A sequencing study of CTLA4 in Pakistani rheumatoid arthritis cases.

Muhammad Muaaz Aslam,Peter John,F Yesim Demirci,M Ilyas Kamboh,Attya Bhatti,Eleanor Feingold,Fazal Jalil,Kang-Hsien Fan,Mahmoud Abu-Shakra

doi:10.1371/journal.pone.0239426

Abstract

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease. The interaction of genetic and environmental factors is likely necessary for RA. Among potential genetic factors, many major histocompatibility complex (MHC) and non-MHC variants may be involved in RA susceptibility. CTLA4 is involved in the regulation of T-cell response during an immune reaction, and multiple CTLA4 single nucleotide polymorphisms (SNPs) have been associated with numerous autoimmune diseases, including RA. To our knowledge, the genetic association of CTLA4 with RA risk has not been examined previously in the Pakistani population. In this study, we sequenced the entire CTLA4 gene and flanking regions in 95 Pakistani RA cases followed the screening of identified variants in Study 1 sample consisting of 350 RA cases and controls. Four common significant variants identified in Study 1 sample were further examined in a larger Study 2 replication sample comprising 1,678 independent RA cases and controls. We report significant associations of three variants from the combined analysis: rs3087243 (OR = 1.26, p = 4.47E-03), rs5742909 (OR = 1.78, p = 4.60E-03), and rs11571319 (OR = 1.48, p = 6.64E-03); the latter is a novel association in the Pakistani sample.

Highlights

Rheumatoid arthritis (RA) is an inflammatory, chronic, autoimmune syndrome that causes articular damage, synovial joint destruction, and related comorbidities [1]
Many major histocompatibility complex (MHC) and non-MHC genetic variants are associated with RA susceptibility [21]
Cytotoxic T-lymphocyte antigen-4 (CTLA4) regulates the T-cell response in an immune reaction and genetic variation CTLA4 has been reported to be associated with RA susceptibility [22]

Summary

Introduction

RA is an inflammatory, chronic, autoimmune syndrome that causes articular damage, synovial joint destruction, and related comorbidities [1]. RA is characterized by increased levels of autoantibodies, inflamed bones and joints, synovitis, and destruction of bone and cartilage that lead to fatigue, chronic pain, and in the worst cases, permanent disability [2]. A complex network of immune cells (B-cells, T-cells, mast cells, plasma cells, and dendritic cells) and cytokines (pro-inflammatory and anti-inflammatory) are involved in the etiology of RA [3]. RA affects almost 0.5 to 1% of the general population [4]; in Pakistan, its prevalence is approximately 0.5% [5]. RA can affect both sexes at any age, but the prevalence of RA is higher in women than men [6].

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Results

Conclusion