title: The TCF7L2 diabetes risk variant is associated with HbA₁(C) levels: a genome-wide association meta-analysis.
abstract: Genome-wide association (GWA) studies have identified around 20 common genetic variants influencing the risk of type 2 diabetes (T2D). Likewise, a number of variants have been associated with diabetes-related quantitative glycaemic traits, but to date the overlap between these genes and variants has been low. The majority of genetic studies have focused on fasting plasma glucose levels; however, this measure is highly variable. We have conducted a GWA meta-analysis of glycated haemoglobin (HbA₁(C) ) levels within three healthy nondiabetic populations. This phenotype provides an estimate of mean glucose levels over 2-3 months and is a more stable predictor of future diabetes risk. Participants were from three isolated populations: the Orkney Isles in the north of Scotland, the Dalmatian islands of Vis, and Korčula in Croatia (total of 1782 nondiabetic subjects). Association was tested in each population and results combined by meta-analysis. The strongest association was with the TCF7L2 gene (rs7903146, P= 1.48 × 10⁻⁷). This is also the strongest common genetic risk factor for T2D but it has not been identified in previous genome-wide studies of glycated haemoglobin.
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Scotland.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Franklin
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Huffman
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Ozren
authors.initials: O
authors.lastname: Polašek
authors.forename: Sara
authors.initials: S
authors.lastname: Knott
authors.forename: Lina
authors.initials: L
authors.lastname: Zgaga
authors.forename: Tatijana
authors.initials: T
authors.lastname: Zemunik
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Wild
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017523:Croatia / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006442:Glycated Hemoglobin / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012606:Scotland / Q000453:epidemiology; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: D006442:Glycated Hemoglobin; D058118:Transcription Factor 7-Like 2 Protein; C544894:TCF7L2 protein, human; C517652:hemoglobin A1c protein, human