Abstract
Citrullination, a posttranslational modification of peptidyl arginine to citrulline, plays an essential role in rheumatoid arthritis (RA). Citrullination is catalyzed by a group of peptidylarginine deiminases (PADs) including PADI 1, 2, 3, 4 and 6. Many studies have indicated that the gene encoding PADI4 is a factor in susceptibility to RA. Some studies have detected PADI2 expression in RA synovial tissues, suggesting that PADI2 also plays an important role in the disease. This study evaluated the possible association between the PADI2-encoding gene and RA. Seventeen tag SNPs across the PAD locus were genotyped using a custom-designed Illumina 96-SNP VeraCode microarray. Peripheral blood samples were collected from patients with RA (n = 267), ankylosing spondylitis (AS, n = 51) and healthy controls (n = 160). The results of genotyping were verified using Sequenom MassARRAY in an independent cohort of 307 patients with RA, 324 patients with AS and 509 healthy controls. A western blot analysis was performed using synovial tissue from patients with RA (n = 7), osteoarthritis (OA, n = 7) and AS (n = 5) to determine the levels of expression of PADI2. A microarray analysis revealed a significant association between three selected PADI2 SNPs (rs2235926, rs2057094, rs2076616) and the presence of RA. The increased susceptibility to RA associated with rs2235926 (OR = 1.706733, 95% CI = [1.576366–1.866587], p = 0.000839) and rs2057094 (OR = 1.360432, 95% CI = [1.065483–1.869482], p = 0.003291) was further confirmed by the Sequenom MassARRAY. No tag SNPs in the PADI2 locus showed a significant association with AS. Increased expression of PADI2 was detected in RA synovial tissues compared with samples from patients with OA and AS. PADI2 is significantly associated with RA and may be involved in the pathogenesis of the disease.
Highlights
Citrullination is a posttranslational modification involving the conversion of arginine residues into the amino acid citrulline
Following the Bonferroni correction, the single nucleotide polymorphisms (SNPs) rs2235926, rs2057094 and rs11203368 still had a significant association with Rheumatoid arthritis (RA) with regards to allele frequency and genotype frequency, indicating that these three SNPs in the PADI2 and PADI4 encoding genes are significantly associated with the disease
We used a custom-designed Illumina microarray to genotype 17 tag SNPs in the peptidylarginine deiminases (PADs) locus to determine their association with susceptibility to RA
Summary
Citrullination is a posttranslational modification involving the conversion of arginine residues into the amino acid citrulline. This modification affects physiology either by directly modulating protein function or by impacting immune recognition of self proteins. Rheumatoid arthritis (RA) is an autoimmune disease, and serum from RA patients contains a spectrum of autoantibodies including rheumatoid factor, anti-filaggrin autoantibody, antikeratin antibody (AKA), anti-perinuclear factor, anti-vimentin and anti-cyclic citrullinated peptide antibody (anti-CCP) [1,2,3,4,5]. Antibodies directed against citrulline-containing proteins are highly specific for RA and can be detected in up to 80% of RA patients. Citrullination plays an essential role in the autoimmune basis of RA [6]
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