Type 2 diabetes risk alleles are associated with reduced size at birth.
OBJECTIVE
Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.


METHODS
We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.


RESULTS
We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none (P(trend) = 5 x 10(-7)). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus.


CONCLUSIONS
Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
Freathy
Rachel M
RM
Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK.
Bennett
Amanda J
AJ
Ring
Susan M
SM
Shields
Beverley
B
Groves
Christopher J
CJ
Timpson
Nicholas J
NJ
Weedon
Michael N
MN
Zeggini
Eleftheria
E
Lindgren
Cecilia M
CM
Lango
Hana
H
Perry
John R B
JR
Pouta
Anneli
A
Ruokonen
Aimo
A
Hyppönen
Elina
E
Power
Chris
C
Elliott
Paul
P
Strachan
David P
DP
Järvelin
Marjo-Riitta
MR
Smith
George Davey
GD
McCarthy
Mark I
MI
Frayling
Timothy M
TM
Hattersley
Andrew T
AT
D001724:Birth Weight; D002874:Chromosome Mapping; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics; D012359:tRNA Methyltransferases
C078492:HHEX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human