| BackgroundSystemic lupus erythematosus(SLE) is a chronic systemic autoimmune disease, characterized by the production of multiple autoantibodies, complement activation, and immune-complex deposition, resulting in tissue and organ damages.The pathogenesis of SLE is still incompletely deciphered. However, two forms of SLE immune abnormality are typical:(i)a stimulatory of humoral immunity characterized by B cell hyperactivity and autoantibody production;(ii)an impaired cell mediated immunity which results from both T lymphocyte and antigen-presenting cell abnormalities.Interleukin-10(IL-10) is a key pleiotrophic immunoregulatory cytokine with immunosuppression and immunostimulation and plays a crucial role in autoimmune pathologies. This cytokine strongly inhibits the activation and the production of Thl cell. In addition, IL-10promotes B-cell-mediated functions, enhancing survival, proliferation, differentiation, and antibody production.Preliminary data have shown a correlation of high IL-10levels with SLE, and suggested that the increased IL-10plays an important role on the immune imbalance of the disease.The human IL-10gene is located on chromosome1(1q31-1q32).The molecular weight is4.7×103. Three common single nucleotide polymorphisms(SNPs):a G to A substitution at position-1082(rs1800896), a C to T at-819(rs1800871) and a C to A at-592(rs1800872), are from the transcriptional start site in the5’ flanking region of the IL-10gene which is a strong determinant for IL-10production. From all the possible haplotypes resulting from the combination of these three SNPs, only three have been described in populations ACC, ATA and GCC. They were also believed to affect innate IL-10production. Several reports have analyzed the influence of these polymorphisms on SLE and showed conflicting results.First, a case-control study was conducted to investigate the possible relationships between these three IL-10promoter gene polymorphisms or haplotypes and SLE susceptibility in Chinese Han population using TaqMan assays. Then, we conducted a meta-analysis to more precisely estimate the association between IL-10-1082G/A polymorphism and SLE susceptibility. In addition, we also performed a meta-analysis to assess the association between the haplotypes formed by polymorphisms at positions-1082G/A,-819C/T and-592C/A and SLE susceptibility.This research was divided into three parts.Part I Association of gene polymorphisms and haplotypes in IL-105’flanking region with SLE susceptibility in Chinese Han populationObjectiveThe aim was to investigate the possible relationships of polymorphisms and haplotypes in IL-105’flanking region with SLE susceptibility by comparing their distributions in cases and controls of Chinese Han population.MethodsA case-control study in individuals with SLE(n=579) and healthy controls(n=632) was conducted. All patients were recruited from the First Affiliated Hospital of Anhui Medical University and Anhui Provincial Hospital, and fulfilled the1997revised criteria of the American College of Rheumatology for the classification of SLE. The healthy blood donors excluded from SLE or other autoimmune diseases were selected as controls. Demographic and clinical data were collected by a questionnaire. EDTA anti-coagulated venous blood samples were collected from all subjects. Genomic DNA was extracted from peripheral blood lymphocytes. Genotyping was performed by TaqMan SNP assay with ABI7300PCR. Haplotype analysis was conducted using SHEsis software.Results(1)No deviations from Hardy-Weinberg equilibrium(HWE) were observed in either the patients with SLE or the controls in each polymorphism(HWE for IL-10-1082G/A: control,χ2=1.348,P=0.246, case, χ2=0.047, P=0.829; For IL-10-819C/T:control,χ2=0.408, P=0.523, case, χ2=2.208, P=0.137; For IL-10-592C/A:control, χ2=0.269, P=0.604, control, x2=2.039, P=0.153).(2)IL-10-1082G/A genotyping:The genotype frequencies of IL-10promoter-1082G/G, G/A, and A/A were4.66%,33.16%, and62.18%in SLE patients and1.11%,15.03%, and83.86%in healthy controls. There was significant difference(x2=74.844, P=5.59×10-17). The allele frequencies of G and A were21.24%and78.76%in SLE patients and8.62%and91.38%in healthy controls. SLE patients had a significantly higher frequency of the G allele compared with control subjects(OR=2.858,95%CI:2.245-3.640; x2=76.946, P=1.769×10-18). According to stratification analysis by sex, both the allele and genotype frequencies showed different between patients and controls[allele of male:OR(95%CI)=2.091(1.204-3.633), χ2=7.075,P=0.008; allele of female:OR(95%CI)=3.192(2.384-4.273),χ2=65.516,P=5.765×10-6; genotype of male: P=0.025(Fisher exact test); genotype of female:χ2=65.635, P=5.591×10-15].(3)IL-10-819C/T genotyping:The genotype frequencies of IL-10promoter-819C/C, C/T, and T/T were8.29%,45.42%and46.29%in SLE patients and11.39%,43.04%and45.57%in healthy controls. There was no significant difference (x2=3.358, P=0.187). The allele frequencies of G and A were31.00%and69.00%in SLE patients and32.91%and67.09%in healthy controls. There was no significant difference [OR(95%CI)=0.916(0.772-1.087), χ2=1.013, P=0.314]. The allele and genotype frequencies showed significant differences between male SLE patients and male controls[allele:OR(95%CI)=0.550(0.345-0.877),x2=6.419,P=0.011;genotype:χ2=6.644, P=0.036]. However, they showed no significant differences in female patients and female controls [allele:OR(95%CI)=1.008(0.829-1.226),χ2=0.007,P=0.936;genotype: χ2=2.534,P=0.282].(4)IL-10-592C/A genotyping:The genotype frequencies of IL-10promoter-592C/C, C/A, and A/A were8.29%,45.25%,46.46%in SLE patients and11.23%,43.20%,45.57%in healthy controls. There was no significant difference(x2=3.006, P=0.222). The allele frequencies of C and A were30.92%and69.08%in SLE patients and32.83%and67.17%in healthy controls. There was no significant difference [OR (95%CI)=0.915(0.771-1.086),χ2=1.022,P=0.312]. The allele and genotype frequencies showed significant differences between male SLE patients and male controls [allele: OR(95%CI)=0.550(0.345-0.877),P=0.011;genotype:x2=6.644, P=0.036]. However, they showed no significant differences in female patients and female controls[allele:OR (95%CI)=1.009(0.830-1.228);χ2=0.008,P=0.927;genotype:χ2=2.067,P=0.356].(5)Haplotype analysis:Linkage analysis showed that the three SNPs were in moderate or high linkage disequilibrium, and the haplotype ATA formed by-1082A,-819T and-592A showed a protective effect against Chinese SLE patients [OR(95%CI)=0.663(0.560-0.785), χ2=22.936, P=1.700×10-6].Conclusions:These findings strongly suggested that IL-10-1082G/A polymorphism was associated with SLE in Chinese Han population. ATA haplotype may play a protective role in SLE of Chinese Han population. polymorphism/Haplotype/Case-control study Part Ⅱ Association of the-1082G/A polymorphism in the IL-10gene with SLE:a meta-analysisObjectiveA great many studies have investigated the-1082G/A polymorphism (rs1800896) in the IL-10with SLE susceptibility, but the results are controversial. The aim of this meta-analysis was to more precisely estimate the relationship.MethodsThe databases of Pubmed and Web of Science updated to Dec,2012were retrieved. The following key words and subject terms were searched:("interleukin10" OR "interleukin-10" OR "IL10" OR "IL-10") and ("systemic lupus erythematosus" OR "SLE") and("polymorphism" OR "allele" OR "genotype" OR "genetic variation" OR "genetic variant"). In addition, references of identified studies and reviewarticles were checked for other potentially relevant publications. OR and corresponding95%CI as effect size were calculated. The risk of allelic contrast model(G vs. A), recessive model(GG vs. GA+AA), dominant model(GG+GA vs. AA) and homozygote contrast model(GG vs. AA) were evaluated. Heterogeneity of within-and between-studies was calculated by means of Cochran’s Q statistic with a p-value of less than0.10indicating significant heterogeneity. The overall or pooled estimate of risk(OR) was obtained by a random-effects or a fixed-effects model in the presence (P≤0.10and I2>50%) or absence (P>0.10or I2≤50%) of heterogeneity, respectively. As publication biases assessment, Begg’s funnel asymmetry plots were generated and Egger’s linear regression tests were performed to further assess. Meta-analysis was conducted by using STATA version11.2. ResultsFourteen studies including2385cases and3032controls were retrieved for this meta-analysis, which in total involved5Asian and9Caucasian populations.(1)G vs. A:The overall OR for the G allele of the IL-70-1082G/A was1.210(0.958-1.530)(P=0.110). The ORs of stratification by ethnicity in Asian and Caucasian were1.407(0.822-2.408)(P=0.213) and1.100(0.976-1.240)(P=0.119) respe-ctively. No significant evidence for publication bias was found.(2)G/G vs. G/A+A/A:No association was found in the overall population between SLE and the IL=10-1082G/A polymorphism by using this model (OR=1.279,95%CI=0.911-1.796, P=0.155). Analysis after stratification by ethnicity indicated that homozygote GG may have a2.60times increased risk of SLE when compared with the variant A allele carriers(GA+AA) in Asian(OR=3.601,95%CI=1.975-6.569, P=0.000). However, in Caucasian, homozygote GG have no association with risk of SLE (OR=1.026,95%CI=0.835-1.260, P=0.807). No significant evidence for publication bias was found.(3)G/G+G/A vs. A/A:The overall OR was1.320(95%CI=1.003-1.736, P=0.047). Using ethnic-specific analysis, the variant G allele carriers (GG+GA) may have a22.2%increased risk of SLE when compared with the homozygote AA in Caucasian (OR=1222,95%CI=1.017-1.468, P=0.032). Conversely, for this dominant model, there was no significant association in Asian(OR=1.412,95%CI=0.754-2.645, P=0.281). Only significant evidence for publication bias for overall was found(P<0.05).(4)G/G vs. A/A:The overall and stratification by ethnicity in Asian revealed a significant association for SLE when compared homozygote GG with the homozygote AA, and the ORs were1.540(95%CI=1.056-2.245,P=0.025) and4.502(95%CI=2.408-8.416,P=0.000) respectively. Whereas, no association was found in Caucasian (OR=1.223,95%CI=0.959-1.560, P=0.104). No publication bias was found. ConclusionsThe IL-10-1082G/A polymorphism is associated with the susceptibility of SLE. To confirm this finding, additional case-control studies based on adequately sized populations are still needed. Part Ⅲ Association of the haplotypes in the IL-10with SLE:a meta-analysisObjectiveNumerous studies have investigated the association between the IL-10promoter haplotypes(at-1082,-819and-592positions of IL-10gene) and SLE susceptibility, but the results were inconsistent. We performed the current meta-analysis to assess precisely the association.MethodsWe conducted a literature search using Pubmed and Web of Science databases (until Dec2012) with the following key words:"interleukin10" OR "interleukin-10" OR "IL10" OR "IL-10","systemic lupus erythematosus" OR "SLE", and "haplotype" OR "haplotypes". In addition, references of identified studies and review articles were checked for other potentially relevant publications. OR and corresponding95%confidence interval(95%CI) as effect size were calculated. The risks of allelic contrast GCC vs. ATA, ACC vs.ATA and GCC vs. ACC were evaluated. Heterogeneity of within-and between-studies was calculated by means of Cochran’s Q statistic with a p-value of less than0.10indicating significant heterogeneity. The overall or pooled estimate of risk(OR) was obtained by a random-effects or a fixed-effects model in the presence (P≤0.10and I2>50%) or absence (P>0.10or I2≤50%) of heterogeneity, respectively. As publication biases assessment, Begg’s funnel asymmetry plots were generated and Egger’s linear regression tests were performed to further assess. Meta-analysis was conducted by using STATA version11.2.ResultsThirteen studies including1790cases and2368controls were retrieved for this meta-analysis, which in total involved5Asian and8Caucasian populations..(1)GCC vs. ATA:The overall OR was1.132(95%CI=0.989-1.295, P=0.073). The ORs of stratification by ethnicity in Asian and Caucasian were1.209(95%CI=0.961-1.520,P=0.105) and1.093(95%CI=0.925-1.292,P=0.298) respectively. No significant evidence for publication bias was found.(2)ACC vs. ATA:No association was found in the overall population(OR=0.923,95%CI=0.765-1.114,P=0.404). The ORs of stratification by ethnicity in Asian and Caucasian were0.939(95%CI=0.662-1.331, P=0.722) and0.949(95%CI=0.792-1.137, P=0.569) respectively. No significant evidence for publication bias was found.(3)GCC vs. ACC:The overall OR was1.173(95%CI=1.026-1.340, P=0.019). Using ethnic-specific analysis, there is no association either in Asian(OR=1.223,95%CI=0.949-1.575, P=0.120) or Caucasian(OR=1.154,95%CI=0.987-1.350, P=0.073). No publication bias was found.ConclusionsThe results indicated that the ATA, GCC and ACC haplotypes revealed no statistically significant association with SLE susceptibility. |
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