PDF(Pubmed)
Abstract：
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease caused by a combination of genetic and environmental factors. Rare variants with low predicted effects in genes participating in the same biological function might be involved in developing complex diseases such as RA. From whole-exome sequencing (WES) data, we identified genes containing rare non-neutral variants with complete penetrance and no phenocopy in at least one of nine French multiplex families. Further enrichment analysis highlighted focal adhesion as the most significant pathway. We then tested if interactions between the genes participating in this function would increase or decrease the risk of developing RA disease. The model-based multifactor dimensionality reduction (MB-MDR) approach was used to detect epistasis in a discovery sample (19 RA cases and 11 healthy individuals from 9 families and 98 unrelated CEU controls from the International Genome Sample Resource). We identified 9 significant interactions involving 11 genes (MYLK, FLNB, DOCK1, LAMA2, RELN, PIP5K1C, TNC, PRKCA, VEGFB, ITGB5, and FLT1). One interaction (MYLK*FLNB) increasing RA risk and one interaction decreasing RA risk (DOCK1*LAMA2) were confirmed in a replication sample (200 unrelated RA cases and 91 GBR unrelated controls). Functional and genomic data in RA samples or relevant cell types argue the key role of these genes in RA.
摘要：
类风湿性关节炎(RA)是一种慢性,由遗传和环境因素共同引起的全身性自身免疫性疾病。在参与相同生物学功能的基因中具有低预测效应的罕见变异可能与发展复杂疾病如RA有关。从全外显子组测序(WES)数据来看，我们在9个法国多重家族中的至少一个家族中鉴定出包含具有完全外显率和无表型的罕见非中性变体的基因。进一步的富集分析强调了粘着斑是最重要的途径。然后，我们测试了参与该功能的基因之间的相互作用是否会增加或降低患RA疾病的风险。基于模型的多因素降维（MB-MDR）方法用于检测发现样本（来自9个家庭的19例RA病例和11例健康个体以及来自国际基因组样本资源的98例无关的CEU对照）中的上位性。我们确定了9个重要的相互作用，涉及11个基因(MYLK，FLNB,DOCK1,LAMA2,RELN,PIP5K1C,TNC,PRKCA,VEGFB,ITGB5和FLT1)。在复制样本（200例无关的RA病例和91例GBR无关的对照）中，证实了一种相互作用（MYLK*FLNB）增加RA风险和一种相互作用降低RA风险（DOCK1*LAMA2）。RA样品或相关细胞类型中的功能和基因组数据证明了这些基因在RA中的关键作用。
