Abstract
Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways.
Highlights
Rheumatoid arthritis (RA) is a complex autoimmune disorder due to the involvement of many genetic, environmental, and stochastic elements in its etiology [1, 2]
The prevalence of RA was higher in females (78%) than males (22%), supporting the earlier data that females are more prone to RA [14]
There have been a number of genome-wide association studies on RA over the past decade that have resulted in the identification of many RA susceptibility loci, improving our understanding of the complex genetic underpinning of RA [15,16,17]
Summary
Rheumatoid arthritis (RA) is a complex autoimmune disorder due to the involvement of many genetic, environmental, and stochastic elements in its etiology [1, 2]. It is characterized by continuous inflammation associated with altered expression of different proinflammatory (TNFα, IL-1, IL-17) and anti-inflammatory (IL-4, IL-10, IL-13, IL-35) cytokines and activation of B and T cells, which leads to the destruction of synovial joints and physical disability [3, 4]. RA prevalence does not differ significantly between rural and urban areas [6] It can affect both sexes at any age, but data suggest that women are three times more prone than men [7]. Twin studies revealed high concordance rates in monozygotic twins (12.3-15.4%) relative to dizygotic twins (3.5%), strongly indicating the presence of a genetic component in RA [9]
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