Genetic association between interleukin-10 promoter region polymorphisms and primary Sjögren's syndrome

OBJECTIVE: To determine whether the haplotypes formed on the basis of single-base-exchange polymorphisms at positions -1082, -819, or -592 of the interleukin-10 (IL-10) gene predispose subjects to primary Sj?gren's syndrome (SS). METHODS: The frequency of IL-10 polymorphisms was analyzed in 62 patients with primary SS and in 400 healthy subjects. These data were assessed for correlations with the concentration of IL-10 in the plasma. RESULTS: The frequency of the IL-10 GCC haplotype (G at position -1082, C at position -819, and C at position -592 of the IL-10 gene) was increased (P < 0.05, odds ratio [OR] 1.90, 95% confidence interval [95% CI] 0.955-3.62) and the frequency of the ACC haplotype decreased (P < 0.05, OR 0.443, 95% CI 0.257-0.764) in primary SS patients compared with healthy controls. Moreover, the frequency of the ATA haplotype was similar in primary SS patients and healthy controls, but the incidence of the GCC/ATA genotype was elevated in the primary SS patients (P < 0.05, OR 2.19, 95% CI 1.19-4.03). The concentration of plasma IL-10 was significantly higher in patients carrying the GCC haplotype than in non-carriers of GCC. CONCLUSION: These results suggest that the presence of the GCC haplotype or the GCC/ATA genotype and the absence of the ACC haplotype of the IL-10 gene are associated with an increased susceptibility to primary SS. This effect is probably mediated by the increased capability to produce IL-10 among carriers of the GCC haplotype.     

Association between ‘interleukin’ 10 gene (IL10) polymorphisms and systemic sclerosis with interstitial lung involvement

Systemic sclerosis (SSc), also termed as “scleroderma”, is a progressive, systemic disease of unknown origin characterized by excessive fibrosis, vascular abnormalities and immune dysfunction. Extracellular matrix (ECM) production by fibroblasts in SSc is modulated and regulated by cytokines. Since IL10 has antiinflamatory properties and, contributes to the fibrotic processes in SSc, we analyzed IL-10 gene polymorphisms including −1082 G/A, −819 C/T and −592C/A in 45 systemic sclerosis patients with lung involvement and 150 healthy control using ARMS-PCR. While no association was found between SSc and −819C/T, −592C/A polymorphism, −1082 G/A allele frequency in SSc patients was higher than that in control and significant association was found between SSc and −1082 G/A (Pc: <0.000, OR: 2.85 95% CI: 1.74–4.63). In addition significant difference was found between the frequencies of the IL-10 GCC, ACC haplotypes (Pc: <0.000, OR: 2.85, 95% CI: 1.74–4.63; Pc: 0.012, O.R: 1.56, 95% CI: 1.09–2.23, respectively), GCC⁺/GCC⁺, GCC⁻/GCC⁻ genotypes (Pc: 0.002, OR: 5.07, 95% CI: 1.82–14.21; Pc: <0.000, O.R: 4.00, 95% CI: 1.87–8.98, respectively) and SSc. Our findings suggest that IL-10 1082 G/A alleles or haplotypes containing these alleles may play role in SSc susceptibility.     

No Correlation Between Interleukin-10 Gene Promoter Polymorphisms and Hepatitis B Virus Infection Outcome

Background

Single nucleotide polymorphisms (SNP) in the promoter region of the interleukin (IL)-10 genes have a role in determining hepatitis B virus (HBV) outcome.

Objectives

This study evaluates the correlation between HBV infection and SNP in IL-10 gene promoter.

Patients and Methods

Ninety-six HBV-infected patients (32 chronic hepatitis B infection patients, 34 healthy carriers, 30 spontaneously recovered cases) and 31 healthy controls were enrolled. Three biallelic (-819,-592,-1082) regions in the IL-10 gene promoter were sequenced for all patients.

