title: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
abstract: 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.affiliation: Department of Biostatistics, Boston University School of Public Health, Massachusetts, USA.
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authors.initials: R
authors.lastname: Sladek
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001786:Blood Glucose / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics; D030541:Databases, Genetic; D000090943:Delta-5 Fatty Acid Desaturase; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005215:Fasting / Q000097:blood*; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D019655:Quantitative Trait, Heritable; D015203:Reproducibility of Results
chemical_list: D001786:Blood Glucose; D000090943:Delta-5 Fatty Acid Desaturase; C000716847:FADS1 protein, human