Identification of susceptibility SNPs in CTLA-4 and PTPN22 for scleritis in Han Chinese

Abstract

The aim of this study was to determine the association between 13 single nucleotide polymorphisms (SNPs) in the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes with scleritis in a Chinese Han population. We recruited 432 scleritis patients and 710 healthy controls. Four tag SNPs of CTLA4 and nine tag SNPs of PTPN22 were selected using Haploview. Genotyping was performed with the Sequenom MassArray® iPLEX GOLD Assay. Genotype and allele frequency differences were analyzed by χ 2 test and Bonferroni correction. Haplotype analysis was performed to further evaluate the association of these two genes with scleritis. In this study, CTLA4/rs3087243 G allele frequency and GG genotype frequency were significantly increased in scleritis patients compared to healthy controls [corrected P-value (Pc) = 0·02, odds ratio (OR) = 1·475, 95% confidence interval (CI) = 1·175-1·851; Pc = 0·04, OR = 1·546, 95% CI = 1·190-2·008, respectively]. None of the tested SNPs in the PTPN22 gene showed an association with scleritis. Haplotype analysis revealed a lower frequency of a CTLA4 TCAA haplotype (order of SNPs: rs733618, rs5742909, rs231775, rs3087243) (Pc = 4·26 × 10 -3 , OR = 0·618, 95% CI = 0·540-0·858) and a higher frequency of a PTPN22 TTATACGCG haplotype (order of SNPs: rs3789604, rs150426536, rs1746853, rs1217403, rs1217406, rs3789609, rs1217414, rs3789612, rs2488457) (Pc = 2·83 × 10 -4 , OR = 1·457, 95% CI = 1·210-1·754) in scleritis patients when compared to healthy controls. In conclusion, our findings indicate that CTLA4 and PTPN22 might confer genetic susceptibility to scleritis in a Chinese Han population.

Impact of Single-Nucleotide Polymorphisms of CTLA-4, CD80 and CD86 on the Effectiveness of Abatacept in Patients with Rheumatoid Arthritis

“…Of all the patients, 71.56% were women (78/109); the mean age at RA diagnosis was 44.94 ± 14.46 years and the median disease duration was 16 [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ] years; 13.76% (15/109) were smokers. All the patients had been treated with other DMARDs, for a median period of 36 [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , …”

“…A total of 14.68% (16/109) were ABA-bionaive, 26.61% (29/109) began the treatment after failure of 1 tumor necrosis factor inhibitor (TNFi), 28.44% (31/109) did so after failure of 2 TNFis and 30.28% (33/109) began treatment with ABA after failure of 3 or more TNFis. The mean age at the start of ABA treatment was 56.37 ± 13.05 years, and the median duration of ABA therapy was 28 [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] months. ABA was administered by SC route in 55.05% (60/109) and by IV route in 44.95% (49/109).…”

“…This modulation is performed physiologically by CTLA-4 [ 52 ]. Several SNPs located on this gene have been investigated for their association with autoimmune diseases [ 22 , 23 , 28 , 53 ]. The CTLA-4 rs5742909 polymorphism ( C > T ) is in the promoter region of exon 1 of the CTLA-4 gene, affecting the ATG transcription initiation codon [ 54 ].…”

“…The polymorphisms associated with the CTLA-4 gene have also been investigated for their association with the risk of developing autoimmune diseases [ 22 , 23 , 28 , 53 ]. In various previous studies, the CTLA-4 rs5742909-T allele has been associated with a lower risk of suffering from autoimmune diseases such as RA, systemic lupus erythematosus or Graves’ disease [ 53 , 56 , 58 , 59 , 71 , 72 ].…”

“…All these receptors are related, in turn, to the mechanism of action of ABA [ 15 , 18 , 26 , 27 , 28 ]. The presence of various SNPs in these genes may entail a conformational change in the proteins they encode, producing variability in the patient’s treatment response.…”