Department of Molecular Medicine & Surgery, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2011;6(6):e21331. doi: 10.1371/journal.pone.0021331. Epub 2011 Jun 21.
A feature of the Asian Indian phenotype is low birth weight with increased adult type 2 diabetes risk. Most populations show consistent associations between low birth weight and adult type 2 diabetes. Recently, two birth weight-lowering loci on chromosome 3 (near CCNL1 and ADCY5) were identified in a genome-wide association study, the latter of which is also a type 2 diabetes locus. We therefore tested the impact of these genetic variants on birth weight and adult glucose/insulin homeostasis in a large Indian birth cohort.
METHODOLOGY/PRINCIPAL FINDINGS: Adults (n = 2,151) enrolled in a birth cohort (established 1969-73) were genotyped for rs900400 (near CCNL1) and rs9883204 (ADCY5). Associations were tested for birth weight, anthropometry from infancy to adulthood, and type 2 diabetes related glycemic traits. The average birth weight in this population was 2.79±0.47 kg and was not associated with genetic variation in CCNL1 (p = 0.87) or ADCY5 (p = 0.54). Allele frequencies for the 'birth weight-lowering' variants were similar compared with Western populations. There were no significant associations with growth or adult weight. However, the 'birth weight-lowering' variant of ADCY5 was associated with modest increase in fasting glucose (β 0.041, p = 0.027), 2-hours glucose (β 0.127, p = 0.019), and reduced insulinogenic index (β -0.106, p = 0.050) and 2-hour insulin (β -0.058, p = 0.010).
The low birth weight in Asian Indians is not even partly explained by genetic variants near CCNL1 and ADCY5 which implies that non-genetic factors may predominate. However, the 'birth-weight-lowering' variant of ADCY5 was associated with elevated glucose and decreased insulin response in early adulthood which argues for a common genetic cause of low birth weight and risk of type 2 diabetes.
亚洲印度人表型的一个特征是出生体重低，成年后患 2 型糖尿病的风险增加。大多数人群都显示出生体重低与成年 2 型糖尿病之间存在一致的关联。最近，在全基因组关联研究中发现了位于染色体 3 上的两个降低出生体重的基因座（靠近 CCNL1 和 ADCY5），后者也是 2 型糖尿病的基因座。因此，我们在一个大型印度出生队列中检测了这些遗传变异对出生体重和成年葡萄糖/胰岛素稳态的影响。
方法/主要发现：1969-1973 年建立的出生队列中的成年人（n=2151）接受了 rs900400（靠近 CCNL1）和 rs9883204（ADCY5）的基因分型。检测了出生体重、从婴儿期到成年期的人体测量学以及 2 型糖尿病相关的血糖特征与这些遗传变异的相关性。该人群的平均出生体重为 2.79±0.47kg，与 CCNL1（p=0.87）或 ADCY5（p=0.54）的遗传变异无关。与西方人群相比，“降低出生体重”变异体的等位基因频率相似。与生长或成年体重均无显著相关性。然而，ADCY5 的“降低出生体重”变异体与空腹血糖（β 0.041，p=0.027）、2 小时血糖（β 0.127，p=0.019）、胰岛素原指数（β -0.106，p=0.050）和 2 小时胰岛素（β -0.058，p=0.010）的适度增加相关。
亚洲印度人的低出生体重不能用 CCNL1 和 ADCY5 附近的遗传变异来部分解释，这意味着非遗传因素可能占主导地位。然而，ADCY5 的“降低出生体重”变异体与成年早期的葡萄糖升高和胰岛素反应降低有关，这表明低出生体重和 2 型糖尿病风险存在共同的遗传原因。
