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Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study
Ist Teil von
Journal of molecular medicine (Berlin, Germany), 2008-03, Vol.86 (3), p.341-348
Ort / Verlag
Berlin/Heidelberg: Springer-Verlag
Erscheinungsjahr
2008
Quelle
MEDLINE
Beschreibungen/Notizen
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.