Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up
Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up
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DOI：
10.1093/hmg/dds099
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发表时间：
2012-06-15
影响因子：
3.5
通讯作者：
Martin, Javier
中科院分区：
文献类型：
--
作者：
Martin, Jose-Ezequiel;Broen, Jasper C.;Martin, Javier
系统性硬化症（SSc）是一种影响结缔组织的复杂自身免疫性疾病;受遗传和环境因素的影响。最近，我们进行了第一次成功的SSc全基因组关联研究（GWAS）。在这里，我们进行了一个大的复制研究，以更好地剖析SSc的遗传成分。我们从以前的GWAS中选择了768个多态性，并在欧洲的7个重复队列中对它们进行基因分型。通过对复制队列和复制-GWAS队列（3237例病例和6097例对照）进行荟萃分析，计算复制的显著SNP的总体显著性。选择先前与SSc无关的区域中的6个SNP在另外5个独立队列中进行验证，总共5270名SSc患者和8326名对照。我们发现了一个新的SSc遗传风险位点的复制和整体全基因组意义的证据：CSK [P值5.04 10（12），比值比（OR）1.20]。此外，我们发现PSD 3（P值3.18 10（7），OR 1.36）和NF KB 1（P值1.03 10（6），OR 1.14）基因座提示相关性。此外，我们加强了先前确认的相关性的证据。这项研究显着增加了已知的SSc推定遗传风险因素的数量，包括基因CSK，PSD 3和NFKB 1，并进一步证实了先前描述的六个。
Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value 5.04 10(12), odds ratio (OR) 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value 3.18 10(7), OR 1.36) and NFKB1 (P-value 1.03 10(6), OR 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.