Banaganapalli Babajan, Rashidi Omran, Saadah Omar I, Wang Jun, Khan Imran Ali, Al-Aama Jumana Y, Shaik Noor Ahmad, Elango Ramu
Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
J Cell Biochem. 2017 Aug;118(8):2193-2207. doi: 10.1002/jcb.25864. Epub 2017 Apr 18.
Celiac disease (CD) is a gluten intolerance disorder with known genetic contribution. The recent fine mapping and genome-wide association studies (GWAS) have identified up to 57 non-HLA CD susceptibility SNPs, majority of which are non-coding variants lacking any functional annotation. Therefore, we adopted multidimensional computational approach for uncovering the plausible mechanisms through which these GWAS SNPs are connected to CD pathogenesis. At initial phase, we identified that 25 (43.85%) out of 57 CD-SNPs lies in evolutionarily constrained genetic element regions. In follow-up phases, through computational (CADD, GWAVA, and FATHMM algorithms) deleterious intensity measurements, we have discovered that 42 (3.94%) out of 1065 variants (57 CD-lead and 1008-linked SNPs; r ≥ 0.8) are differentially deleterious in nature to CD. Further functional scrutinization of these CD variants by public domain eQTL mapping, gene expression, knockout mouse model, and pathway analyses revealed that deleterious SNPs of CCR2 gene influences its expression levels and may also elicit a cascade of T-cell-mediated immunological events leading to intestinal gluten intolerance in genetically susceptible individuals. This study demonstrates the utility of integrated in silico analysis of annotations, gene expression, and pathways in prioritizing the potential complex disease variants from large-scale open source genomic data. J. Cell. Biochem. 118: 2193-2207, 2017. © 2017 Wiley Periodicals, Inc.
乳糜泻（CD）是一种已知有遗传因素参与的麸质不耐受疾病。最近的精细定位和全基因组关联研究（GWAS）已鉴定出多达57个非HLA CD易感性单核苷酸多态性（SNP），其中大多数是非编码变异，缺乏任何功能注释。因此，我们采用多维计算方法来揭示这些GWAS SNP与CD发病机制相关的可能机制。在初始阶段，我们发现57个CD-SNP中有25个（43.85%）位于进化上保守的遗传元件区域。在后续阶段，通过计算（CADD、GWAVA和FATHMM算法）有害强度测量，我们发现1065个变异（57个CD主导和1008个连锁SNP；r≥0.8）中有42个（3.94%）在本质上对CD有不同程度的有害性。通过公共领域的eQTL定位、基因表达、基因敲除小鼠模型和通路分析对这些CD变异进行进一步的功能审查，发现CCR2基因的有害SNP会影响其表达水平，还可能引发一系列T细胞介导的免疫事件，导致遗传易感个体出现肠道麸质不耐受。本研究证明了在对来自大规模开源基因组数据的潜在复杂疾病变异进行优先级排序时，整合注释、基因表达和通路的计算机模拟分析的实用性。《细胞生物化学杂志》118：2193 - 2207，2017年。©2017威利期刊公司。