Results

Genotypes and haplotypes of IL-10 gene promoter region at position -1082, -819 and -592 were not significantly different among controls, HBV recovered cases, carriers and chronic HBV patients. Nevertheless, A/A genotype at position -592 and T/T genotype at position -819 were more frequently seen in the HBV clearance group, while frequency of G/G genotype at position -1082 was more prevalent in the persistence group. GCC/GCC and GCC/ACC haplotypes were significantly observed in anti-HBe positive individuals.

Conclusions

Our findings showed that IL-10 promoter polymorphisms were not correlated with HBV infection prognosis. Nevertheless, individuals carrying high and intermediate producer of IL-10 haplotypes had a better ability to develop anti-HBe than low producer carriers.     

Effects of interleukin-10 gene polymorphism on the development of gastric cancer and peptic ulcer in Japanese subjects

BACKGROUND: Anti-inflammatory cytokines play an important role in downregulation of inflammation and the prevention of neoplastic disorders. Genetic variations of anti-inflammatory cytokines are assumed to influence such responses. The aim of the present study was to clarify the association between the IL-10 polymorphism, one of the representative anti-inflammatory cytokines, and susceptibility to gastric cancer and peptic ulcer in Japan. METHODS: The IL-10-1082 (A/G)/-819 (T/C)/-592 (A/C) polymorphisms were assessed in Helicobacter pylori-positive patients with gastritis only (n = 162), gastric ulcers (n = 110), duodenal ulcers (n = 94), or gastric cancers (n = 105), and H. pylori-negative controls (n = 168) by allele specific primer-polymerase chain reaction methods. RESULTS: The carriage of IL-10-592 C (age and sex-adjusted odds ratio [OR]: 1.851, 95% confidence interval [CI]: 1.018-3.380) and IL-10-819 C (adjusted OR: 1.868, 95%CI: 1.023-3.411) allele were associated with an increased risk for gastric cancer development, not gastric ulcer and duodenal ulcer. The IL-10-1082 polymorphism had no association with development of gastric cancer and peptic ulcers. The presence of the ATA/GCC haplotype of IL-10-1082/-819/-592 polymorphism significantly increased the risk of gastric cancer development (adjusted OR: 2.805, 95%CI: 1.258-6.254) compared with presence of the ATA/ATA haplotype. CONCLUSIONS: The IL-10-1082/-819/-592 genotype status and haplotype were associated with an increased risk for gastric cancer development, not peptic ulcer, in Japan. The genotyping test of this anti-inflammatory cytokine would be useful for the detection of individuals with higher risk of gastric cancer development.     

Interleukin-10 - 1082 GG polymorphism influences the occurrence and the clinical characteristics of hepatitis C virus infection

BACKGROUND/AIMS: In this study, we determined the genotypic and allelic frequencies of the Interleukin (IL)-10(-1082G/A) IL-10(-592A/C), and IL-10(-819C/T) polymorphisms, and their association with the risk to develop B cell Non Hodgkin Lymphoma (NHL) in hepatitis virus C (HCV) carriers. RESULTS: Genetic polymorphisms in the IL-10 gene promoter were studied in 250 consecutive patients with B-cell NHL with no clinical and/or laboratory findings of cryoglobulinemia, 142 NHL/HCV- and 108 NHL/HCV+ with chronic hepatitis (CH), 120 consecutive subjects with HCV-related CH, and 110 age, sex-matched healthy blood donors. The frequency of the IL-10(-1082GG) genotype vs remaining genotypes (IL-10(-1082GA/AA)) was higher in NHL/HCV+ patients than HCV-related CH patients (P=0.0002, OR=2.89, CI: 1.62-5.15) and in NHL/HCV+ than NHL/HCV- patients (P=0.0001, OR=2.99, CI: 1.72-5.19). Moreover, the IL-10(-1082GG) genotype was more prevalent in indolent NHL/HCV+ cases than aggressive NHL/HCV+ (P=0.0004, OR=4.97, CI: 2.10-11.79). Finally, we confirmed that IL-10(-1082GG) genotype is associated with higher IL-10 production compared to AA homozygous (P=0.037). CONCLUSIONS: The high IL-10 production, due to IL-10(-1082GG) genotype, influences the clinical expression of the HCV infection by increasing susceptibility to develop NHL and might contribute to the indolent form of the disease.     

IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn＇s disease location

AIM： To determine the distribution and frequencies of the genotypes and haplotypes of the genes encoding for the glucocorticoid receptor （GR）, the tumor necrosis factor （TNF）-α and the interleukin （IL）-10 in childhood Crohn＇s disease （CD） and to assess the impact of the corresponding DNA variants on clinical and disease phenotypes.
METHODS： Ten variants in GR, TNF-a and IL-10 were genotyped in 113 childhood CD cases and 95 healthy subjects, both of French-Canadian origin.
RESULTS： For the GR polymorphisms （R23K and N363S） and IL-10 variants in the 5＇flanking region （-1082 G 〉 A, -819 T 〉 C and -592 A 〉 C）, no difference was observed in allele and genotype frequencies between CD patients and controls. At the haplotype level, we found three IL-10 haplotypes previously described in Caucasians （GCC, ACC and ATA） and three novel haplotypes only present in IBD patients. When we analyzed the haplotype distribution with the anatomical location of the disease, the GCC haplotype was associated with the colonic and the ACC haplotype with the terminal ileum location, respectively. The genotyping of five polymorphisms in the promoter region of the TNF-α gene （-1031 T 〉 C, -863 A 〉 C, -857 T 〉 C, -308 A 〉 G and -238 A 〉 G） revealed a significant overrepresentation of homozygous -1031 CC among CD patients （OR = 9.9） and an association with the colonic location. For TNF-α, eleven haplotypes were inferred, including two frequent ones, TCCGG and CACGG, which were significantly observed more frequently in controls and cases, respectively.
CONCLUSION： This is one of the first studies investigating the association between haplotype structure and disease location in a CD pediatric cohort. Our results will help to increase our understanding of the genetic determinants of childhood CD.     

Interleukin-10 Promoter Polymorphisms and Breast Cancer Risk in Iranian Women

Background: IL-10 is an anti-inflammatory cytokine which is involved in tumorigenesis. Over production of IL-10 and elevated number of IL-10 generating mononuclear cells in breast tumor tissue has already been shown. Objective: To determine the association of IL-10 promoter polymorphisms with increased risk of breast cancer and its association with breast cancer prognostic factors. Methods: Peripheral blood samples from 275 female breast cancer patients and 320 cancer free controls were used to detect three single nucleotide polymorphisms in IL-10 promoter region ( -1082, -819, -592 ) by PCR method. Results: The frequency of genotypes and alleles of three mentioned regions of IL-10 promoter and their haplotypes (GCC, ATA, and ACC) showed no statistically significant difference between patients and controls. In the case of prognostic factors, progesterone receptor (PR) status exhibited significant relation with -1082 genotypes (P=0.03) and haplotypes (P=0.02). -1082 AA genotype was associated with negative PR expression whereas AG and GG genotypes of this site were positively associated with PR expression. Similarly GCC haplotype correlated with positive PR expression and ATA and ACC with negative PR expression. Conclusion: The data of this study showed that IL-10 promoter gene polymorphisms may not be considered as one of the risk factors for breast cancer in Iranian patients.     

Distinct tumour necrosis factor alpha, interferon gamma, interleukin 10, and cytotoxic T cell antigen 4 gene polymorphisms in disease occurrence and end stage renal disease in Wegener's granulomatosis

BACKGROUND: Cytokines and T cell regulatory proteins play an important role in the pathogenesis of Wegener's granulomatosis (WG). OBJECTIVE: To investigate cytokine and cytotoxic T cell antigen-4 (CTLA4) gene polymorphisms and HLA class II alleles in generalised WG. METHODS: The distribution of cytokine and cytotoxic T cell antigen 4 (CTLA4) gene polymorphisms and HLA class II alleles was analysed in 32 patients with generalised WG and 91 healthy controls. Genotyping was carried out for HLA-DRB1 and HLA-DQB1 and for polymorphism of the genes encoding TNF alpha (-238, -308, -376), TGF beta (codon 10 and 25), IFN gamma (+874), IL6 (-174), IL10 (-592, -819, -1082), CTLA4 (-318, +49), and the (AT)(n) repeats of the CTLA4 gene. In addition, stratification analysis was carried out according to the presence (n = 15) or absence (n = 17) of end stage renal disease. RESULTS: An increase in the IFN gamma +874 T/T (odds ratio (OR) = 3.14) and TNF alpha -238 G/A (OR = 5.01) genotypes was found in WG patients. When ESRD positive and negative patients were compared, the IFN gamma +874 A/A and the CTLA4 -318 C/C genotypes were found more often in the ESRD subgroup (OR = 10.6 and OR = 2.25). WG patients without ESRD had a higher frequency of the IL10 GCC/ACC promotor genotype (OR = 0.13) and long CTLA4 (AT)(n) repeats (OR = 0.4). No effect was seen for HLA-DR and -DQ markers. CONCLUSIONS: Disease susceptibility and clinical course in WG may be associated with distinct polymorphisms of cytokine and CTLA4 genes.     

IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn's disease location

AIM: To determine the distribution and frequencies of the genotypes and haplotypes of the genes encoding for the glucocorticoid receptor (GR), the tumor necrosis factor (TNF)-α and the interleukin (IL)-10 in childhood Crohn's disease (CD) and to assess the impact of the corresponding DNA variants on clinical and disease phenotypes. METHODS: Ten variants in GR, TNF-α and IL-10 were genotyped in 113 childhood CD cases and 95 healthy subjects, both of French-Canadian origin. RESULTS: For the GR polymorphisms (R23K and N363S) and IL-10 variants in the 5'flanking region (-1082 G > A, -819 T > C and -592 A > C), no difference was observed in allele and genotype frequencies between CD patients and controls. At the haplotype level, we found three IL-10 haplotypes previously described in Caucasians (GCC, ACC and ATA) and three novel haplotypes only present in IBD patients. When we analyzed the haplotype distribution with the anatomical location of the disease, the GCC haplotype was associated with the colonic and the ACC haplotype with the terminal ileum location, respectively. The genotyping of five polymorphisms in the promoter region of the TNF-α gene (-1031 T > C, -863 A > C, -857 T > C, -308 A > G and -238 A > G) revealed a significant overrepresentation of homozygous -1031 CC among CD patients (OR = 9.9) and an association with the colonic location. For TNF-α, eleven haplotypes were inferred, including two frequent ones, TCCGG and CACGG, which were significantly observed more frequently in controls and cases, respectively. CONCLUSION: This is one of the first studies investigating the association between haplotype structure and disease location in a CD pediatric cohort. Our results will help to increase our understanding of the genetic determinants of childhood CD.     

Polimorfismo de genes de citocinas: ¿factores de riesgo cardiovascular en la población venezolana?

Objective:

To examine whether the polymorphisms of the IL6, TNFA and IL10 genes represent a risk marker for acute myocardial infarction (AMI) and to analyze their correlation with risk factors, age of occurrence and type of AMI.

Method:

Association study that included 310 unrelated Venezuelan individuals, grouped in 190 patients with AMI and 120 controls with or without cardiovascular risk factors. The IL6-174 G/C (rs1800795), TNFA -308 G/A (rs1800629), and IL10-1082 A/G (rs1800896), -819 C/T (rs1800871) and -592 C/A (rs1800872) polymorphisms were determined using the polymerase chain reaction technique with sequence-specific primers.

Results:

Comparison of genotypic and allelic frequencies, using adjusted logistic regression analysis for risk factors, showed a significantly increased frequency of the genotype combination G/G-A/A of TNFA-308 G/A (odds ratio [OR]: 3.8; p = 0.00007), GG/-C/C of IL6-174 G/C (OR: 2.3; p = 0.009), A/G-G/G of IL10-1082 A/G (OR: 3.8; p = 0.00001) and the GCC haplotype of IL10 (OR: 3.71; p = 0.0053) in infarcted patients compared to controls. Interactions between the IL10-1082 A/G and TNFA-308 G/A polymorphisms and hypertension were observed.

Conclusions:

The association of the variants of the TNFA, IL6 and IL10 genes with AMI suggest that the imbalance in the production of cytokines promotes an exacerbated inflammatory process, supporting the fundamental role of inflammation in all stages of the atherosclerotic process.Key words: Polymorphism, Cytokines, Acute myocardial infarction, Acute coronary syndrome     

Polymorphisms of IL‐10 affect the severity and prognosis of myelodysplastic syndrome

Polymorphisms of the interluekin‐10 (IL‐10) gene, which alter the production of IL‐10, have been implicated in many cancers. We investigated the association between gene polymorphisms of the promoter region of IL‐10 (‐1082 G/A, IL‐10‐819 C/T, and ‐592 C/A) and the risk to develop myelodysplastic syndrome (MDS) and clinical features of MDS. Genomic DNA was extracted from 119 patients with MDS or chronic myelomonocytic leukemia and 202 healthy controls. Genotypes were determined by PCR‐restriction fragment length polymorphism. There were no statistically significant differences in the genotype, allele, and haplotype frequencies of IL‐10 ‐1082 G/A, IL‐10‐819 C/T, and ‐592 C/A between the patients with MDS and the control group. However, the IL‐10 ‐592 CC genotype group (IL‐10 high producer type) was associated with lower hemoglobin level (7.85 ± 2.02 g/dL vs. 9.37 ± 2.25 g/dL, P = 0.027) and poorer prognosis as compared to the IL‐10 ‐592 non‐CC genotype group (median survival time 50.2 m vs. not reached, p = 0.026). In addition, the IL‐10 high producer haplotype group (GCC/ACC or ACC/ACC) was also associated with lower hemoglobin level and shorter survival time. Our findings indicate that IL‐10 gene polymorphisms may not contribute to susceptibility to MDS, but they may be associated with the severity and prognosis of MDS.     

Neuropsychiatric systemic lupus erythematosus is associated with imbalance in interleukin 10 promoter haplotypes

OBJECTIVE: To investigate the association of interleukin 10 (IL10) promoter polymorphisms and neuropsychiatric manifestations of systemic lupus erythematosus (SLE). METHODS: IL10 haplotypes of 11 healthy volunteers were cloned to confirm that in the Dutch population, only the three common haplotypes (-1082/-819/-592) GCC, ACC and ATA exist. The IL10 promoter polymorphisms of 92 SLE patients and 162 healthy controls were determined. The medical records of the SLE patients were screened for the presence of neuropsychiatric involvement. RESULTS: All cloned haplotypes were either GCC, ACC or ATA. Forty two SLE patients had suffered from neuropsychiatric manifestations (NP-SLE). In NP-SLE patients, the frequency of the ATA haplotype is 30% versus 18% in the controls and 17% in the non-NP-SLE group (odds ratios 1.9, p = 0.02, and 2.1, p = 0.04, respectively), whereas the GCC haplotype frequency is lower in the NP-SLE group compared with controls and non-NP-SLE patients (40% versus 55% and 61%, odds ratios 0.6, p = 0.02 and 0.4 p = 0.006). The odds ratio for the presence of NP-SLE is inversely proportional to the number of GCC haplotypes per genotype when the NP-SLE group is compared with non-NP-SLE patients. CONCLUSIONS: The IL10 locus is associated with neuropsychiatric manifestations in SLE. This suggests that IL10 is implicated in the immunopathogenesis of neuropsychiatric manifestations in SLE.     

