title: Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study.
abstract: Recently, Genome Wide Association (GWA) studies identified novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D) in several case-control studies of European descent. However, the impact of these markers on glucose homeostasis in a population-based study remains to be clarified. The French prospective D.E.S.I.R. study (N = 4,707) was genotyped for 22 polymorphisms within 14 loci showing nominal to strong association with T2D in recently published GWA analyses (CDKAL1, IGFBP2, CDKN2A/2B, EXT2, HHEX, LOC646279, SLC30A8, MMP26, KCTD12, LDLR, CAMTA1, LOC38776, NGN3 and CXCR4). We assessed their effects on quantitative traits related to glucose homeostasis in 4,283 normoglycemic middle-aged participants at baseline and their contribution to T2D incidence during 9 years of follow-up. Individuals carrying T2D risk alleles of CDKAL1 or SLC30A8 had lower fasting plasma insulin level (rs7756992 P = 0.003) or lower basal insulin secretion (rs13266634 P = 0.0005), respectively, than non-carriers. Furthermore, NGN3 and MMP26 risk alleles associated with higher fasting plasma glucose levels (rs10823406 P = 0.01 and rs2499953 P = 0.04, respectively). However, for these SNPs, only modest associations were found with a higher incidence of T2D: hazard ratios of 2.03 [1.00-4.11] for MMP26 (rs2499953 P = 0.05) and 1.33 [1.02-1.73] for NGN3 (rs10823406 P = 0.03). We confirmed deleterious effects of SLC30A8, CDKAL1, NGN3 and MMP26 risk alleles on glucose homeostasis in the D.E.S.I.R. prospective cohort. However, in contrast to TCF7L2, the contribution of novel loci to T2D incidence seems only modest in the general middle-aged French population and should be replicated in larger cohorts.
authors.affiliation: CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cauchi
authors.forename: Christine
authors.initials: C
authors.lastname: Proença
authors.forename: Hélène
authors.initials: H
authors.lastname: Choquet
authors.forename: Stefan
authors.initials: S
authors.lastname: Gaget
authors.forename: Franck
authors.initials: F
authors.lastname: De Graeve
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Jean
authors.initials: J
authors.lastname: Tichet
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D005215:Fasting; D005260:Female; D005602:France / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000453:epidemiology; D015994:Incidence; D007328:Insulin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016016:Proportional Hazards Models; D044465:White People / Q000235:genetics*
chemical_list: D007328:Insulin; D005947:Glucose