Genotype Study Of Rheumatoid Arthritis-related Interstitial Lung Diseases

IntroductionRheumatoid arthritis(RA)is a systemic inflammatory disorder characterized by the targeted progressive destruction of joints in the body.RA affects approximately 0.50%-1%of the population and bring a heavy burden for both patients and society.The disease burden is even greater in patients developing extra-arlticular manifestation of RA,which affects about 50%of patients.Pulmonary involvement is a common extra-articular feature of RA.Interstitial lung disease(ILD)is the most common and potentially most devastating manifestation of RA in the lung,predicting a poor prognosis for patients.The etiology of Rheumatoid arthritis associated interstitial lung disease(RA-ILD)is unknown.It is likely that genetic factor plays a role in triggering the disease.Some of the genetic polymorphisms have been studied in RA-ILD patients.For example,the HLA-DR allele and familial idiopathic pulmonary fibrosis-linked genes.This study will focus on the gene variations probably be associated to RA-ILD.Objecrtives1.Find the gene variations associate with RA-ILD.2.Study the Genotype-phenotype relationship.3.Reveal the underlying pathogenesis mechanism for RA-ILD by analyzing gene function.Methods45 RA-ILD patients and 22 RA patients without ILD are accepted into this research.All patients were enrolled by Peking Union Medical College Hospital from Oct.2016 to Mar.2018.The peripheral blood of the patients was collected for whole exome sequencing.The gene variations found by the sequencing were filtered by a series of methods including the 1000G data,functional test,removing of synonymous mutations,and software assessment.Those variations will also go through share gene analysis and pathogenesis analysis to determine the susceptible genes.Statistic methods were used to analyze whether there are significant differences between the gene variations of RA-ILD and RA groups.Also,Genotype-phenotype analysis is performed,by.dividing the RA-ILD patients into subgroups according to clinical features.Result1.The age of RA-ILD group is significantly higher than the RA group,while sex,age at RA onset years,RA duration years,active smoker,Serum CCP positive,Serum RF positive,erosive disease show no statistical difference.2.1357353 gene variations are found by whole exome sequencing.The number reduce to 14249 after the screening methods.3.4632 variations passing the share gene analysis are further analyzed by pathogenesis analyzing and statistical methods.4.Variations of HLA-DRB1、HLA-DPB1、ADRA2B、RELN、FABP7、MUC5B、RBM20、MSH3、SYNE1、MTCL1、DMBT1 are be assessed to have the possibility of connectingto RA-ILD.SYNE1、MTCL1、DMBT1 of the RA-ILD group significantly differs from the RA group.MUC5B、SYNE1 show significant difference among subgroups divided by clinical features.Conclusion1.MUC5B、HLA-DRB1、SYNE1、MTCL1、DMBT1 gene variations are associated to RA-ILD.Further research will be needed to confirm the conclusion.2.RA-ILD patients may share some of the genetic predisposition with RA patients.Other gene variations possibly trigger the injury to the lung and cause RA-ILD.3.MUC5B,DMBT1 gene variations probably contribute to the pathogenesis of RA-ILD,the pathway of which may have similarity with that of idiopathic pulmonary fibrosis.