Interleukin‐1β and ‐10 polymorphisms influence erosive reflux esophagitis and gastritis in Taiwanese patients

Background and Aims: Helicobacter pylori (H. pylori) infection induces cytokine production and is associated with gastrointestinal diseases. This study examined the relationship of gene polymorphisms, including interleukin (IL)‐1β, ‐10, ‐8, and tumor necrosis factor‐α (TNF‐α), H. pylori infection, and susceptibility to gastrointestinal disorders in Taiwanese patients. Methods: IL‐1β?511/?31/+3953, ‐10?1082/?819/?592, ‐8?251, and TNF‐α?308 polymorphisms were assessed in 628 gastrointestinal disease patients, and 176 healthy controls were analyzed using the polymerase chain reaction?restriction fragment length polymorphism method. Results: IL‐1β?511 T/T and ?31 C/C genotypes, and IL‐1β?511 T and ?31 C alleles were associated with an increased risk of reflux esophagitis (P = 0.034, odds ratio [OR] = 1.384, 95% confidence interval [CI]: 1.023–1.871; P = 0.031, OR = 1.388, 95% CI: 1.028–1.873; P = 0.044, OR = 1.342, 95% CI: 1.008–1.786; and P = 0.040, OR = 1.349, 95% CI: 1.014–1.796, respectively). No relationship was found between H. pylori infection and the risk of reflux esophagitis. IL‐10?819 C/T and ‐10?592 A/C genotypes and IL‐10?1082/?819/?592 ATA/ACC and ATA/GCC haplotypes were associated with an increased risk of gastritis (P = 0.021, OR = 1.721, 95% CI: 1.084–2.733; P = 0.016, OR = 1.766, 95% CI: 1.112–2.805; P = 0.039, OR = 1.662, 95% CI: 1.024–2.697; and P = 0.035, OR = 1.600, 95% CI: 1.024–2.499, respectively). Conclusion: Among Taiwanese patients, IL‐1β and ‐10 polymorphisms were associated with an increased risk of erosive reflux esophagitis and gastritis, respectively.     

Tumor necrosis factor-alpha promoter -308 A/G polymorphism and rheumatoid arthritis susceptibility: a metaanalysis

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) promoter -308 A/G polymorphism has been reported to be associated with rheumatoid arthritis (RA) with inconsistent results. We investigated whether TNF-alpha -308 A/G polymorphism confers susceptibility to RA. METHODS: We conducted a random effect metaanalysis on the association of genotypes A/A (recessive effect), A/A + A/G (dominant effect), A allele, and A/A vs G/G genotypes of the TNF-alpha -308 polymorphisms with RA overall and within different ethnic populations. RESULTS: Fourteen studies, 10 of Europeans, 3 of Latin Americans, and one Asian, were included in this metaanalysis. An association between RA and the TNF-alpha -308 A allele was not found in the overall population (OR 1.005, 95% CI 0.715-1.412, p = 0.976). However, stratification by ethnicity indicated that the TNF-alpha A allele was significantly associated with RA in Latin Americans (OR 2.004, 95% CI 1.158-3.467, p = 0.013). Conversely, there was no association detected for the TNF-alpha A allele with RA patients from the European samples (OR 0.911, 95% CI 0.684-1.212, p = 0.520). The OR for the A/A + A/G genotype, the A/A genotypes, and the A/A vs G/G genotypes in samples overall and in each ethnic group showed a similar trend to those for the TNF-alpha A allele. CONCLUSION: This metaanalysis demonstrates that the TNF-alpha -308 A/G polymorphism may represent a significant risk factor for RA in Latin Americans, but not in Europeans.     

