title: Gene-Based Genome-Wide Association Analysis in European and Asian Populations Identified Novel Genes for Rheumatoid Arthritis.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is a complex autoimmune disease. Using a gene-based association research strategy, the present study aims to detect unknown susceptibility to RA and to address the ethnic differences in genetic susceptibility to RA between European and Asian populations.
  
  
  METHODS
  Gene-based association analyses were performed with KGG 2.5 by using publicly available large RA datasets (14,361 RA cases and 43,923 controls of European subjects, 4,873 RA cases and 17,642 controls of Asian Subjects). For the newly identified RA-associated genes, gene set enrichment analyses and protein-protein interactions analyses were carried out with DAVID and STRING version 10.0, respectively. Differential expression verification was conducted using 4 GEO datasets. The expression levels of three selected 'highly verified' genes were measured by ELISA among our in-house RA cases and controls.
  
  
  RESULTS
  A total of 221 RA-associated genes were newly identified by gene-based association study, including 71'overlapped', 76 'European-specific' and 74 'Asian-specific' genes. Among them, 105 genes had significant differential expressions between RA patients and health controls at least in one dataset, especially for 20 genes including 11 'overlapped' (ABCF1, FLOT1, HLA-F, IER3, TUBB, ZKSCAN4, BTN3A3, HSP90AB1, CUTA, BRD2, HLA-DMA), 5 'European-specific' (PHTF1, RPS18, BAK1, TNFRSF14, SUOX) and 4 'Asian-specific' (RNASET2, HFE, BTN2A2, MAPK13) genes whose differential expressions were significant at least in three datasets. The protein expressions of two selected genes FLOT1 (P value = 1.70E-02) and HLA-DMA (P value = 4.70E-02) in plasma were significantly different in our in-house samples.
  
  
  CONCLUSIONS
  Our study identified 221 novel RA-associated genes and especially highlighted the importance of 20 candidate genes on RA. The results addressed ethnic genetic background differences for RA susceptibility between European and Asian populations and detected a long list of overlapped or ethnic specific RA genes. The study not only greatly increases our understanding of genetic susceptibility to RA, but also provides important insights into the ethno-genetic homogeneity and heterogeneity of RA in both ethnicities.
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.|Department of Child and Adolescent Health, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xia
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Xing-Bo
authors.initials: XB
authors.lastname: Mo
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Lin
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Qiu
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Neng-Jun
authors.initials: NJ
authors.lastname: Yi
authors.affiliation: Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Deng
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Suzhou, Jiangsu, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Lei
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology; D044466:Asian People / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers