Examination of Type 2 Diabetes Loci Implicates CDKAL1 as a Birth Weight Gene

OBJECTIVE A number of studies have found that reduced birth weight is associated with type 2 diabetes later in life; however, the underlying mechanism for this correlation remains unresolved. Recently, association has been demonstrated between low birth weight and single nucleotide polymorphisms (SNPs) at the CDKAL1 and HHEX-IDE loci, regions that were previously implicated in the pathogenesis of type 2 diabetes. In order to investigate whether type 2 diabetes risk–conferring alleles associate with low birth weight in our Caucasian childhood cohort, we examined the effects of 20 such loci on this trait. RESEARCH DESIGN AND METHODS Using data from an ongoing genome-wide association study in our cohort of 5,465 Caucasian children with recorded birth weights, we investigated the association of the previously reported type 2 diabetes–associated variation at 20 loci including TCF7L2, HHEX-IDE, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B, and JAZF1 with birth weight. RESULTS Our data show that the minor allele of rs7756992 (P = 8 × 10−5) at the CDKAL1 locus is strongly associated with lower birth weight, whereas a perfect surrogate for variation previously implicated for the trait at the same locus only yielded nominally significant association (P = 0.01; r2 rs7756992 = 0.677). However, association was not detected with any of the other type 2 diabetes loci studied. CONCLUSIONS We observe association between lower birth weight and type 2 diabetes risk–conferring alleles at the CDKAL1 locus. Our data show that the same genetic locus that has been identified as a marker for type 2 diabetes in previous studies also influences birth weight.

[1]  D. Melzer,et al.  A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses. , 2006, American journal of human genetics.

[2]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[3]  M. Jarvelin,et al.  Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals. , 2007, American journal of human genetics.

[4]  Sian Ellard,et al.  Mutations in the glucokinase gene of the fetus result in reduced birth weight , 1998, Nature Genetics.

[5]  A. Hattersley,et al.  Insulin gene mutations as a cause of permanent neonatal diabetes , 2007, Proceedings of the National Academy of Sciences.

[6]  Joseph T. Glessner,et al.  A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene , 2007, Nature.

[7]  J. Dudenhausen,et al.  Birth weight and subsequent risk of type 2 diabetes: a meta-analysis. , 2007, American journal of epidemiology.

[8]  J. Sterne,et al.  Socioeconomic status, occupation, and risk of hospitalisation due to coxarthrosis in Denmark 1981–99 , 2004, Journal of epidemiology and community health.

[9]  L. Groop,et al.  Interaction between prenatal growth and high-risk genotypes in the development of type 2 diabetes , 2009, Diabetologia.

[10]  L. Groop,et al.  Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus , 2008, Nature Genetics.

[11]  A. Hattersley,et al.  The fetal insulin hypothesis: an alternative explanation of the association of low bir thweight with diabetes and vascular disease , 1999, The Lancet.

[12]  A. Hattersley,et al.  Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes. , 2006, The Journal of clinical endocrinology and metabolism.

[13]  Inês Barroso,et al.  Variants in MTNR1B influence fasting glucose levels , 2009, Nature Genetics.

[14]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[15]  M. McCarthy,et al.  Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes , 2008, Nature Genetics.

[16]  Mark I. McCarthy,et al.  Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth , 2009, Diabetes.

[17]  P. Elliott,et al.  A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk , 2009, Nature Genetics.

[18]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[19]  D. Altshuler,et al.  Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion , 2009, Nature Genetics.

[20]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[21]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[22]  T. Hansen,et al.  SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations , 2008, Nature Genetics.

[23]  T. Frayling,et al.  The role of genetic susceptibility in the association of low birth weight with type 2 diabetes. , 2001, British medical bulletin.

[24]  Debbie A Lawlor,et al.  Birth weight and risk of type 2 diabetes: a systematic review. , 2008, JAMA.

[25]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.