Absence of Birth-Weight Lowering Effect of ADCY5 and Near CCNL, but Association of Impaired Glucose-Insulin Homeostasis with ADCY5 in Asian Indians
Absence of Birth-Weight Lowering Effect of ADCY5 and Near CCNL, but Association of Impaired Glucose-Insulin Homeostasis with ADCY5 in Asian Indians
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DOI：
10.1371/journal.pone.0021331
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发表时间：
2011-06-21
期刊：
影响因子：
3.7
通讯作者：
Karpe, Fredrik
中科院分区：
文献类型：
--
作者：
Vasan, Senthil K.;Neville, Matt J.;Karpe, Fredrik
背景：亚洲印度人表型的一个特点是出生体重低，成年 2 型糖尿病风险增加。大多数人群显示低出生体重与成人 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鉴定出3号染色体上的两个降低出生体重的位点（靠近CCNL1和ADCY5），后者也是2型糖尿病位点。因此，我们在一个大型印度出生队列中测试了这些遗传变异对出生体重和成人葡萄糖/胰岛素稳态的影响。方法/主要发现：对出生队列（成立于 1969-73 年）中登记的成年人（n = 2,151）进行了 rs900400（靠近 CCNL1）和 rs9883204（ADCY5）的基因分型。对出生体重、从婴儿期到成年期的人体测量以及与 2 型糖尿病相关的血糖特征之间的关联进行了测试。该人群的平均出生体重为 2.79 +/- 0.47 kg，与 CCNL1 (p = 0.87) 或 ADCY5 (p = 0.54) 的遗传变异无关。与西方人群相比，“出生体重降低”变异的等位基因频率相似。与生长或成人体重没有显着相关性。然而，ADCY5 的“降低出生体重”变体与空腹血糖（β 0.041，p = 0.027）、2 小时血糖（β 0.127，p = 0.019）的适度增加以及胰岛素生成指数（β -0.106，p = 0.050）和 2 小时胰岛素（β -0.058，p = 0.050）的降低相关。 0.010).结论：亚洲印度人的低出生体重甚至不能部分地由 CCNL1 和 ADCY5 附近的遗传变异来解释，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”变体与成年早期血糖升高和胰岛素反应降低有关，这表明低出生体重和 2 型糖尿病风险是一个常见的遗传原因。
Background: 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 (beta 0.041, p = 0.027), 2-hours glucose (beta 0.127, p = 0.019), and reduced insulinogenic index (beta -0.106, p = 0.050) and 2-hour insulin (beta -0.058, p = 0.010).Conclusions: 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.