Study of programmed cell death 1 (PDCD1) gene polymorphims in Iranian patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease, characterized by axial arthritis in which the genetic-environmental factors seem to be involved in the pathogenesis of the disease. This study was performed to investigate the role of polymorphisms of the programmed cell death 1 (PDCD1) gene on susceptibility to AS. In this study, 161 Iranian patients with AS and 208 normal controls were enrolled; two single-nucleotide polymorphisms (SNPs) of the PDCD1 gene PD-1.3 (G, A) in nucleotide position +7146 of intron 4 and PD-1.9 (C, T) in nucleotide +7625 of exon 5 were studied. Analysis of PD-1.3 revealed that 82% of patients and 79% of controls had GG genotype, while GA and AA genotypes were detected in 17% and 0.6% of patients, respectively, and 20% and 1.4% of controls, respectively. Moreover, the genotype CC (PD-1.9) was present in 92% of patients and 97% of controls. Although these differences were not statistically significant between patients and controls, comparisons of genotypes frequencies in the AS patients, based on human leukocyte antigen (HLA)-B27, revealed that all patients who had CT genotype (PD-1.9) were HLA-B27 positive, whereas 30% of patients with CC genotype were HLA-B27 negative. There was no evidence of association for PDCD1 SNPs with AS in our study, but CT genotype (PD-1.9) seems to be associated with HLA-B27 positivity in the patients with AS.     

Failure to confirm association between PDCD1 polymorphisms and rheumatoid arthritis in a Japanese population

Programmed cell death 1 (PDCD1) is a necessary negative regulator to maintain peripheral tolerance and is a key molecule in the development of autoimmune diseases. Although PDCD1 gene polymorphisms and haplotypes were reported to be associated with rheumatoid arthritis (RA), replication studies later on showed conflicting results. Here, we analyzed the association of PDCD1 with RA using a large series of Japanese RA patients and population-based controls. DNA samples were obtained from 1,504 RA patients and 449 sex-matched controls. All samples were genotyped for three SNPs on PDCD1 (PD-1.1, PD-1.3 and PD-1.5) using the TaqMan fluorogenic 5′ nuclease assay. Chi-square testing was performed for a case-control study, and the PENHAPLO program was used for haplotype estimation. We could not observe any significant association of PD-1.1 or PD-1.5 polymorphisms between RA. PD-1.3, which was reported to be involved in susceptibility to RA in patients of European descent, was non-polymorphic in the Japanese population. We conclude that polymorphisms in the PDCD1 gene analyzed here are not associated with RA in a Japanese population.     

Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus

A regulatory single nucleotide polymorphism (SNP) PD1.3G/A located on programmed cell death 1 (PDCD1) gene, was shown to be involved in susceptibility to systemic lupus erythematosus (SLE) in Swedish, European American, and Mexican cases. However, association to childhood-onset SLE has not been analyzed. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with susceptibility to childhood-onset SLE in Mexican population. Three PDCD1 SNPs, PD1.3G/A, PD1.5C/T, PD1.6G/A, were analyzed in 250 childhood-onset SLE Mexican patients and 355 healthy controls in a case-control association study. Polymorphisms were genotyped by TaqMan technology. Stratification analysis was performed on the SLE cohort to investigate the SNP association with renal disorder. In addition, haplotypes were constructed with these three SNPs. The PD1.3A allele was significantly associated to childhood-onset SLE (P=0.0019, odds ratio (OR) 2.73, 95% confidence interval (95% CI) 1.35-5.56). The other PDCD1 SNPs did not show association. A total of 155 patients (62%) had nephritis, and no association was observed with PDCD1 SNPs. The ACG haplotype (PD1.3A, PD1.5C, PD1.6G) included almost all PD1.3A alleles, and it was more frequent in SLE patients (5.5%) than in controls (2.1%) (P=0.003; OR 2.73, 95% CI 1.37-5.46). The haplotype structure in Mexican controls was significantly different from those reported in Spanish and Swedish. Our results support association of the PD1.3A SNP to susceptibility of childhood-onset SLE in Mexican population and does not show association to lupus nephritis in this age group.     

