Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid-specific phosphatase (Lyp), which is a key negative regulator of T lymphocyte activation. The aim of this study was to evaluate the genetic contribution of PTPN22 -1123G>C and +1858C>T polymorphisms and their haplotypes in SLE patients, as well as mRNA expression according to -1123G>C promoter polymorphism and disease activity. One hundred and fifty SLE patients and 150 unrelated healthy controls (HC), both Mexican mestizos, were genotyped by PCR-RFLP technique for the PTPN22 -1123G>C and +1858C>T polymorphisms. PTPN22 mRNA expression levels were determined by real-time PCR from PBMCs of thirty patients with SLE and fifteen HC carrying different genotypes. Distributions of genotype and allelic frequencies were similar between SLE and HC. The most frequent alleles were -1123 G and +1858 C in both groups (69 vs. 66 % and 97 vs. 98 %, in SLE and HC, respectively). However, the recessive model of inheritance analysis showed a lower frequency of -1123 CC genotype in SLE patients (7 vs. 15 %), suggesting a protection effect to develop SLE (OR 0.41, CI 1.10-5.28, p = 0.02). Haplotype analysis showed strong linkage disequilibrium D' = 0.98 for PTPN22 -1123G>C and +1858C>T polymorphisms, but haplotypes were not associated with SLE. The PTPN22 mRNA expression did not show differences among -1123G>C genotypes; nevertheless, a significant negative correlation with disease activity was found (r = -0.64, p < 0.01). SLE inactive patients showed similar PTPN22 mRNA expression levels to healthy controls, whereas in patients with severe flare, the expression was nearly depleted. In conclusion, we found a lack of association of PTPN22 -1123G>C and +1858C>T polymorphisms with the risk of developing SLE in a Mexican population. Moreover, decreased or absent PTPN22 mRNA expression in SLE patients with severe flare suggests that Lyp plays an important regulatory role, and its absence contributes to the inflammatory response and disease activity in SLE. However, further analysis in a prospective study could help us determine its usefulness as a genetic marker of disease activity in SLE.

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

“…It should be noted that studies in autoimmune disease showed controversial results concerning allele and genotype associations with several SNPs as well as other haplotype associations in the CTLA4 and PTPN22 genes [25,27,44,45]. This may be due to ethnic or geographical factors of the studied population.…”

“…Protein tyrosine phosphatase non-receptor type 22 (PTPN22) also serves as a negative factor on TCR signaling [12]. A number of studies have shown that several SNPs of CTLA4 and PTPN22 are associated with a number of systemic autoimmune diseases, such as rheumatoid arthritis (RA) [14,15], inflammatory bowel disease (IBD) [16,17], systemic lupus erythematosus (SLE) [18,19], ankylosing spondylitis (AS) [20,21], Graves' disease (GD) [22,23], type 1 diabetes (T1D) [24][25][26], alopecia areata [27,28] and psoriatic arthritis [29]. A number of studies have shown that several SNPs of CTLA4 and PTPN22 are associated with a number of systemic autoimmune diseases, such as rheumatoid arthritis (RA) [14,15], inflammatory bowel disease (IBD) [16,17], systemic lupus erythematosus (SLE) [18,19], ankylosing spondylitis (AS) [20,21], Graves' disease (GD) [22,23], type 1 diabetes (T1D) [24][25][26], alopecia areata [27,28] and psoriatic arthritis [29].…”

“…It has been reported that both CTLA-4 and PTPN22 play important roles in autoimmune responses [12,13]. A number of studies have shown that several SNPs of CTLA4 and PTPN22 are associated with a number of systemic autoimmune diseases, such as rheumatoid arthritis (RA) [14,15], inflammatory bowel disease (IBD) [16,17], systemic lupus erythematosus (SLE) [18,19], ankylosing spondylitis (AS) [20,21], Graves' disease (GD) [22,23], type 1 diabetes (T1D) [24][25][26], alopecia areata [27,28] and psoriatic arthritis [29]. Our previous studies have identified the association of CTLA4 and PTPN22 genetic polymorphisms with Vogt-Koyanagi-Harada (VKH) disease, a common autoimmune uveitis entity in China [30,31].…”

Association Study of the PTPN22 Gene Polymorphisms with Systemic Lupus Erythematosus in Lorestan Province of Iran

“…In this SNP, missense mutation in -1123 position converts G to C; therefore, the -1123 allele can affect the expression of mRNA of PTPN22 and cause dysregulation in B-and T-cells of patients with SLE (13). In the white Europeans, PTPN22 -1123G > C is often expressed with PTPN22 1858C > T (20).…”

“…In this SNP, a missense mutation in nucleotide position 1858 in the coding area of gene converts cytosine into thymine, causing the single amino acid arginine to be converts into tryptophan in position 620 in exon 14 (11,12). Another SNP in gene PTPN22 is rs2488457 (-1123G > C) in which a missense mutation in nucleotide position 1123 in promoter area converts guanine to cytosine (13). The PTPN22 mutations may cause T-cell activation and the induction of autoimmune diseases such as SLE, rheumatoid arthritis, autoimmune thyroid, and type 1 diabetes mellitus (T1DM) (14).…”