Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program

• Published in: PloS one Vol. 7; no. 9; p. e44424
• Main Authors: Florez, Jose C, Jablonski, Kathleen A, McAteer, Jarred B, Franks, Paul W, Mason, Clinton C, Mather, Kieren, Horton, Edward, Goldberg, Ronald, Dabelea, Dana, Kahn, Steven E, Arakaki, Richard F, Shuldiner, Alan R, Knowler, William C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11-09-2012; Public Library of Science (PLoS)
• Subjects: Alleles; Biology; Blood Glucose - metabolism; Clinical Medicine; Clinical trials; Cohort Studies; Development and progression; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - ethnology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - prevention & control; Disease control; Endocrinology; Endocrinology and Diabetes; Endokrinologi och diabetes; Epidemiology; Ethnic Groups; Fasting; Gene loci; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic research; Genetic variance; Genomes; Genotype; Glucose; Health care; Health risk assessment; Health risks; Homeostasis; Humans; Incidence; Insulin; Insulin - metabolism; Insulin resistance; Insulin-like growth factor I; Kidney diseases; Klinisk medicin; Life Style; Lifestyles; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine; Metabolism; Metformin; Metformin - pharmacology; Nutrition; Placebos; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population genetics; Prediabetic state; Prevention; Preventive medicine; Proportional Hazards Models; Regression Analysis; Risk; Type 2 diabetes; Indiana; United States > US; Maryland; Massachusetts; Arizona
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0044424

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.