Association of programmed death‐1 gene polymorphisms with the risk of basal cell carcinoma

Environmental and genetic factors play a fundamental role in the pathogenesis of basal cell carcinoma (BCC) defined as the most common cancer of skin. Programmed death‐1 (PD‐1), encoded by programmed cell death‐1 (PDCD1) gene, serves as an inhibitory molecule in the suppression of immune responses and a risk factor in the development of different cancers. In this study, we investigated the role of two single nucleotide polymorphisms (SNPs) within PDCD1 gene, and haplotypes defined by these SNPs, in the development of BCC in an Iranian population. Whole blood samples were obtained from 210 BCC and 320 healthy subjects. Genomic DNA was extracted from whole blood samples, polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) was used to genotype determinations of PD1.3 (rs11568821) and PD1.5 (rs2227981) SNPs, and 4 haplotypes were constructed by PDCD1 SNPs. The frequency of G allele of PD1.3 was significantly higher in BCC patients than healthy subjects (p < 0.02), while these significant differences were not observed in the frequencies of PD1.5 alleles between BCC and healthy subjects. Moreover, we found that there were no statistically significant differences in PD1.3 and PD1.5 genotypes between BCC and control groups. Of all estimated haplotypes for PDCD1, only AC haplotype was associated with BCC (OR = 0.22, 95% CI = 0.06–0.79, p < 0.01). These findings suggest that PD1.3G allele and AC haplotype of PDCD1 contribute to BCC in the Iranian population. However, further studies in different populations with larger sample size are required to confirm this study.     

Association of PD-1.5 C/T,but Not PD-1.3 G/A,with Malignant and Benign Brain Tumors in Iranian Patients

Programmed death-1 (PD-1) negatively regulates the immune response. The aims of this study were to assess the association of two single nucleotide polymorphisms in the PD-1 gene, PD-1.5 (+7785 C/T–rs2227981) and PD-1.3 (+7146 G/A- rs11568821), with benign and malignant brain tumors. Patients with brain tumors (96 patients with benign and 56 with malignant brain tumors) and 150 healthy control individuals were included. PCR-RFLP was performed for genotyping. It was revealed that the genotype and allele frequencies of PD-1.5 C/T polymorphism were significantly different between all brain tumor patients and the control group. The frequencies of the CT genotype and T allele were higher in brain tumor patients. In contrast, the frequency of PD-1.3 G/A genotypes and alleles showed no significant difference between all brain tumor patients and controls. Patients were then divided into malignant and benign groups. The results revealed a significant difference in both patients groups compared with the controls only at PD-1.5 C/T position. Arlequin analysis showed the GC haplotype was the most frequent haplotype in the whole group of patients and controls, and the GT haplotype was significantly different between patient and control groups. In conclusion, we demonstrate that PD-1.5 C/T polymorphism, but not PD-1.3 G/A, is associated with brain tumors in Iranian patients.     

Effects of the programmed cell death 1 (PDCD1) polymorphisms in susceptibility to systemic lupus erythematosus

The failure of immunological tolerance to self‐antigens plays a fundamental role in the pathogenesis of systemic lupus erythematosus (SLE). PD‐1 is an inhibitory receptor for regulating the immune system and preventing development of autoimmune disorders. This study aimed to determine the role of four single‐nucleotide polymorphisms (SNPs) within programmed cell death 1 (PDCD1 or PD‐1) gene and haplotypes defined by these SNPs in susceptibility to SLE in the Iranian population. Blood samples were obtained from 253 SLE and 564 healthy subjects. Red blood cells were lysed and genomic DNAs were extracted using salting‐out method. Genotype determinations of PD1.1, PD1.3, PD1.5 and PD1.9 SNPs were performed by polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP), and 12 haplotypes were constructed by PDCD1 SNPs. Our results showed significant differences in PD1.5 genotype frequencies between patient and control groups (p < .001). The frequencies of PD1.5 C/C, C/T and T/T genotypes versus other genotypes in SLE patients significantly differed from healthy subjects (p < .001, p = .001 and p = .002, respectively). Allelic analysis indicated a significant association between the frequency of PD1.5C allele and development of SLE in our population (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.51–2.42, p < .001). At the haplotype level, GGCC, GACT and GGCT haplotypes were significantly different between SLE and control groups (OR = 2.14, 95% CI = 1.73–2.66, p < .001; OR = 9.76, 95% CI = 4.47–21.3, p < .001; and OR = 0.32, 95% CI = 0.24–0.42, p < .001, respectively). Based on these findings, PD1.5 SNP and some haplotypes of PDCD1 contribute to SLE risk in the Iranian population.     

