Shaik Noor Ahmad, Banaganapalli Babajan
Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
Front Genet. 2019 Mar 7;10:168. doi: 10.3389/fgene.2019.00168. eCollection 2019.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder of bone joints caused by the complex interplay between several factors like body physiology, the environment with genetic background. The recent meta-analysis of GWAS has expanded the total number of RA-associated loci to more than 100, out of which approximately ∼97% (98 variants) loci are located in non-coding regions, and the other ∼3% (3 variants) are in three different non-HLA genes, i.e., TYK2 (Prp1104Ala), IL6R (Asp358Ala), and PTPN22 (Trp620Arg). However, whether these variants prompt changes in the protein phenotype with regards to its stability, structure, and interaction with other molecules, remains unknown. Thus, we selected the three clinically pathogenic variants described above, as positive controls and applied diverse computational methods to scrutinize if those mutations cause changes in the protein phenotype. Both wild type and mutant protein structures of PTPN22 (W620R), IL6R (D358A), and TYK2 (P1104A) were modeled and studied for structural deviations. Furthermore, we have also studied the secondary structure characteristics, solvent accessibility and stability, and the molecular interaction deformities caused by the amino acid substitutions. We observed that simple nucleotide predictions of SIFT, PolyPhen, CADD and FATHMM yields mixed findings in screening the RA-missense variants which showed a ≥-value threshold of 5 × 10 in genome wide association studies. However, structure-based analysis confirms that mutant structures shows subtle but significant changes at their core regions, but their functional domains seems to lose wild type like functional interaction. Our findings suggest that the multidirectional computational analysis of clinically potential RA-mutations could act as a primary screening step before undertaking functional biology assays.
类风湿性关节炎（RA）是一种慢性骨关节自身免疫性疾病，由身体生理、具有遗传背景的环境等多种因素之间的复杂相互作用引起。最近对全基因组关联研究（GWAS）的荟萃分析已将与RA相关的基因座总数扩展到100多个，其中约97%（98个变体）的基因座位于非编码区，另外约3%（3个变体）位于三个不同的非HLA基因中，即TYK2（Prp1104Ala）、IL6R（Asp358Ala）和PTPN22（Trp620Arg）。然而，这些变体是否会在蛋白质表型的稳定性、结构以及与其他分子的相互作用方面引发变化，仍然未知。因此，我们选择上述三个临床致病变体作为阳性对照，并应用多种计算方法来仔细研究这些突变是否会导致蛋白质表型发生变化。对PTPN22（W620R）、IL6R（D358A）和TYK2（P1104A）的野生型和突变型蛋白质结构进行了建模，并研究了其结构偏差。此外，我们还研究了由氨基酸取代引起的二级结构特征、溶剂可及性和稳定性以及分子相互作用畸形。我们观察到，SIFT、PolyPhen、CADD和FATHMM的简单核苷酸预测在筛选全基因组关联研究中显示≥5×10阈值的RA错义变体时产生了混合结果。然而，基于结构的分析证实，突变结构在其核心区域显示出细微但显著的变化，但其功能域似乎失去了野生型样的功能相互作用。我们的研究结果表明，对临床潜在的RA突变进行多方向计算分析可作为进行功能生物学检测之前的初步筛选步骤。
