Gene-Based Genome-Wide Association Analysis in European and Asian Populations Identified Novel Genes for Rheumatoid Arthritis

Abstract

ObjectiveRheumatoid 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.MethodsGene-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.ResultsA 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.ConclusionOur 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.

Genetic Susceptibility to Rheumatoid Arthritis in West African Patients: Correlation with Rheumatoid Factor, Anticitrullinated Protein Antibody and Radiological Damage

“…Through a systematic review of published works, some authors identified some common HLA class II alleles that contribute to susceptibility to AIDs like RA in Americans an European populations [16]. In our study we observed associations of different HLADRB1 alleles with RA In Benin populations.…”

“…In Asian populations, the frequency was 6 and 5% and in the European populations it was 25.3% and 26.5% respectively [15]. These various studies reveal the very great variability of the HLADRB01 gene in the different populations [10,11,16]. However, in both the Asian and European populations the reported frequency was limited to some alleles of HLA DRB1 04 [16,17].…”

“…Susceptibility to and outcome for rheumatoid arthritis (RA) have been associated with particular HLA-DR alleles, but these alleles vary among ethnic groups and geographic areas [15][16][17]. The frequency of HLA-DR1 (HLA-DRB1*0101, DRB1*0102) and HLA-DR4 (DRB1*0401, DRB1*0404) alleles is elevated among Caucasian and magrebian patients with RA [10,11,16].…”

“…The frequency of HLA-DR1 (HLA-DRB1*0101, DRB1*0102) and HLA-DR4 (DRB1*0401, DRB1*0404) alleles is elevated among Caucasian and magrebian patients with RA [10,11,16].…”

“…These various studies reveal the very great variability of the HLADRB01 gene in the different populations [10,11,16]. However, in both the Asian and European populations the reported frequency was limited to some alleles of HLA DRB1 04 [16,17]. In SubSaharian africa, the high cost of HLA genotyping (which is often not realized on the spot but rather routed in France or Belgium) does not allow a mapping of the gene in the populations.…”