Programmed Death-1 Gene Polymorphisms in Patients With Systemic Lupus Erythematosus in Taiwan

To investigate the role of programmed cell death-1 (PD-1) gene polymorphisms in the development of systemic lupus erythematosus (SLE) in Taiwan, 109 patients with SLE and 100 healthy controls were enrolled in this study. The PD-1 gene polymorphisms were determined by the method of polymerase chain reaction/restriction fragment length polymorphism. This study showed that the genotype distributions of PD-1 7209 C/T polymorphisms were significantly different between the patients with SLE and controls (P=0.002, Pc=0.018). The frequencies of the PD-1 7209 C/C genotype and PD-1 7209 C allele were significantly higher in the patients with SLE than those of the controls (P=0.001, OR=2.6, 95% CI=1.5–4.6, and P=0.002, OR=2.1, 95% CI=1.3–3.4, Pc=0.018, respectively). Moreover, the association of PD-1 7209 C with susceptibility to SLE was independent of the PD-1 ligand. This study also showed that the PD-1-536 A 7146 G 7209 C 7499 G haplotype was associated with the development of SLE in Taiwan.Both Authors Contributed equally to this work     

Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis

T cell activation is regulated by inhibitory molecules such as PD-1 and CTLA-4, whose expression may be affected by gene polymorphisms. Increased T cell activation is present in patients with ANCA-associated vasculitis (AAV). We investigated two single-nucleotide polymorphisms (SNPs) in PDCD1 and five polymorphisms in CTLA4 in 102 patients with AAV and 188 healthy controls (HC). The distributions of the PD-1.3 and PD-1.5 SNPs, and the distributions of the CTLA4 promoter polymorphisms -1722T/C, -1661A/G, -318 C/T, and the (AT)(n) microsatellite in the 3'-untranslated region of CTLA4, did not differ between patients and HC. However, the +49 G allele was significantly more often present in patients with AAV. Furthermore, the co-occurrence of the PD-1.5 T allele with CTLA4 +49 AA homozygosity (i.e., the absence of a G allele) was less often present in patients compared to HC. These genetic polymorphisms may lead to hyperreactivity of T cells and thus may contribute to the pathogenesis of AAV.     

Inflammasome polymorphisms in juvenile systemic lupus erythematosus

Abstract

Inflammasome is the cytoplasmic complex responsible for pro-IL1?β cleavage and secretion of IL-1β. Recently our group reported the first association between polymorphisms in the inflammasome receptor NLRP1 and adult-onset systemic lupus erythematosus (SLE) “di per se” and especially in SLE-associated renal disease, suggesting the involvement of NLRP1-inflammasome in the immune dysregulation characteristic of SLE patients. Considering that juvenile-onset SLE (JSLE) is more severe than adult SLE, and that the genetic background plays a major role in the early development of autoimmune diseases, we analysed selected polymorphisms in inflammasome genes (NLRP1, NLRP3, CARD8, IL1B, TNFAIP3) of children and adolescents with JSLE (n?=?90) and in healthy controls (n?=?144). A single polymorphism in IL1B, and not NLRP1, gene resulted in association with JSLE, suggesting that IL-1?β is involved in the pathogenesis of SLE, but different genes could play specific role in adult- or early-onset disease.     

