Genome-wide association study identifies PERLD1 as asthma candidate gene.
Genome-wide association study identifies PERLD1 as asthma candidate gene.
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DOI：
10.1186/1471-2350-12-170
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发表时间：
2011-12-21
影响因子：
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通讯作者：
Chew FT
中科院分区：
文献类型：
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作者：
Anantharaman R;Andiappan AK;Nilkanth PP;Suri BK;Wang de Y;Chew FT
最近针对哮喘的全基因组关联研究已经成功地确定了新的关联，这些关联已经被很好地复制。这项研究的目的是使用GWAS方法确定影响新加坡华裔人群哮喘易感性的基因变异。过敏性哮喘的病例样本和无哮喘和特应性疾病的对照样本进行了两阶段GWAS检查。在发现阶段，对490例病例和490例对照样本进行了混合基因分型。在第二阶段的521个病例和524个对照样本的重复队列中，评估了第一阶段的显著相关性。在发现阶段使用的相同980个样本也被单独进行了基因分型，以便进行联合分析。另外1445名非哮喘特应性对照样本也进行了基因分型。对超过我们的全基因组P值阈值5.52×10-8的19个有希望的SNPs进行了单独的基因分型。在1011例病例和1014例对照样本的联合分析中，染色体17q12上PERLD1的SNP rs2941504与哮喘显著相关(P=1.48×10-6，ORAG=0.526(0.369~0.700)，ORAA=0.480(0.361~0.639))和等位基因水平(P=9.56×10-6，OR=0.745(0.654~0.848))。这些发现在其他3项哮喘GWAS研究中被发现是重复的，从而验证了我们自己的结果。对特应性对照样本的分析表明，SNP与过敏性哮喘有关，而与哮喘或过敏成分无关。对Rs2941504两侧100kb的额外SNPs的基因分型进一步证实了该关联确实与PERLD1有关。PERLD1参与修饰CD48和CD59等细胞表面标志的糖基磷脂酰肌醇锚定，已知CD48和CD59在T细胞的激活和增殖中发挥多种作用。这些发现揭示了PERLD1作为一种新的哮喘候选基因的关联，并加强了17q12-21染色体区域的基因在哮喘病因中的参与。
Recent genome-wide association studies (GWAS) for asthma have been successful in identifying novel associations which have been well replicated. The aim of this study is to identify the genetic variants that influence predisposition towards asthma in an ethnic Chinese population in Singapore using a GWAS approach. A two-stage GWAS was performed in case samples with allergic asthma, and in control samples without asthma and atopy. In the discovery stage, 490 case and 490 control samples were analysed by pooled genotyping. Significant associations from the first stage were evaluated in a replication cohort of 521 case and 524 control samples in the second stage. The same 980 samples used in the discovery phase were also individually genotyped for purposes of a combined analysis. An additional 1445 non-asthmatic atopic control samples were also genotyped. 19 promising SNPs which passed our genome-wide P value threshold of 5.52 × 10-8 were individually genotyped. In the combined analysis of 1011 case and 1014 control samples, SNP rs2941504 in PERLD1 on chromosome 17q12 was found to be significantly associated with asthma at the genotypic level (P = 1.48 × 10-6, ORAG = 0.526 (0.369-0.700), ORAA = 0.480 (0.361-0.639)) and at the allelic level (P = 9.56 × 10-6, OR = 0.745 (0.654-0.848)). These findings were found to be replicated in 3 other asthma GWAS studies, thus validating our own results. Analysis against the atopy control samples suggested that the SNP was associated with allergic asthma and not to either the asthma or allergy components. Genotyping of additional SNPs in 100 kb flanking rs2941504 further confirmed that the association was indeed to PERLD1. PERLD1 is involved in the modification of the glycosylphosphatidylinositol anchors for cell surface markers such as CD48 and CD59 which are known to play multiple roles in T-cell activation and proliferation. These findings reveal the association of a PERLD1 as a novel asthma candidate gene and reinforce the involvement of genes on the 17q12-21 chromosomal region in the etiology of asthma.