The role of interleukin-10 promoter polymorphisms in primary Sjogren's syndrome

OBJECTIVE: To determine the impact of a broad spectrum of different polymorphisms within the interleukin-10 (IL-10) promoter gene on disease susceptibility to primary Sjogren's syndrome (pSS), clinical manifestations, and autoantibody production. METHODS: We genotyped 111 unrelated German Caucasian patients with pSS and 145 healthy controls for the single nucleotide polymorphisms (SNPs) at positions -2849, -2776, -2769, -2763, -1349, -1082, -851, -819, -657, and -592 and for the microsatellites IL10.R and IL10.G. Allele and haplotype distributions were compared between patients and controls and between subgroups of patients with different clinical and laboratory findings. RESULTS: We found no significant differences in the allele or haplotype frequencies between pSS patients and healthy controls. After Bonferroni correction we found a significant association of the ACC haplotype (at the -1082, -819, and -592 loci) with immunoglobulin (Ig)A antibodies to anti-alpha-fodrin. CONCLUSION: Overall we found no associations of IL-10 promoter polymorphisms with the susceptibility to pSS in our cohort. The finding that the production of IgA anti-alpha-fodrin antibodies is associated with polymorphisms within the IL-10 promoter region suggests a genetic contribution to the generation of these antibodies.     

Protective role of interleukin-10 promoter gene polymorphism in the pathogenesis of invasive pulmonary aspergillosis after allogeneic stem cell transplantation

The current study attempted to evaluate the association between the IL-10 promoter gene single nucleotide polymorphism (SNP) and invasive pulmonary aspergillosis (IPA) after allogeneic stem cell transplantation (SCT) in 105 patients. Three single-nucleotide polymorphisms were investigated in the proximal region of the IL-10 promoter gene (-1082/-819/-592). Two haplotypes (1082*A/819*T/592*A [ATA] and 1082*A/819*C/592*C [ACC]) were found in the current study. The overall incidence of IPA was estimated as 14.1+/-4.5% with a median onset at 186 days post-transplant (62 approximately 405 days). An increased occurrence of IPA was noted dependent on the IL-10 haplotype (0% vs 11.5+/-6.4% vs 19.7+/-7.7% for ACC/ACC vs ATA/ACC vs ATA/ATA haplotype, P=0.0307 when comparing ACC with non-ACC haplotype). In a multivariate survival analysis using Cox's proportional hazard model, the IL-10 promoter gene SNPs were identified as an independent predictive factor for the development of IPA (P=0.012, hazard ratio (HR) 9.3), along with an histocompatibility leukocyte antigen (HLA)-identical donor (P=0.005, HR 16.3), the CD34+ cell dose transplanted (P=0.004, HR 26.5), and time-dependent chronic graft-versus-host disease (GVHD; P=0.049, HR 16.0). The IL-10 ACC haplotype was found to have an apparent protective role in the development of IPA after allogeneic transplantation, regardless of HLA-disparity or chronic GVHD.     

IL-6, IL-10 and IL-17 Gene Polymorphisms in Iranian Women with Recurrent Miscarriage

Background: Pro-inflammatory and anti-inflammatory cytokines and polymorphisms of their genes have been described to be involved in the pathogenesis of recurrent miscarriage (RM). Objective: To investigate the association between RM and five polymorphisms of cytokine genes, interleukin 10 (IL-10), (-592 A/C, -819 C/T, -1082 A/G), IL-6 (-174 C/G) and IL-17 (-197 G/A) in Iranian women. Method: Polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) was performed to determine the frequencies of the IL-6, IL-10 and IL-17 gene polymorphisms in 85 women with RM compared with 104 healthy controls. Results: The frequencies of IL- 10 promoter gene polymorphisms (-592 A/C and -819 C/T) were significantly higher in RM women than those in controls (p=0.003). However, no statistically significant differences were observed in the frequencies of IL-6 (-174 C/G), IL-10 (-1082 A/G) and IL-17 (-197 G/A) polymorphisms between RM women and controls. Conclusion: These results suggest that IL-10 gene polymorphism screening might have some relevance in patients with RM, a suggestion which requires further studies.     