PTPN22, PDCD1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Polish patients

Type 1 diabetes (T1DM) is a common autoimmune disease with a complex genetic background. This study was aimed to investigate the association of PTPN22 G(-1123)C and C1858T, PDCD1 G7146A and CYP27B1 C(-1260)A polymorphisms with T1DM among Polish subjects. The PTPN22 gene encodes lymphoid tyrosine phosphatase, a potent negative regulator of T cell activation. PDCD1 gene gives rise to an inhibitory cell-surface receptor, expressed on activated lymphocytes. CYP27B1 encodes 1-alpha hydroxylase, responsible for conversion of the vitamin D₃ precursor into its active form, involved in the immune function. Polymorphic variants of these genes have previously been associated with various autoimmune disorders. The four polymorphisms were genotyped by PCR-restriction fragment assays in a case–control study comprising 215 T1DM patients and 236 healthy controls. The PTPN22 T1858 allele appeared significantly increased in T1DM compared to the control group (P = 0.004), yielding an OR of 1.73 (95% CI 1.19–2.51). The difference in distribution of C1858T genotypes also demonstrated statistical significance (P = 0.015). The frequencies of PTPN22 G(-1123)C alleles and genotypes did not differ between T1DM cases and controls, although the haplotype comprising both mutant PTPN22 alleles, C(-1123) and T1858, was significantly more frequent in affected individuals (P = 0.003). G(-1123)C and C1858T were in linkage disequilibrium (D′ = 0.98; r² = 0.61 in T1DM and D′ = 0.97; r² = 0.41 in controls). No significant differences in the allele and genotype frequencies of PDCD1 and CYP27B1 polymorphisms were found between patients and controls. This study confirms the association of PTPN22 C1858T polymorphism with T1DM, whereas the effects of PTPN22 G(-1123)C, PDCD1 G7146A and CYP27B1 C(-1260)A seem unlikely, at least in the Polish population.     

Interleukin-10 Gene Polymorphisms in Recurrent Aphthous Stomatitis

Recurrent aphthous stomatitis (RAS) is a common oral inflammatory disease with unknown etiology in which the immune system seems to have a role in oral tolerance. Interleukin (IL)-10 is a cytokine synthesis inhibitory factor. Single nucleotide polymorphisms (SNPs) of IL10 gene could alter this cytokine production. The aim of this study was to investigate frequencies of IL10 alleles and genotypes in a group of individuals with RAS. Genomic DNA of 60 Iranian patients with RAS were typed for IL10 gene (C/A ?1082, C/T ?819, and C/A ?592), using PCR-SSP method. Frequency of each allele and genotype was compared to control group.

A significantly higher frequencies of the T allele at position ?819 (p?=?0.006) and the A allele at position of ?592 (p?<?0.001) were found in the patients with RAS group, when compared to the controls. IL10 GA genotype at position ?1082 (p?=?0.007), CA genotype at position ?592 (p?=?0.001), and CT genotype at position ?819 (p?=?0.001) were significantly higher in the RAS patients. The results of this study suggest that certain SNPs of IL10 gene have association with predisposition of individuals to RAS. However, further multicenter studies should be conducted to confirm the results of this study.     

The PD-1 rs36084323 A > G polymorphism decrease cancer risk in Asian: A meta-analysis

