Disease association of the interleukin-18 promoter polymorphisms in Taiwan Chinese systemic lupus erythematosus patients

Interleukin (IL)-18, an important mediator of innate and adaptive immunity, plays multiple roles in chronic inflammation, in autoimmune diseases, in a variety of cancers and in number of infectious diseases. IL-18 promoter polymorphisms have been also noted associated with various inflammatory diseases. We investigated the association of IL-18 promoter polymorphisms (-656T/G, -607A/C and -137C/G) with systemic lupus erythematosus (SLE) in Taiwan Chinese patients and controls. Six haplotypes (hts) were identified from the three promoter polymorphisms. The genotype distribution of the ht1 (GCC), ht2 (TAC), ht4 (GAC) and ht5 (TCC) were different in patients and controls (P<0.002). Moreover, the haplotype and genotype frequencies of ht1 were significantly increased in patients with discoid rash (P=0.045, odds ratio (OR): 2.01, 95% confidence interval (CI): 1.01-4.00; P=0.027, OR: 5.13, 95% CI: 1.41-18.68). In addition, the homozygous genotype ht1/ht1 was significant increased in patients with serositis (P=0.015, OR: 9.78, 95% CI: 1.55-61.73). These observations suggest that the three promoter polymorphisms contribute to the genetic background of SLE pathogenesis.     

Cytokine gene polymorphisms in Colombian patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) patients exhibit alterations in cytokine production that may be relevant to SLE pathogenesis. There is evidence that cytokine gene polymorphisms control cytokine production; thus, these polymorphisms may be associated with SLE or its clinical manifestations. To establish the association of tumor necrosis factor alpha (TNF-alpha), transforming growth factor (TGF) beta1, interleukin (IL)-10, and IL-6 gene polymorphisms in Colombian SLE patients and their clinical manifestations, 120 SLE patients and 102 healthy controls were studied. Single nucleotide polymorphisms were studied by sequence-specific primers polymerase chain reaction (SSP-PCR) at: TNFalpha-308 (G/A), TGFbeta1 codon 10 (C/T) and codon 25 (G/C), IL-10 -1082 (G/A), -819 (C/T) and -592 (C/A), and IL-6 + 174 (G/C). Human leukocyte antigen (HLA)-DRbeta1 was typed by SSP-PCR. SLE patients had increased frequency of allele C at TGFbeta1 codon 25 (P = 0.0001, odds ratio (OR): 4.25, 95% confidence interval (CI): 2.17-8.35) and allele A at TNFalpha-308 (P = 0.0004 OR: 3.9, 95% CI: 1.65-5.80) compared with healthy controls. There was higher frequency of GC genotype at TGFbeta1 codon 25 in SLE patients (P < 0.0001). Extended genotypic analysis showed that SLE patients have decreased frequency of TNFalphaLow/TGFbeta1High (0.50) compared with healthy controls (0.80) (P < 0.0001). No association was found between these polymorphisms and SLE clinical manifestations except for Sm and Ro autoantibodies that were associated with TNFalpha allele A. There is an association between TNFalpha-308A/TGFbeta1 codon 25C with SLE susceptibility in Colombian population. This association may result in a highly inflammatory response with a decrease regulatory function mediated by TNFalpha and TGFbeta1, respectively. The TNFalpha-308A/TGFbeta1 25C genotype may be one component of genetic susceptibility to SLE in Colombian population.     

G/T polymorphism in the interleukin-2 exon 1 region among Han Chinese systemic lupus erythematosus patients in Taiwan

Interleukin-2 (IL-2), one of the crucial immunoregulatory cytokines required for T lymphocyte activation, plays an important role in autoimmune diseases. An IL-2 genetic G/T polymorphism (rs2069763) has been linked with multiple sclerosis and rheumatoid arthritis. We tested a hypothesis that this polymorphism confers systemic lupus erythematosus (SLE) susceptibility. Study participants were Han Chinese SLE patients and a healthy control group in Taiwan. Our results indicate (a) a significantly higher G allele frequency in SLE patients (P=1.91 x 10(-14); OR=3.94; 95% CI=2.74-5.66), (b) a significantly higher G allele frequency in SLE patients with antinuclear antibodies (ANA) (P=0.033; OR=4.21; 95% CI=1.01-17.51) and (c) a significantly lower G allele frequency in SLE patients with discoid rash (P=0.019; OR=0.41; 95% CI=0.19-0.88). Our results suggest that this polymorphism may be involved in the genetic background of Taiwanese SLE.     

Interleukin-10 promoter polymorphisms in patients with systemic lupus erythematosus from the Canary Islands

The purpose of this study was to examine whether several allelic variants in the polymorphic interleukin (IL)-10 promoter region were related with an increased risk of developing systemic lupus erythematosus (SLE) in Spanish patients from Canary Islands. Microsatellites (MS) at positions -4000 and -1200 (IL10R and IL10G, respectively) and single nucleotide polymorphisms (SNPs) (MS) at positions -1082G/A, -819C/T and -592C/A of the IL-10 promoter were analysed in patients with SLE and healthy controls from Canary Islands (Spain). We found that SNPs but not MS were associated with SLE. The GCC haplotype frequency was significantly higher in SLE patients (0.43) than in healthy donors (0.33) [P = 0.02; OR = 1.50 (95% CI = 1.06-2.14)], whereas the ACC haplotype was less represented in patients (0.28 vs. 0.37) [P = 0.02; OR = 0.64 (95% CI = 0.44-0.92)]. To assess the functional role of genotypes, serum IL-10 levels from patients and controls were quantified by ELISA. Also, the lipopolysaccharide-induced IL-10 secretion by monocytes from healthy controls was evaluated in vitro. Serum IL-10 levels were higher in patients [median (interquartile range) = 2.8 pg/mL (1.8-4.2)] than in controls [0.9 pg/mL (0-3.5)] (P = 0.02), but no association was observed between serum IL-10 levels or lipopolysaccharide-induced IL-10 secretion and the IL-10 promoter haplotypes. These data suggest that the IL-10 promoter haplotype that produces higher levels of cytokine is associated with SLE in patients from Canary Islands.     

Association and interaction of the TNF-alpha gene with other pro- and anti-inflammatory cytokine genes and HLA genes in patients with type 1 diabetes from North India

Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where major histocompatibility complex (MHC) genes and the insulin-linked polymorphic region have been shown to play major roles. We report here an integrated effect of tumor necrosis factor (TNF) alpha with other cytokine genes. The TNF-alpha-308 GA and AA (high secretor) polymorphisms were significantly increased in the patients with T1D (n = 235) [P < 7 x 10(-6), odds ratio (OR) = 3.04, 95% confidence interval (CI) = 1.8-5.3] compared with the controls (n= 128). The variants of interferon-gamma (IFN-gamma) (A(+874)T), interleukin (IL)-6 (G(-174)C), IL-10 (A(-1082)G, T(-819)C, C(-592)A) and transforming growth factor (TGF) beta1 (T(cdn10)C, G(cdn25)C) did not show a significant difference between patients and controls. However, simultaneous presence of TNF-alpha-308 GA+AA along with both high and low secretor genotypes of IFN-gamma (P < 0.003) was significantly increased in patients. Simultaneous presence of TNF-alpha-308 GA + AA along with high secretor genotypes of IL-6 (P < 0.0001, OR = 2.61, 95% CI = 1.5-4.56), IL-10 (P < 0.0001, OR = 4.26, 95% CI = 1.9-10.1) and TGF-beta1 (P < 0.00004, OR = 2.8, 95% CI = 1.6-4.86) was also significantly increased in patients with T1D. Low secretor genotype of TNF-alpha-308 GG along with low secretor genotypes of IFN-gamma (P < 0.001, OR = 0.465, 95% CI = 0.28-0.77), high secretor genotypes of IL-6 (P < 0.000004, OR = 0.76, 95% CI = 0.227-0.621) and TGF-beta1 (P < 0.000006, OR = 0.336, 95% CI = 0.198-0.568) was protective. The TNF-alpha-308 G allele was in linkage disequilibrium (LD) with the human leukocyte antigen (HLA)-B*0801-DRB1*0301 haplotype, while TNF-alpha-308 A allele was in LD with the HLA-B*5001-DRB1*0301 and B*5801-DRB1*0301 haplotypes, suggesting that the effect of TNF-alpha -308 A allele is not because of its being in LD with any HLA alleles, but because of its functional role and its integrated effect with other cytokines.     

Allergic rhinitis and polymorphisms of the interleukin 1 gene complex.

BACKGROUND: Allergic rhinitis is a chronic inflammatory disease with a genetic background. Inflammatory reactions are regulated by cytokines. Cytokine genes are polymorphic and have been implicated as candidate genes in allergy. OBJECTIVES: To study the significance of the interleukin 1 (IL-1) gene complex in allergic rhinitis. METHODS: Population-based, cross-sectional study. We studied the polymorphisms of 3 IL-1 gene complex genes, IL1A (+4845G>T), IL1B (-511 degrees C>T), and IL1RN (variable number of tandem repeats; IVS2, 86 bp, duplicates 2 to 5), in patients with allergic rhinitis. The study group consisted of 405 nonasthmatic individuals of whom 56 had allergic rhinitis. RESULTS: The genotype distribution differed significantly in all cytokine genes studied between subjects with and without allergic rhinitis. The difference was mainly due to an increased number of IL1A allele G homozygotes (67.9% vs 43.2%; odds ratio [OR], 2.8; 95% confidence interval [CI], 1.5-5.1), IL1B heterozygotes (72.2% vs 47.4%; OR, 2.8; 95% CI, 1.5-5.3), and IL1RN allele 2 homozygotes (18.5% vs 7.5%; OR, 2.8; 95% CI, 1.3-6.2) in allergic rhinitis. Haplotype analysis revealed a significant difference in the distribution of IL-1 gene complex haplotypes between subjects with and without allergic rhinitis (P = 0.005, 10 df). CONCLUSIONS: The IL-1 gene complex polymorphism is strongly associated with allergic rhinitis in nonasthmatic individuals.     

Increase in interleukin-6 following arterial injury is related to insulin resistance, the -174G-->C polymorphism and complex plaque morphology

Interleukin-6 (IL-6) is associated with many disease states in humans. We prospectively sought to determine whether IL-6 levels increased following percutaneous coronary intervention (PCI) in the absence of myonecrosis. Additionally, we systematically assessed other clinical and anatomic factors associated with IL-6 levels in a population of patients with coronary atherosclerosis undergoing PCI. Blood samples were collected from 117 patients at baseline, 8 and 16 h following PCI. Samples were assayed for IL-6, creatine kinase-myocardial band (CK-MB), troponin-I (Tn-I), high sensitivity C-reactive protein, glucose, haemoglobin A1c, and a lipid profile. Genotyping of the -174G-->C polymorphism of the IL-6 gene was performed. IL-6 levels increased following PCI among the study group (slope = 0.4 pg/mL/h, P = 0.001). IL-6 levels increased to a similar degree in the absence of myonecrosis. Patients with the XC genotype (either having the GC or the CC allele) had higher IL-6-values at baseline compared to GG genotype patients (4.9 +/- 6.4 vs. 2.6 +/- 1.8 pg/mL, P = 0.02). Multivariable predictors of detectable baseline IL-6 levels included XC genotype (odds ratio [OR]: 4.14, 95% CI 1.58-10.82, P = 0.004), ACC/AHA type C lesion classification (OR: 4.08, 95% CI 1.54-10.84, P = 0.005), elevated baseline Tn-I (OR: 3.31, 95% CI 1.16-9.43, P = 0.025), diabetes (OR: 3.00, 95% CI 1.11-8.09, P = 0.030), and waist circumference (OR: 1.49, 95% CI 1.08-2.06, P = 0.015). Predictors of peak IL-6 following PCI included the XC genotype (estimate 1.4, 95% CI 1.06-1.87, P = 0.019), homeostasis model assessment (estimate 0.99, 95% 0.982-0.999, P = 0.042) and baseline Tn-I > upper limit of normal (estimate 0.7, 95% CI 0.50-0.96, P = 0.039). Lastly, IL-6 increased following PCI even in the absence of myonecrosis as measured by Tn-I elevation. IL-6 levels are also related to the -174G-->C polymorphism, arterial injury, lesion complexity, and insulin resistance.     

Interleukin-10 promoter polymorphisms in male and female fertility and fecundity

Interleukin-10 (IL10) is assumed beneficial for a successful pregnancy; it may increase fertility and fecundity. Allele frequencies of IL10 polymorphisms at position -2849, -1082 and -592 were analyzed in association with a past history of fertility and fecundity in men and women of at least 85 years old. Fertility was decreased in association with the -2849 A allele in females; 27% of the AA genotype carriers produced no offspring in marriage compared to 14% of the G allele carriers (odds ratio (OR): 2.2, 95% confidence interval (CI): 1.2-4.2, P=0.01). Effective fecundability was decreased in association with the -2849 A allele in females; 7% of female -2849 AA genotype carriers had a child within 371 days of marriage (therefore, conceived within 3 months of marriage) compared to 28% of female G allele carriers (OR: 0.2, 95% CI: 0.04-0.7, P=0.01). This suggests an association between the -2849 AA genotype and a decreased fertility and fecundity in females.     

IL23R, NOD2/CARD15, ATG16L1 and PHOX2B polymorphisms in a group of patients with Crohn's disease and correlation with sub-phenotypes

Recent genomic research has identified interleukin-23 receptor (IL23R), nucleotide-binding oligomerization domain containing 2 caspase-activation recruitment domain?15 (NOD2/CARD15), autophagy related 16-like 1 (ATG16L1) and paired-like homeobox 2b (PHOX2B) as susceptibility loci for Crohn's Disease (CD). Our aim was to investigate these gene variants in a group of CD patients and to analyse the correlation to sub-phenotypes such as gender, smoking habits, disease behaviour at diagnosis, severity of disease and extra-intestinal manifestations. Nineteen patients with CD and 20 healthy controls were included in the study. The gene variants IL23R rs7517847 and rs11209026, NOD2/CARD15 rs2066845, PHOX2B rs16853571, ATG16L1 rs2241879 and rs2241880 were genotyped by PCR followed by sequencing. The frequency of the G risk allele of IL23R rs7517847 was found to be increased in patients with CD (42%) compared to that in control subjects (20%) [odds ratio (OR), 2.9; 95% confidence interval [CI], 1.06-7.9; P=0.03]. In addition, the homozygous condition GG was also associated with CD (OR, 8.70; 95% CI, 0.9-81.6; P=0.038). The analysis of correlation of genotype to sub-phenotypes showed an association of ATG16L1 rs2241879 with the lack of extra-intestinal manifestations (OR, 0.03; 95% CI, 0.002-0.45; P=0.006), and the patients defined as non-smokers displayed an increased frequency of the risk allele C (P=0.03). The present study confirms the association of the heterozygous and homozygous IL23R rs7517847 variant with CD and suggests an additive effect of smoking to the ATG16L1 rs2241879 C risk allele SNP, in the context of the multifactorial model established for the development of CD and a protective effect of the same allele against extra-intestinal manifestations.     

Association of RIP2 gene polymorphisms and systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association of receptor interacting protein 2 (RIP2) single-nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese population. A case-control study was performed on the SNPs rs16900617 and rs16900627 in 590 Chinese SLE patients and 660 healthy controls. These SNPs were typed by TaqMan allele discrimination assays. We found a significant association of rs16900617 G allele [odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.41-0.72] and rs16900627 G allele (OR = 1.28, 95% CI 1.04-1.58) with SLE. Significant differences in genotype frequency distribution were also found in SLE and control individuals (rs16900617: AG versus AA, OR = 0.59, 95% CI 0.44-0.81; GG versus AA, OR = 0.08, 95% CI 0.01-0.65; AG + GG versus AA, OR = 0.55, 95% CI 0.41-0.75; rs16900627: AG versus AA, OR = 1.51, 95% CI 1.17-1.93; AG + GG versus AA, OR = 1.43, 95% CI 1.13-1.82). Analysis of the haplotypes revealed that two haplotypes of AG and GA were also significantly associated with SLE (OR = 1.37, 95% CI 1.11-1.70; OR = 0.60, 95% CI 0.45-0.79). Our findings suggest that the RIP2 gene polymorphisms may be associated with susceptibility to SLE in the Chinese population.     

Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism

Tumor necrosis factor (TNF) is involved in the pathogenesis of systemic lupus erythematosus (SLE), but the role of TNF polymorphisms in SLE susceptibility remains unclear. Previous studies in different populations report an inconsistent association of the TNF-alpha -308A allele with SLE, sometimes depending on the presence of HLA-DR3. We examined the association of polymorphisms in TNF-alpha (-308G/A, -238G/A) and TNFbeta (+252A/G) in a population-based study of SLE in the southeastern United States and considered TNF-SLE associations with respect to HLA-DR3 and DR2 and the interleukin (IL)-1alpha -889C/T polymorphism, previously linked to SLE in this population. Genotypes were analyzed for 230 recently diagnosed SLE patients who met American College of Rheumatology classification criteria and 276 age- and sex-matched controls, randomly selected from driver's license registries. Carriage of the TNF-alpha -308A allele was significantly associated with SLE in Caucasians (OR = 2.3; 95% CI 1.4, 3.9), but not African Americans. Analyses stratified by IL-1alpha -889 genotypes (C/C vs C/T or T/T) revealed independent associations of SLE with TNF-alpha -308A or HLA-DR2 and DR3. This reflected a significant interaction of TNF and IL-1 genotypes in Caucasians, and yielded a strong association (OR = 8.0, p < 0.00001) for the combined "HLA-DR3, TNF-alpha -308A, IL-1alpha -889C/C" genotype. These findings provide evidence of cytokine gene epistasis in SLE susceptibility.     

Meta-analysis of TNF-alpha promoter -308 A/G polymorphism and SLE susceptibility

Alleles of tumor necrosis factor-alpha (TNF-alpha) gene have been inconsistently associated with systemic lupus erythematosus (SLE), particularly the 308-A/G functional promoter polymorphism. To generate large-scale evidence on whether 308-A/G promoter polymorphism is associated with SLE susceptibility we have conducted a meta-analysis. We have identified 21 studies of this polymorphism and SLE using MEDLINE search. Meta-analysis was performed for genotypes A/A (recessive effect), A/A+A/G (dominant effect), and A allele in fixed or random effects models. All control samples were in Hardy-Weinberg proportion. The overall odds ratio (OR) of the A/A genotype was 3.2 (95% CI=2.0-5.3, P<0.001). Stratification by ethnicity indicated that the A/A genotype was associated with SLE in European-derived population (OR=4.0, CI=2.5-6.4, P<0.001). No association was detected in Asian-derived population (OR, 1.3, CI=0.3-6.3, P=0.76). The overall OR for the risk genotypes (A/A and A/G) was 2.0 (CI=1.3-3.1, P<0.001). Similar results were found between the risk allele A and SLE where a significant association was found in European population (OR=2.1, CI=1.6-2.7, P<0.001), but not in Asian (OR=1.4, CI=0.8-2.3, P=0.2) or African (OR=1.2, CI=0.6-2.5, P=0.59) populations. In summary, this meta-analysis demonstrates that the TNF-alpha promoter -308 A/G polymorphism may confer susceptibility to SLE, especially in European-derived population.     

Association of CTLA4 exon-1 polymorphism with the tumor necrosis factor-α in the risk of systemic lupus erythematosus among South Indians

Cytotoxic T lymphocyte associated-antigen (CTLA4) is a potential negative regulatory molecule of T-cells and associated with several autoimmune diseases. Several reports from different ethnic groups showed that the polymorphisms of the CTLA4 gene have been associated with autoimmune diseases including SLE. Therefore, we aimed to investigate the +49 A/G polymorphism in South Indian SLE patients and its association with disease aetiology and serological markers. A total of 534 samples were genotyped for the +49 A/G polymorphism in exon 1 of the CTLA-4 gene through PCR-RFLP method. We found significant association of genotype and allele frequencies with +49 A/G polymorphism in SLE patients. The frequency of the +49 A/G polymorphism rs231775 ‘GG’ genotype was significantly higher in patients with SLE (12.32%) than those in healthy control subjects (4.6%) (OR: 1.797; 95% CI 1.264–2.554; p = 0.001). The frequency of mutant allele ‘G’ also found to be significantly higher in cases (36.01%) than controls (24.92%) (OR: 1.695, 95% CI: 1.298–2.214, p < 0.001). We observed significant increase in serum TNF-α, interferon-α, IL-10 and IL-12 in SLE cases compared to controls. We also found a significant association of serum TNF-α, interferon-α, IL-10 and IL-12 with SLE phenotypes. In addition there was a significant increase in serum TNF-α level in “GG” genotype SLE subjects suggesting that it might play a major role in the advancement of SLE disease.     

Evidence of association of macrophage migration inhibitory factor gene polymorphisms with systemic lupus erythematosus

The aim of this study was to evaluate the potential association of functional polymorphisms of macrophage migration inhibitory factor with systemic lupus erythematosus. Our study includes 711 systemic lupus erythematosus (SLE) patients and 755 healthy controls. We genotyped the migration inhibitory factor (MIF) -173G/C using a polymerase chain reaction (PCR) system with predeveloped TaqMan allelic discrimination assay and the MIF -794 CATT(n) microsatellite polymorphism using a PCR-fluorescent method. A statistically significant difference in the distribution of the MIF -173(*)C allele between SLE patients and controls (P=0.004, OR=1.34, 95% CI=1.05-1.27) was observed. In addition, the frequency of the MIF -173(*)C/C genotype was higher in SLE patient (P=0.002, OR=2.58, 95% CI=1.32-5.10). No differences in the distribution of CATT(n) were found. However, the haplotypes analyses showed that only the CATT(7)-MIF -173(*)C haplotype was associated with a higher susceptibility to SLE (P=0.001, OR 1.84, 95% CI 1.35-2.79). No association with clinical features was detected in any case. These results suggest that both, MIF -173(*)C allele and CATT(7)-MIF -173(*)C haplotype, confer susceptibility to SLE in our population.     

Genetic variations of interleukin-8, CXCR1 and CXCR2 genes and risk of acute pyelonephritis in children

Acute pyelonephritis (APN) is the most severe form of urinary tract infection, the etiopathogenesis of which is still not well understood. Previous studies demonstrated that chemotaxis of neutrophils into the tissue and across the infected epithelial layer is a key step in rapid bacterial clearance. Variations within genes encoding the major chemokine interleukin-8 and its receptors CXCR1 and CXCR2 are therefore attractive candidates for participation in genetic predisposition to APN. The aim of our study was to evaluate the association of single nucleotide polymorphisms (SNPs) -251 T/A, +781 C/T, +1633 C/T and +2767 A/T in the IL-8 gene, +2608 G/C in the CXCR1 gene and +1208 C/T in the CXCR2 gene with susceptibility to APN in the Slovak population. PCR-SSP and PCR-RFLP were used to genotype SNPs in 147 children with APN (62 with recurrent and 85 with episodic form) and 215 healthy individuals. Statistical analysis revealed significantly increased frequency of CXCR1 +2608 C allele (P = 0.0238, OR = 2.452, 95% CI = 1.147-5.243) and GC genotype (P = 0.0201, OR = 2.627, 95% CI = 1.188-5.810) and lower frequency of CXCR2 +1208 T allele (P = 0.0408, OR = 0.645, 95% CI = 0.429-0.972) and TT+TC genotypes (P = 0.0497, OR = 0.5273, 95% CI = 0.288-0.964) in patients with recurrent APN compared with healthy controls. Furthermore, the A allele of IL-8 -251 T/A SNP was also significantly overrepresented in patients with recurrent APN when compared with those with only single episode of APN (P = 0.0439, OR = 1.627, 95% CI = 1.019-2.599). Our results indicate that the minor CXCR1 +2608 C allele is associated with significantly increased susceptibility to APN in childhood, while the CXCR2 +1208 T allele confers protection from recurrent APN. Moreover, allele A of the IL-8 -251 T/A may also increase the risk of developing recurrent attacks after the first-time APN.     

白细胞介素-18基因多态性与广西壮族系统性红斑狼疮的遗传易感性

目的 探讨白细胞介素-18(interleukin 18,IL-18)基因单核苷酸多态性与广西壮族系统性红斑狼疮(systematic lupus erythematosus,SLE)易感性之间的关系.方法 以115例SLE患者和160名健康对照者为研究对象,应用聚合酶链反应-限制性片段长度多态性和DNA测序的方法对IL-18基因-137G/C、-607C/A单核苷酸多态性进行基因分型.结果 IL-18基因-137G/C多态性在SLE组和正常人群中的分布差异无统计学意义(P>0.05),而IL-18基因-607C/A多态性在两组人群中的分布差异有统计学意义(P<0.05),等位基因频率的相对风险分析发现,-607 C等位基因携带者患系统性红斑狼疮的风险是-607A等位基因的1.619倍(OR=1.619,95%CI:1.150-2.281).联合基因型分析发现,IL-18的-137G/-607C等位基因频率在SLE组中显著高于对照组(P<0.05).-137G/-607C等位基因携带者显著增加了SLE的发病风险(OR=1.484,95%CI:1.056-2.087).结论 IL-18基因-607C/A多态性与SLE的发病具有相关性,其中-607 C等位基因可能是SLE的遗传易感基因.     

Association of interferon gamma and interleukin 10 genes with tuberculosis in Hong Kong Chinese

Interferon gamma (IFN-gamma) and interleukin 10 (IL-10) are believed to play opposing roles in host immunity against mycobacterial infection. IFN-gamma activates macrophages, while IL-10 downregulates the expression of T helper type 1 cytokines, MHC class II antigens and costimulatory molecules on macrophages. Associations of IFN-gamma -179 (G/T), +874 (A/T), +875 miscrosatellite CA repeats and +4766 (C/T), and IL-10 -1082 (A/G), -819 (C/T) and -592 (C/A) with tuberculosis (TB) were investigated in 385 HIV-negative patients and 451 controls in a Hong Kong Chinese population. The frequency of a low IFN-gamma-producing +874 A/A genotype was significantly over-represented in the patient group (P<0.001, OR=3.79, 95% CI=1.93-7.45). We identified 10 alleles in the IFN-gamma CA repeats and observed a significant difference in allele frequency distribution between patients and controls (P<0.001). By grouping alleles into 12 and non-12 CA repeats, the non-12/non-12 genotype yielded a similar significant result (P<0.001, OR=4.56, 95% CI=2.21-9.43) as observed in +874 A/A genotype. Weak associations of the IL-10 GCC/- genotype (P=0.04) and the low IFN-gamma-producing A/A genotype (P=0.06) with TB relapse/extrapulmonary cases were found. This study suggests the possible role of interferon gamma in TB susceptibility.     

The synergistic effect of FC gamma receptor IIa and interleukin-10 genes on the risk to develop systemic lupus erythematosus in Thai population

Several linkage analyses have consistently shown that systemic lupus erythematosus (SLE) susceptible genes are located on chromosome 1q21-44. In this study, two major candidate genes, interleukin-10 (IL-10) and Fc gamma receptor IIa (FcgammaRIIa), within these regions were investigated in Thai SLE patients. The genotyping of three single-nucleotide polymorphisms (promoter area: -1082, -819 and -592) within IL-10 gene and one polymorphism (change amino acid at position 131) within FcgammaRIIa gene was determined in 195 SLE patients and 159 ethnically matched controls. The RR/RH genotypes of FcgammaRIIa were found to be significantly increased in SLE patients compared with healthy controls [OR = 2.01, 95% confidence interval (CI) = 1.28-3.14, P= 0.001]. Interestingly, the synergistic effect between RR/RH genotypes of FcgammaRIIa and ACC/ACC haplotype of IL-10 in susceptibility to SLE was observed (OR = 7.84, 95% CI = 1.60-52.04, P= 0.002). In addition, the FcgammaRIIa, RR homozygotes was also strongly associated with anticardiolipin antibody production (OR = 6.09, 95% CI = 1.38-30.54, P= 0.006). The result demonstrated that ACC haplotype of IL-10 gene and FcgammaRIIa R131 polymorphism can be used as marker for genetic susceptibility and severity to SLE in Thai population, particularly individuals carrying both specific genotypes.