Interleukin-10 Promoter 1082/−819/−592 Polymorphisms are Associated with Asthma Susceptibility in Asians and Atopic Asthma: A Meta-Analysis

Background

Although interleukin-10 (IL-10) is a potent inhibitor of allergic diseases, the association between promoter ?1082/?819/?592 polymorphisms and asthma susceptibility remains inconclusive. We sought to determine if IL-10 promoter ?1082/?819/?592 polymorphisms contribute to asthma susceptibility and are associated with phenotypes of atopic asthma.

Methods

Systematic computerized searches were performed. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by using random-effect and fixed-effect models, based on between-study heterogeneity. Subgroup analyses were performed according to age, ethnicity, and atopy. Publication bias was detected by funnel plot using Egger’s test.

Results

A total of 4,716 asthmatic patients and 5,093 controls were included. The asthma susceptibility correlated significantly with IL-10 promoter gene ?1082 polymorphism [OR (95 % CI) 1.26 (1.02, 1.55) for AA vs. AG + GG] and ?592 polymorphism [OR (95 % CI) 1.12 (1.07, 1.34) for AC + AA vs. CC] (both P < 0.05), but not with ?819 polymorphism (P > 0.05). Subgroup analyzes suggested that the AA versus AG + GG genotype of ?1082A/G polymorphism and AC + AA versus CC genotype of ?592A/C polymorphism contributed significantly to increased asthma susceptibility in adults [OR (95 % CI) 1.39 (1.03, 1.87) for ?1082A/G and 1.53 (1.25, 1.87) for ?592A/C polymorphism]. The Asian population [OR (95 % CI) 1.35 (1.1, 1.7) for ?1082A/G and 1.4 (1.12, 1.64) for ?592A/C polymorphism] and subjects with atopic asthma [OR (95 % CI) 1.49 (1.18, 1.88) for ?1082A/G and 1.23 (1.01, 1.48) for ?592A/C polymorphism] also had an increased susceptibility of asthma. No publication bias was detected.

Conclusions

IL-10 promoter ?1028A/G, ?592A/C polymorphisms and their haplotypes, but not ?819T/C polymorphism, correlate with asthma susceptibility.     

Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection

Host genetic factors have been reported to influence the natural history of hepatitis C virus (HCV) infection. We examined whether variation in interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-alpha) genes would predict the likelihood of sustained response to antiviral therapy. Single nucleotide polymorphisms (SNPs) and microsatellites at two loci encoding the cytokines IL-10 and TNF-alpha were determined by polymerase chain reaction (PCR)-based techniques. Their relationship to the outcome of antiviral therapy for chronic HCV infection was studied in 49 white patients who had a virologically sustained response (SR) and in 55 white nonresponders (NR) to a combination of interferon alfa-2b and ribavirin (IFN + R). Several IL-10 variants were more frequent among SRs compared with NRs. Carriage of the -592A or the -819T SNP was associated with SR (odds ratio [OR] = 2.2; P =.016). The -592A/A and the exclusively linked -819T/T genotypes were also associated with SR (OR = 16.6; P =.013 for either). The haplotype consisting of the 108-bp IL-10.R microsatellite and -3575T, -2763C, -1082A, -819T, -592A was also associated with SR (OR = 2.65; P =.01). Stratification for viral genotype, baseline viral RNA concentration, and histologic status identified homozygosity for the haplotype as the principal determinant: all 5 homozygous individuals achieved SR (OR(crude) = 13.7; P =.025; stratified ORs = 1.9-7.0), whereas heterozygotes differed only slightly from wild-type carriers. In contrast, TNF alleles defined by promoter sequences -238G/A and -308G/A were approximately equally distributed among SR and NR. In conclusion, homozygosity for -592A, -819T or the extended haplotype (108bp) - (-2575T) - (-2763C) - (-1082A) - (-819T) - (-592A) is associated with SR to IFN + R.