Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.
Curr Opin Clin Nutr Metab Care. 2012 May;15(3):258-64. doi: 10.1097/MCO.0b013e328351f543.
Smaller size at birth is associated with a higher risk of type 2 diabetes in later life, but the mechanisms behind this association are poorly understood. Genetic variants which influence susceptibility to type 2 diabetes via effects on insulin secretion or action are good candidates for association with birth weight because foetal insulin is a key foetal growth factor. This review will focus on recent progress in identifying associations between common genetic variants and birth weight.
Foetal genetic variants at two loci (near CCNL1 and in ADCY5) were robustly associated with birth weight via the foetal genotype in the first genome-wide association study of birth weight. The birth weight-lowering allele at ADCY5 also predisposes to type 2 diabetes. In addition, evidence from studies of other type 2 diabetes loci is accumulating for association between the foetal risk alleles at CDKAL1 and HHEX-IDE and lower birth weight, and the maternal risk alleles at GCK and TCF7L2 and higher birth weight.
The associations with birth weight at ADCY5, CDKAL1 and HHEX-IDE support the foetal insulin hypothesis, which proposed that type 2 diabetes and lower birth weight could be two phenotypes of the same genotype. The associations at GCK and TCF7L2 illustrate that maternal genes are also important determinants of birth weight.
出生体重较小与日后发生 2 型糖尿病的风险增加相关，但这种关联的机制尚不清楚。通过影响胰岛素分泌或作用而影响 2 型糖尿病易感性的遗传变异是与出生体重相关的良好候选者，因为胎儿胰岛素是胎儿生长的关键因子。这篇综述将重点介绍鉴定常见遗传变异与出生体重之间关联的最新进展。
在首个全基因组出生体重关联研究中，通过胎儿基因型，两个位点（CCNL1 附近和 ADCY5 内）的胎儿遗传变异与出生体重显著相关。ADCY5 上降低出生体重的等位基因也易患 2 型糖尿病。此外，其他 2 型糖尿病位点研究的证据也在不断积累，提示 CDKAL1 和 HHEX-IDE 上的胎儿风险等位基因与较低的出生体重相关，而 GCK 和 TCF7L2 上的母系风险等位基因与较高的出生体重相关。
ADCY5、CDKAL1 和 HHEX-IDE 与出生体重的关联支持胎儿胰岛素假说，该假说认为 2 型糖尿病和较低的出生体重可能是同一基因型的两种表型。GCK 和 TCF7L2 上的关联表明，母系基因也是出生体重的重要决定因素。
