Interaction between prenatal growth and high-risk genotypes in the development of type 2 diabetes.
OBJECTIVE
Early environmental factors and genetic variants have been reported to be involved in the pathogenesis of type 2 diabetes. The aim of this study was to investigate whether there is an interaction between birthweight and common variants in the TCF7L2, HHEX, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B and JAZF1 genes in the risk of developing type 2 diabetes.


METHODS
A total of 2,003 participants from the Helsinki Birth Cohort Study, 311 of whom were diagnosed with type 2 diabetes by an OGTT, were genotyped for the specified variants. Indices for insulin sensitivity and secretion were calculated.


RESULTS
Low birthweight was associated with type 2 diabetes (p = 0.008) and impaired insulin secretion (p = 0.04). Of the tested variants, the risk variant in HHEX showed a trend towards a low birthweight (p = 0.09) and the risk variant in the CDKN2A/2B locus was associated with high birthweight (p = 0.01). The TCF7L2 risk allele was associated with increased risk of type 2 diabetes. Pooling across all nine genes, each risk allele increased the risk of type 2 diabetes by 14%. [corrected] Risk variants in the HHEX, CDKN2A/2B and JAZF1 genes interacted with birthweight, so that the risk of type 2 diabetes was highest in those with lower birthweight (p <or= 0.05). The interaction was also present in the pooled data.


CONCLUSIONS
Low birthweight might affect the strength of the association of some common variants (HHEX, CDKN2A/2B and JAZF1) with type 2 diabetes. These findings need to be replicated in independent cohorts.
Pulizzi
N
N
Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy. drpulizzi@gmail.com
Lyssenko
V
V
Jonsson
A
A
Osmond
C
C
Laakso
M
M
Kajantie
E
E
Barker
D J
DJ
Groop
L C
LC
Eriksson
J G
JG
D000368:Aged; D001724:Birth Weight; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D005387:Finland / Q000453:epidemiology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D011247:Pregnancy; D018570:Risk Assessment; D051820:TCF Transcription Factors / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C430460:JAZF1 protein, human; D009363:Neoplasm Proteins; D047495:PPAR gamma; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein