Systemic Lupus Erythematosus In European Population Research Articles

Telomere Length and Development of Systemic Lupus Erythematosus: A Mendelian Randomization Study.

Previous observational studies demonstrated that a subset of patients with systemic lupus erythematosus (SLE) have markedly short telomere length in leukocytes. This study was undertaken to test whether leukocyte telomere length is causally associated with risk of SLE. A 2-sample Mendelian randomization (MR) analysis was conducted to estimate causality of telomere length on SLE in European populations. A replication 2-sample MR study using Asian genetic data was also conducted. A reverse MR analysis was then performed to test the effects of SLE on telomere length. The autoantibodies targeting telomere-associated protein (telomeric repeat-binding factor 1 [TERF1] autoantibodies) were detected in patients with SLE, healthy controls, and patients with rheumatoid arthritis. The results of the inverse variance-weighted method (odds ratio [OR] 2.96 [95% confidence interval (95% CI) 1.58-5.55], P < 0.001) showed strong evidence for a causal relationship between longer telomere length and risk of SLE in people with European ancestry. The outcomes of MR-Egger regression analysis (OR 29.46 [95% CI 3.02-287.60], P=0.033) and MR pleiotropy residual sum and outlier analysis (OR 3.62 [95% CI 2.03-6.46], P=0.002) also showed that longer telomere length was significantly associated with increased risk of SLE in a European population. Sensitivity analyses using different methods and summary data sets showed that the results were still broadly consistent. A replication MR study using Asian genetic data yielded similar findings. However, the reverse MR analysis showed that genetically predicted SLE was not causally associated with telomere length. In addition, we found that TERF1 autoantibodies were present in 2 of 40 SLE patients (5.0%). In contrast with previous observational studies, MR analyses show that longer telomere length is significantly associated with increased risk of SLE.

Association of MBL2 gene polymorphisms and systemic lupus erythematosus susceptibility: A meta-analysis.

Mannose binding lectin (MBL) gene single nucleotide polymorphisms have been associated with systemic lupus erythematosus (SLE) risk with inconsistent results. This study aimed to explore whether MBL2 A\B, A\C, A\D, A\O, L\H and Y\X polymorphisms affected SLE susceptibility. A meta-analysis was performed on 20 studies, containing allelic contrast, additive, dominant and recessive models. Odds ratio (OR) was calculated to reflect the effect of association. A total of 64 pooled comparisons were conducted, including 7194 SLE patients and 7401 healthy controls. The meta-analysis inducted a significant association between allele B and SLE (OR=0.766, 95% CI=0.681-0.862, P<.001). The genotype BB in the additive model and AB+BB in the recessive model both reduced the risk of SLE (OR=0.611, 95% CI=0.422-0.882, P=.009; OR=0.806, 95% CI=0.688-0.944, P=.008). Regarding A\O polymorphisms, results revealed statistical differences in allelic contrast, additive model and recessive models (OR=0.826, 95% CI=0.732-0.931, P=.002; OR=0.737, 95% CI=0.557-0.977, P=.034 and OR=0.793, 95% CI=0.683-0.921, P=.002, respectively). As for L\H, meta-analysis revealed that allele H and genotype HH both decreased SLE susceptibility in allelic contrast and dominant models (OR=1.463, 95% CI=1.097-2.007, P=.018; OR=1.383, 95% CI=1.124-1.701, P=.002). Stratification by ethnicity indicated that allele H related to SLE in European populations (OR=0.736, 95% CI=0.617-0.879, P=.001), and the recessive model correlated with SLE in Asians (OR=0.808, 95% CI=0.667-0.979, P=.03). The present study suggests that A\B and A\O polymorphisms were associated with SLE susceptibility, and the allele H may be a protective factor in SLE.

Evaluation of genetic susceptibility between systemic lupus erythematosus and GRB2 gene

Multiple lines of evidence have shown that systemic lupus erythematosus (SLE) is attributable to both genetic and environmental factors. The product of GRB2 is a key factor in the activation of B cells and has been reported to be significantly associated with SLE in European populations. In the study, we aimed to investigate the relationship between GRB2 and SLE. A total of 1,710 Han Chinese women comprising 567 SLE patients and 1,143 controls were recruited to genotype 20 selected tagging SNPs. We tested the potential association between 13 clinical variables of SLE and the significant polymorphisms related to SLE. The eQTL data were extracted from the GTEx database to examine the functional consequences of the targeted SNPs. A significant association signal was identified between rs36023980 and SLE in both genotypic and allelic analyses (OR = 0.61, P = 0.0003). Complement inhibition was shown to be significantly associated with the genotypes of SNP rs36023980 in SLE patients (Pgenotype = 0.003). Further stratification analyses showed that the genetic association signal of SNP rs36023980 on SLE could only be identified in cases with complement inhibition. SNP rs36023980 was also identified to be significantly associated with the expression of GRB2 in whole blood and sun-exposed skin. In conclusion, our findings confirm the results from the previous GWAS and are the first to report the association of GRB2 with SLE in Han Chinese population.

Comprehensive assessment of the association between genes on JAK-STAT pathway (IFIH1, TYK2, IL-10) and systemic lupus erythematosus: a meta-analysis.

Previous studies have reported that genes relating to JAK-STAT pathway (IFIH1, TYK2 and IL-10) conferred the susceptibility to SLE. In this study, we performed a meta-analysis (including 43 studies) to evaluate the association between IFIH1 (9288 patients and 24,040 controls), TYK2 (4928 patients and 11,536 controls), IL-10 (3623 patients and 4907 controls) polymorphisms and systemic lupus erythematosus (SLE) in a comprehensive way. We found that IFIH1 rs1990760_T allele was associated with risk of SLE in overall population under three models (allelic: P = 2.56 × 10-11, OR 1.135, 95% CI 1.094-1.179, dominant: P = 1.8 × 10-8, OR 1.203, 95% CI 1.128-1.284, recessive: P = 2.6 × 10-7, OR 1.163, 95% CI 1.098-1.231). A strong association had been observed between TYK2 polymorphism rs2304256_C allele and SLE in Europeans (P = 5.82 × 10-5, OR 1.434, 95% CI 1.203-1.710). When coming to overall population, TYK2 rs2304256_C showed a significant association with SLE under recessive model (P = 8.05 × 10-3, OR 1.314, 95% CI 1.074-1.608). However, the other two SNPs (rs12720270, rs280519) of TYK2 were not significant. The results also indicated an association between IL-10 rs1800896_G allele and SLE in Asians under recessive model (P = 4.65 × 10-3, OR 2.623, 95% CI 1.346-5.115), while, IL-10 rs1800896_G had a trend of association with SLE in European population in dominant model (P = 1.21 × 10-2, OR 1.375, 95% CI 1.072-1.764). In addition, we found IL-10 rs1800896 GG homozygote might be associated with increased susceptibility to SLE (GG vs AA, P = 4.65 × 10-3, OR 1.539, 95% CI 1.142-2.072). We concluded that IFIH1 rs1990760_T and TYK2 rs2304256_C alleles were significantly associated with SLE, and IL-10 rs1800896 GG homozygote might have an enhancement effect on SLE risk.

Associations between eNOS polymorphisms and susceptibility to systemic lupus erythematosus and rheumatoid arthritis: ameta-analysis.

The aim of this study was to determine whether endothelial nitric oxide synthase (eNOS) polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Ameta-analysis was conducted on associations between the 4b/a, T786C, and G894T polymorphisms of eNOS and SLE or RA using the following methods: (1)allele contrast, (2)recessive model, (3)dominant model, and (4)homozygous contrast. Nineteen studies were included in this meta-analysis, comprising eleven studies on SLE (1561 patients and 1565 controls) and eight on RA (1624 patients and 2118 controls). Meta-analysis showed asignificant association between SLE and the 4b/a polymorphism using the recessive model and the homozygous contrast (odds ratio [OR]= 1.836, 95 % confidence interval [CI]= 1.171-2.878, p= 0.008; OR= 2.055, 95 % CI= 1.302-3.243, p= 0.002). Ethnicity-specific meta-analysis showed asignificant association between the aa vs. bb of the 4b/a polymorphism and SLE in European populations (OR= 2.096, 95 % CI= 1.288-4.0, p= 0.027), but not in Arab populations. Stratification by presence of lupus nephritis (LN) indicated asignificant association between the aallele and the aa+ ab genotype of the 4b/a polymorphism and LN in SLE patients (OR= 2.125, 95 % CI= 1.289-3.054, p= 0.003; OR= 2.655, 95 % CI= 1.509-4.671, p= 0.001). Meta-analysis indicated no association between SLE and the T786C and G894T polymorphisms. No association was found between the eNOS 4b/a, T786C, and G894T polymorphisms and RA CONCLUSIONS: This meta-analysis of published studies shows that the eNOS 4b/a polymorphism may be associated with the development of SLE, but the 4b/a, T786C, and G894T polymorphisms may be not associated with RA susceptibility.

Single-nucleotide polymorphisms of MAMDC1 are associated with rash and photosensitivity, but not disease risk, of systemic lupus erythematosus in Chinese mainland population

Systemic lupus erythematosus (SLE) is a complex immune disease affected by both genetic dispositions and environmental factors. Recently, the polymorphisms in MAMDC1 gene have been reported to associate with disease risk of SLE in European population. However, whether this association is replicated in Chinese population is unknown yet. A total of 491 SLE patients and 533 controls were recruited. Unlabeled probe-based high-resolution melting analysis (HRMA) was used in genotyping. HRMA with unlabeled probe successfully distinguished all genotypes. SNP rs961616 was associated with rash [P = 0.015, odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.57-0.94] and photosensitivity (P = 0.001, OR = 0.63, 95%CI = 0.48-0.84), but not the disease risk (P = 0.133, OR = 0.88, 95%CI = 0.74-1.04), of SLE in Chinese population. Polymorphisms of rs961616 in MAMDC1 gene were associated with rash and photosensitivity, but not disease risk, of systemic lupus erythematosus in Chinese population.

A single-nucleotide polymorphism of the TNFAIP3 gene is associated with systemic lupus erythematosus in Chinese Han population

Systemic lupus erythematosus (SLE) is a complex systemic disease influenced by genetic and environmental factors. The exact pathogenesis of SLE is still unknown. Recently, several genome-wide association studies (GWA) in European population have found many novel susceptibility genes for SLE including TNFAIP3. In order to examine whether TNFAIP3 is associated with SLE in Chinese Han population, we genotyped one of its non-synonymous mutation SNP rs2230926, showing significant association evidence with SLE in European population, with 1,420 cases and 4,461 controls of Chinese Han by using Sequenom MassArray system. Highly significant association between SNP rs2230926 and SLE of Chinese Han was detected [OR = 1.65, 95% confidence interval (CI): 1.392-1.986, P = 2.03 x 10(-8)]. Interestingly, rs2230926 of TNFAIP3 was also associated with arthritis, ANA and some other subphenotypes of the disease. Our findings suggest that SNP rs2230926 in the TNFAIP3 might be a common genetic factor for SLE within different populations in terms of Chinese Han and European population.