The rs36084323 A?>?G polymorphism in programmed cell death-1(PD-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to identify the potential association, by searching the PubMed, EMBASE, Cochrane Library, and the Chinese CNKI, WANFANG and CBM databases. Data were extracted and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the strength of the association. A total of 10 relevant studies involving 4445 cancer cases and 5126 controls were recruited. Overall, the results indicated that the PD-1 rs36084323 A?>?G polymorphism was not statistically associated with cancer risk. However, stratified analysis revealed that there was a statistically reduced cancer risk in Asians(G vs. A, OR?=?0.89, 95%CI:0.81–0.97, P?=?0.008, I²?=?48.8%; GG vs. AA, OR?=?0.79, 95% CI:0.66–0.94, P?=?0.008, I²?=?48.7%; GG/AG vs. AA, OR?=?0.87, 95%CI:0.76–0.98, P?=?0.017, I²?=?34.9%; GG vs. AG/AA, OR?=?0.85, 95%CI:0.75–0.97, P?=?0.027, I²?=?40%) and in the patients with EOC(AG vs. AA, OR?=?0.69, 95%CI:0.54–0.90, P?=?0.005, I²?=?0%; GG/AG vs. AA, OR?=?0.67, 95%CI:0.52–0.85, P?=?0.001, I²?=?0). Meta-regression showed that ethnicity (P?=?0.029) but not cancer types (P?=?0.792), source of controls (P?=?0.207) or ample size (P?=?0.585) were the sources of heterogeneity. This meta-analysis demonstrates the PD-1 rs36084323 A?>?G polymorphism is associated with decreased cancer risk in Asian, and suggests it could potentially serve as a biomarker to screen high-risk individuals. Large-scale and well-designed case-control studies are needed to enrich the evidence of this result.     

Interleukin‐4 single nucleotide polymorphisms in juvenile systemic lupus erythematosus

Juvenile systemic lupus erythematosus (JSLE) is a chronic, recurrent multisystem inflammatory disease, caused by a combination of environmental events and genetic risk factors. As cytokines, including interleukin‐4 (IL‐4), seem to have a role in the pathogenesis of JSLE, the investigation was performed to evaluate the associations of specific single nucleotide polymorphisms (SNPs) of IL‐4 and IL‐4RA genes in a case–control study. Fifty‐nine patients with JSLE were recruited in this study as patients' group and compared with 140 healthy volunteers. Genotyping was performed for IL‐4 gene at positions ?1098, ?590 and ?33, as well as IL‐4 receptor α (IL‐4RA) gene at position +1902, using polymerase chain reaction with sequence‐specific primers method. Following alleles were found to be more common among patients with JSLE: C at ?590 and ?33 and T at ?1098 of IL‐4 gene (P value < 0.001; OR = 4.6, P value < 0.001; OR = 2.7 and P value < 0.001; OR = 2.1, respectively). Additionally, significant positive associations for the following genotypes were recognized in JSLE cases, compared with controls: C/C at ?33, C/C at ?590 and T/T at ?1098 of IL‐4 gene (P value < 0.001; OR = 5.3, P value < 0.001; OR = 29.5 and P value < 0.001; OR = 3.3, respectively), while following genotypes were less frequent among patients with JSLE: T/C at ?33 and ?590 and T/G at ?1098 of IL‐4 gene (P value < 0.001; OR = 0.1, P value < 0.001; OR = 0.03 and P value < 0.001; OR = 0.3, respectively). Furthermore, we noticed an astonishing negative haplotypic association for JSLE for IL‐4 (positions ?1098, ?509 and ?33) TTC, GCC and TTT haplotypes (P value < 0.001). There was also a significant relationship between TCC haplotype (IL‐4 gene at positions ?1098, ?590 and ?33) and having JSLE (P value < 0.001). On the other hand, we found no significant associations between IL‐4R polymorphisms and the susceptibility to JSLE. Cytokine gene polymorphisms may influence susceptibility to JSLE. Particular IL‐4 gene variants are associated with JSLE and might have a role in the pathophysiology of disease.     

Association study of interleukin‐1 family and interleukin‐6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis

Recurrent aphthous stomatitis (RAS) is a common painful, ulcerative oral inflammatory disorder with unknown aetiology. Immune system and aberrant cytokine cascade deemed to be critical in outbreaks of RAS ulcers. Interleukin‐1 (IL‐1) and IL‐6 are the most potent pro‐inflammatory cytokines. Single nucleotide polymorphisms (SNPs) of IL‐1 and IL‐6 genes can affect the secretion of these cytokines. The aim of this study was to investigate the association between RAS and IL‐6 and IL‐1 in Iranian subjects with minor RAS. Genomic DNA was obtained from 64 Iranian patients with RAS. IL‐1α C ?889 T, IL‐1β C ?511 T, IL‐1β C +3962 T, IL‐1R C pst‐I 1970 T, IL‐1Ra C Mspa‐I11100 T, IL‐6 C ?174 G and IL‐6 A nt +565 G polymorphisms were determined using polymerase chain reaction with sequence‐specific primers (PCR‐SSP). The frequency of C ?174 C genotype in the patients group was significantly different from the healthy control. No other significant differences were found in genotype and alleles frequencies between the two groups. These results indicate that certain SNPs of IL‐6 gene at position ?174 which located in promoter have association with predisposition of individuals to RAS.     

Tumor necrosis factor-alpha single nucleotide polymorphisms in juvenile systemic lupus erythematosus

BackgroundJuvenile systemic lupus erythematosus (JSLE) is a multi-system autoimmune disorder of unknown origin. Given the importance of the contribution of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), towards the pathogenesis of JSLE, this study was performed to assess TNFA gene polymorphisms in a case-control study.MethodsFifty nine patients with JSLE were enrolled in this study as case group and compared with healthy control subjects. The frequency of alleles, genotypes, and haplotypes of TNFA single-nucleotide polymorphisms (SNPs) at positions −308 and −238 were evaluated, using polymerase chain reaction with sequence-specific primers method.ResultsThe G allele at position −238 in TNFA promoter region was significantly more frequent in patients with JSLE than in the healthy controls (P value < 0.001), while the frequency of A allele at the same position was significantly lower than controls. Furthermore, a significant positive association for G/G genotype at the same position was detected in patients’ group compared with control subjects (P value < 0.001). The GA haplotype of TNFA (positions −308, −238) was significantly less frequent in case group than in controls (P value < 0.001), while GG was the most frequent haplotype for TNFA in the patient group, compared to controls (P value < 0.01).ConclusionsPro-inflammatory cytokine gene polymorphisms may influence susceptibility to JSLE. Particular TNFA gene variants are associated with JSLE and could be used as a genetic marker for susceptibility to JSLE.     

Interleukin-18 and its three gene polymorphisms relating to allergic rhinitis

The study aimed to examine an association of three different single nucleotide polymorphisms (SNPs) of the IL-18 gene (−607 C/A, −137 G/C and −133 C/G) on chromosome 11q22 with allergic rhinitis (AR). Genotyping for the SNPs was performed using 539 patients with AR and 312 healthy control volunteers. Positivity to the skin prick test for the fungus Alternaria sp. in patients with AR, and IgE levels according to particular genotypes of selected SNPs, were also determined. There were no significant differences in the distribution of single IL-18 alleles or genotypes between controls and AR patients. However, frequencies of combined IL-18 genotypes arising from combinations of the three common polymorphisms (−607, −137 and −133) were significantly different between both groups (P = 0.009, P _corr < 0.05, OR = 5.35, 95% CI: 1.9–15.2). There was a marginally significant association of the IL-18–607 variant with IgE levels (P = 0.05) in patients, but not in the case of the other SNPs. Patients allergic to Alternaria, but not those allergic to other antigens, showed a significant association with the IL-18–607 polymorphism (P = 0.0037, P _corr < 0.05). Results suggest that IL-18 gene variants may be one of the factors participating in the pathogenesis of AR or its intermediary phenotypes.     

