Hagedorn Research Institute, Niels Steensens Vej 1, Gentofte, Denmark.
Diabetologia. 2010 Sep;53(9):1908-16. doi: 10.1007/s00125-010-1790-0. Epub 2010 May 20.
AIMS/HYPOTHESIS: The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies.
Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes.
Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (beta = -33 g [95% CI -55, -10], p = 0.004) and CDKAL1 rs7756992 (beta = -22 g [95% CI -43, -1], p = 0.04). The association for the latter locus was confirmed in a meta-analysis (n = 24,885) (beta = -20 g [95% CI -29, -11], p = 5 x 10(-6)). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p = 0.09); however, in a meta-analysis (n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight (beta = -16 g [95% CI -24, -8], p = 8 x 10(-5)). On average, individuals with high genetic risk (>or=25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (beta = -35 g [95% CI -69, -2], p = 0.037).
CONCLUSIONS/INTERPRETATION: We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.
目的/假设：胎儿胰岛素假说表明，影响胰岛素分泌或作用的胎儿基因型变异可能导致低出生体重和 2 型糖尿病。我们在丹麦 Inter99 人群中的个体以及包括 Inter99 数据和报告研究的荟萃分析中，研究了 25 种已确认的 2 型糖尿病风险变异与出生体重之间的关联。
丹麦国家档案馆的助产士记录提供了有关母亲年龄和产次以及新生儿出生体重、出生时身长和早产的信息，在基于人群的 Inter99 研究的 4744 名个体中。我们对与 2 型糖尿病具有全基因组关联的 25 个风险等位基因进行了基因分型。
出生体重与 2 型糖尿病风险等位基因 ADCY5 rs11708067（β=-33g[95%CI-55，-10]，p=0.004）和 CDKAL1 rs7756992（β=-22g[95%CI-43，-1]，p=0.04）呈负相关。该后一位置的关联在荟萃分析（n=24885）中得到证实（β=-20g[95%CI-29，-11]，p=5×10（-6））。HHEX-IDE rs1111875 变异在丹麦人中没有显示出显著的相关性（p=0.09）；然而，在荟萃分析（n=25164）中，这种 2 型糖尿病风险等位基因与较低的出生体重相关（β=-16g[95%CI-24，-8]，p=8×10（-5））。平均而言，高遗传风险（>或=25 个 2 型糖尿病风险等位基因）的个体出生时体重略低于低遗传风险（<25 个 2 型糖尿病风险等位基因）的个体（β=-35g[95%CI-69，-2]，p=0.037）。
结论/解释：我们报告了胎儿 ADCY5 2 型糖尿病风险等位基因与出生体重降低之间的新关联，并在荟萃分析中证实了 HHEX-IDE 和 CDKAL1 的 2 型糖尿病风险等位基因与出生体重降低之间的关联。不能将 25 种常见的 2 型糖尿病风险等位基因归因于出生体重的强烈普遍影响。
