A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus.
OBJECTIVE
Genetic and epidemiological studies suggest an association between gestational diabetes mellitus and type 2 diabetes. Both are polygenic multifactorial disorders characterised by beta cell dysfunction and insulin resistance. Our aim was to investigate whether common genetic variants that have previously been associated with type 2 diabetes or related phenotypes would also confer risk for gestational diabetes mellitus.


METHODS
In 1,881 unrelated pregnant Scandinavian women (649 women with gestational diabetes mellitus, 1,232 non-diabetic control subjects) we genotyped the transcription factor 7-like 2 (TCF7L2 rs7903146), adiponectin (ADIPOQ +276G > T), peroxisome-proliferator activated receptor, gamma 2 (PPARG Pro12Ala), PPARG-coactivator, 1 alpha (PPARGC1A Gly482Ser), forkhead box C2 (FOXC2 -512C > T) and beta3-adrenergic receptor (ADRB3 Trp64Arg) polymorphisms using TaqMan allelic discrimination assay or RFLP.


RESULTS
The CC, CT and TT genotype frequencies of the TCF7L2 rs7903146 variant differed significantly between women with gestational diabetes mellitus and control women (46.3, 43.6 and 10.1% vs 58.5, 35.3 and 6.2%, p = 3.7 x 10(-6), corrected p value [Pc] for multiple testing Pc = 2.2 x 10(-5)). The T-allele was associated with an increased risk of gestational diabetes mellitus (odds ratio 1.49 [95% CI 1.28-1.75], p = 4.9 x 10(-7) [Pc = 2.8 x 10(-6)]). Compared with wild-type CC-genotype carriers, heterozygous (CT-genotype) and homozygous (TT-genotype) carriers had a 1.6-fold (95% CI 1.26-1.93, p = 3.7 x 10(-5) [Pc = 0.0002]) and a 2.1-fold (95% CI 1.41-2.99, p = 0.0001 [Pc = 0.0008]) increased risk of gestational diabetes mellitus, respectively. The other polymorphisms studied were not significantly associated with gestational diabetes mellitus (ADIPOQ +276G > T: 1.17 [1.01-1.36], p = 0.039 [Pc = 0.23]; PPARG Pro12Ala: 1.06 [0.87-1.29], p = 0.53; PPARGC1A Gly482Ser: 0.96 [0.83-1.10], p = 0.54; FOXC2 -512C > T: 1.01 [0.87-1.16], p = 0.94; and ADRB3 Trp64Arg: 1.22 [0.95-1.56], p = 0.12).


CONCLUSIONS
The TCF7L2 rs7903146 variant is associated with an increased risk of gestational diabetes mellitus in Scandinavian women.
Shaat
N
N
Department of Clinical Sciences/Diabetes & Endocrinology, Malmö University Hospital, Lund University, Malmö, Sweden. nael.shaat@med.lu.se
Lernmark
A
A
Karlsson
E
E
Ivarsson
S
S
Parikh
H
H
Berntorp
K
K
Groop
L
L
D052242:Adiponectin / Q000235:genetics; D019943:Amino Acid Substitution; D016640:Diabetes, Gestational / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D047495:PPAR gamma / Q000235:genetics; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012016:Reference Values; D018570:Risk Assessment; D012537:Scandinavian and Nordic Countries / Q000453:epidemiology; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D052242:Adiponectin; D047495:PPAR gamma; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein