New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Journal article

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Authors: Dupuis, J; Langenberg, C; Prokopenko, I; Saxena, R; Soranzo, N

• Publication status: Published
• Journal: Nature genetics
• Volume: 42
• Issue: 2
• Pages: 105-116
• Publication date: 2010-02-01
• DOI: 10.1038/ng.520
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Adolescent; Anders Hamsten on behalf of Procardis Consortium; MAGIC investigators; DNA Copy Number Variations; Polymorphism, Single Nucleotide; Humans; Quantitative Trait, Heritable; Homeostasis; Diabetes Mellitus, Type 2; Databases, Genetic; GIANT Consortium; Genetic Predisposition to Disease; Reproducibility of Results; Meta-Analysis as Topic; Fasting; Genetic Loci; Blood Glucose; Genome-Wide Association Study; Adult; Global BPgen Consortium; Alleles; Gene Expression Regulation; Child; Quantitative Trait Loci; DIAGRAM Consortium