Replication and Meta-Analysis of Candidate Loci Identified Variation at RAB3GAP1 Associated With Keratoconus
Replication and Meta-Analysis of Candidate Loci Identified Variation at RAB3GAP1 Associated With Keratoconus
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DOI：
10.1167/iovs.13-12377
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发表时间：
2013-07-01
影响因子：
4.4
通讯作者：
Burdon, Kathryn P.
中科院分区：
文献类型：
--
作者：
Ha Ae Bae;Mills, Richard A. D.;Burdon, Kathryn P.
目的.圆锥角膜是一种常见的复杂性角膜扩张症，可导致严重的视力损害。虽然遗传因素是公认的，但圆锥角膜的遗传危险因素尚未完全阐明。Li等人最近进行的一项全基因组关联研究（GWAS）发现了15种可能相关的单核苷酸多态性（SNP）。在这里，我们的目的是复制这些协会，并进行荟萃分析，目前和以前的研究。我们对524例澳大利亚白人圆锥角膜患者和2761例对照者的15个相关SNPs进行了基因分型。在PLINK中进行关联分析。采用Fisher方法对既往发表的GWAS的调整后P值进行荟萃分析，以联合收割机P值。我们的澳大利亚队列显示了在RAB 3GAP 1、KCND 3、IMMPL 2附近的SNP和染色体13q33.3上的基因沙漠中的关联（P < 0.003），提供了复制已发表结果的证据。Meta分析结果显示，RAB 3GAP 1基因附近的SNP rs 4954218与圆锥角膜显著相关，P = 9.26 x 10（-9），超过全基因组显著性水平。尽管疾病关联的机制尚未确定，但SNP rs 4954218与圆锥角膜一致相关，并可能标记有助于疾病易感性的功能变体。
PURPOSE. Keratoconus is a common complex corneal ectasia that can lead to severe visual impairment. Although a genetic component is well recognized, the genetic risk factors for keratoconus are yet to be fully elucidated. A recent genome-wide association study (GWAS) by Li et al. identified 15 potentially associated single nucleotide polymorphisms (SNPs). Here, we aimed to replicate these associations, and conduct a meta-analysis of the current and previous studies.METHODS. We genotyped the 15 reported associated SNPs in 524 Australian Caucasian cases with keratoconus and 2761 controls. Association analysis was conducted in PLINK. A meta-analysis of this study with the adjusted P values of the previously published GWAS was conducted using the method of Fisher to combine P values.RESULTS. Our Australian cohort showed association (P < 0.003) at SNPs near RAB3GAP1, KCND3, IMMPL2, and in a gene desert on chromosome 13q33.3, providing evidence of replication of the published results. The meta-analysis showed SNP rs4954218 near RAB3GAP1 gene was associated significantly with keratoconus, with P = 9.26 x 10(-9) passing the genome-wide significance level.CONCLUSIONS. Although the mechanism of disease association is yet to be determined, SNP rs4954218 is associated consistently with keratoconus and likely tags a functional variant that contributes to disease susceptibility.