Association of STAT4 rs7574865 with Susceptibility to Systemic Lupus Erythematosus in Iranian Population

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with complex genetic inheritance that affecting different organs and systems. STAT4 has been newly identified as a susceptible gene in the development of SLE. According to recent studies, STAT4 has been associated with SLE in various populations. We investigated whether STAT4 single nucleotide polymorphisms (SNPs) were associated with susceptibility and clinical features of SLE in Iranian patients. The study group comprised 280 patients with SLE and 281 sex-, age-, and ethnicity-matched healthy controls of Iranian ancestry. Two SNPs (rs7574865 and rs7601754) were genotyped using the TaqMan MGB Allelic Discrimination method. Our results showed a significant association betweenrs7574865 T allele (odds ratio (OR)?=?1.50, 95 % CI?=?1.18–1.92, P?=?0.002) and susceptibility to SLE. The rs7574865TT genotype (P?=?0.02, OR?=?1.94, 95 % CI?=?1.74–3.19) and GT genotype (P?=?0.008, OR?=?1.71, 95 % CI?=?1.19–2.45) showed a significant association with the risk of SLE in the Iranian population. We concluded that STAT4 rs7574865 is associated with SLE susceptibility in the Iranian population and this SNP might be a factor in the pathogenesis of SLE. However, further studies are required to investigate the mechanism by which polymorphisms in this gene lead to SLE.     

Increased Serum Concentration of Sphingosine-1-phosphate in Juvenile-onset Systemic Lupus Erythematosus

Purpose

Sphingosine-1-phosphate (S1P) is an active sphingolipid with chemotactic abilities and has been linked to inflammatory mediators and autoimmune disease. The aim of this study was to assess whether children with juvenile-onset systemic lupus erythematosus (JSLE) express increased systemic and/or urinary concentrations of S1P.

Methods

A subgroup of patients participating in the UK JSLE Cohort Study, were invited to participate. Cross sectional serum and urine samples were prospectively collected along with demographic and standard clinical data. Results were compared to a cohort of disease controls (Henoch Schonlein Purpura; HSP) and healthy controls (HC).

Results

The median age of JSLE patients (n?=?15) was 13.6?years (7.2–16.9?years). The serum concentrations of S1P in JSLE patients (7.4?uM, IQR 6.3–12.3?uM) were statistically significantly increased when compared to patients with HSP (n?=?10; 5.2?uM, IQR 4.0–7.9?uM; p?=?0.016) and HCs (n?=?10; 3.8?uM, IQR 2.1–5.8?uM; p?=?0.003). There was a trend towards increased serum S1P concentrations between patients with active lupus nephritis (n?=?8; 8.7?uM, IQR 6.2–15.3?uM) compared to lupus non-nephritis (n?=?7; 6.6?uM, IQR 6.3–10.6?uM; p?=?0.355). No relationship was found between disease activity markers and S1P. Urine S1P concentrations were no different between JSLE patients (56.0?nM, IQR 40.3–96.6?nM) and HCs (58.7?nM, IQR 0–241.9?nM; p?=?0.889).

Conclusions

We have demonstrated, for the first time, an increased serum concentration of S1P in a cohort of JSLE patients. These findings highlight a role of S1P in the pathophysiology of JSLE that warrants further investigation.     

Decreased risk for myocardial infarction and lower tumor necrosis factor-alpha levels in carriers of variants of the PDCD1 gene

Increasing interest has been directed toward the inflammatory mechanisms involved in the pathogenesis of myocardial infarction (MI). In the search for genetic mechanisms underlying these inflammatory components, we studied variants of programmed cell death-1 (PDCD1), an immunoinhibitory receptor that inhibits lymphocyte activation and cytokine production, previously shown to be associated with several autoimmune disorders. The PD1.1, PD1.3, and PD1.6 polymorphisms of the PDCD1 gene were typed in the Stockholm Heart Epidemiology Program, a population-based clinical material consisting of 1179 first-time MI case patients and 1528 unaffected control subjects. Individual alleles and haplotypes were studied for association with levels of the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein and risk for MI. We observed a weak protective effect of PD1.3A allele for MI (odds ratio: 0.78, 95% confidence interval: 0.61-0.98). We also observed decreased levels of TNF-alpha in carriers of the PD1.1A/PD1.3G/PD1.6A haplotype, which is consistent with our previous observation that this haplotype may be protective from autoimmune conditions. Carriers of variants of the PDCD1 gene exhibit a decreased risk for nonfatal myocardial infarction, and PDCD1 mediates variation in TNF-alpha levels.