significance in the meta-analysis after accounting for multiple testing, three variants exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to offspring BMI z-score: rs10733682 near Show less

Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program. Show less