Al Safar Habiba S, Cordell Heather J, Jafer Osman, Anderson Denise, Jamieson Sarra E, Fakiola Michaela, Khazanehdari Kamal, Tay Guan K, Blackwell Jenefer M
Centre for Forensic Science, The University of Western Australia, Crawley, Western, Australia; Khalifa University of Science, Technology & Research, Biomedical Department, Abu Dhabi, United Arab Emirates.
Ann Hum Genet. 2013 Nov;77(6):488-503. doi: 10.1111/ahg.12036. Epub 2013 Aug 13.
Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome-wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N=178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome-wide significance (commonly P=5×10(-8)) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12-p13 (KCTD8: rs4407541, P=9.70×10(-6); GABRB1: rs10517178/rs1372491, P=4.19×10(-6)) and 14q13 (PRKD1: rs10144903, 3.92×10(-6)), supported by analysis using a linear mixed model approximation in GenABEL (4p12-p13 GABRG1/GABRA2: rs7662743, Padj-agesex=2.06×10(-5); KCTD8: rs4407541, Padj-agesex=1.42×10(-4); GABRB1: rs10517178/rs1372491, Padj-agesex=0.027; 14q13 PRKD1: rs10144903, Padj-agesex=6.95×10(-5)). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (Padj-agesex=0.030) and rs2055942 (Padj-agesex=0.022) at COX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: Padj-agesex=0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: Padj-agesex-combined=3×10(-4)) and at KCTD8 (rs4695718: Padj-agesex-combined=2×10(-4)). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; Padj-agesex=0.031; Padj-agesex-combined=2×10(-4)). These genes may provide important functional leads in understanding disease pathogenesis in this population.
在阿拉伯联合酋长国（UAE），20%年龄在20至79岁的人患有2型糖尿病（T2D）。尚未有关于阿拉伯国家开展全基因组关联研究（GWAS）以鉴定T2D相关基因的报道。我们对一个扩展的阿联酋家族（N = 178；66名糖尿病患者；112名健康者）进行了探索性GWAS，使用Illumina Human 660 Quad Beadchip进行基因分型，并在116例病例和199例对照中对最显著结果进行独立验证。因此，达到全基因组显著性（通常P = 5×10⁻⁸）的检验效能有限。尽管如此，在FBAT中进行的传递不平衡检验在4号染色体p12 - p13区域（KCTD8：rs4407541，P = 9.70×10⁻⁶；GABRB1：rs10517178/rs1372491，P = 4.19×10⁻⁶）和14号染色体q13区域（PRKD1：rs10144903，3.92×10⁻⁶）发现了最显著结果，GenABEL中使用线性混合模型近似法的分析也支持这些结果（4号染色体p12 - p13区域GABRG1/GABRA2：rs7662743，经年龄和性别校正后P = 2.06×10⁻⁵；KCTD8：rs4407541，经年龄和性别校正后P = 1.42×10⁻⁴；GABRB1：rs10517178/rs1372491，经年龄和性别校正后P = 0.027；14号染色体q13区域PRKD1：rs10144903，经年龄和性别校正后P = 6.95×10⁻⁵）。GABRG1/GABRA2区域的单核苷酸多态性（SNP）未得到验证，而COX7B2/GABRA4区域更靠近近端的SNP rs7679715（经年龄和性别校正后P = 0.030）和rs2055942（经年龄和性别校正后P = 0.022）得到了验证，此外KCTD8区域远端也有一个趋势（rs4695718：经年龄和性别校正后P = 0.096）。对探索性和验证性数据的建模支持GABRA4（rs2055942：经年龄、性别合并校正后P = 3×10⁻⁴）和KCTD8（rs4695718：经年龄、性别合并校正后P = 2×10⁻⁴）存在独立信号。PRKD1的rs1953722（rs10144903的替代SNP）得到了验证（经年龄和性别校正后P = 0.031；经年龄、性别合并校正后P = 2×10⁻⁴）。这些基因可能为理解该人群疾病发病机制提供重要的功能线索。
Zotero 插件