Common variants at the GCK, GCKR, G6PC2-ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations
Common variants at the GCK, GCKR, G6PC2-ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations
复制标题
DOI：
10.1007/s00125-009-1595-1
复制
发表时间：
2010-02-01
期刊：
影响因子：
8.2
通讯作者：
Kato, N.
中科院分区：
文献类型：
--
作者：
Takeuchi, F.;Katsuya, T.;Kato, N.
为了测试欧洲人群中最近被全基因组关联(GWA)研究确定或验证的四个座位上的空腹血糖相关性，我们在两个亚洲人群中进行了一项复制研究。我们在普通日本人(n=4,813)和斯里兰卡人(n=2,319)人群中对5个以前在欧洲人中报道的常见变异进行了基因分型：rs1799884(GCK)、rs780094(GCKR)、rs560887(G6PC2-ABCB11)以及rs1387153和rs10830963(MTNR1B)。为了识别新的变异，我们通过对776个非糖尿病日本样本的GWA扫描数据进一步检查了每个基因座附近的遗传关联。在南亚人(斯里兰卡)和东亚人(日本)中，在p<；0.05(单尾检验)的5个单核苷酸多态(SNPs)中复制了空腹血糖关联。在GWA扫描数据的精细定位中，我们在G6PC2-ABCB11区域发现了一个新的SNP，rs3755157，与日本(p=2.6x10(-8))和斯里兰卡(p=0.001)人群显著相关。在rs3755157上的关联强度比原始SNP的rs560887更显著，检测到这两个SNP之间存在等位基因的异质性。在分析相关SNPs的累积效应时，我们发现每个等位基因的梯度(日本人和斯里兰卡人的β分别为0.055和0.069 mmoL/L)与欧洲人的报告几乎相同。四个测试基因座的空腹血糖关联被证明是可在种族群体中复制的。尽管总体上是一致的，但在连锁不平衡的模式和强度上肯定存在种族多样性，并有助于在GWA研究后显著减少潜在的因果变异。
To test fasting glucose association at four loci recently identified or verified by genome-wide association (GWA) studies of European populations, we performed a replication study in two Asian populations.We genotyped five common variants previously reported in Europeans: rs1799884 (GCK), rs780094 (GCKR), rs560887 (G6PC2-ABCB11) and both rs1387153 and rs10830963 (MTNR1B) in the general Japanese (n = 4,813) and Sri Lankan (n = 2,319) populations. To identify novel variants, we further examined genetic associations near each locus by using GWA scan data on 776 non-diabetic Japanese samples.Fasting glucose association was replicated for the five single nucleotide polymorphisms (SNPs) at p < 0.05 (one-tailed test) in South Asians (Sri Lankan) as well as in East Asians (Japanese). In fine-mapping by GWA scan data, we identified in the G6PC2-ABCB11 region a novel SNP, rs3755157, with significant association in Japanese (p = 2.6 x 10(-8)) and Sri Lankan (p = 0.001) populations. The strength of association was more prominent at rs3755157 than that of the original SNP rs560887, with allelic heterogeneity detected between the SNPs. On analysing the cumulative effect of associated SNPs, we found the per-allele gradients (beta = 0.055 and 0.069 mmol/l in Japanese and Sri Lankans, respectively) to be almost equivalent to those reported in Europeans.Fasting glucose association at four tested loci was proven to be replicable across ethnic groups. Despite this overall consistency, ethnic diversity in the pattern and strength of linkage disequilibrium certainly exists and can help to appreciably reduce potential causal variants after GWA studies.