Polymorphisms of IL-10 gene in patients infected with HCV under antiviral treatment in southern Brazil

Interleukin-10 (IL-10) is a cytokine that plays an important role in the regulation of the immune system. Gene polymorphisms of IL-10 have been associated with the different expression levels of this cytokine. In hepatitis C virus infection, IL-10 appears to interfere with the progression of disease, viral persistence and the response to therapy. This study investigated genetic variability in the IL-10 gene promoter between patients infected with hepatitis C virus (HCV) and healthy individuals, associating the frequency of polymorphisms with different aspects of viral infection. This is a case-control study with 260 patients who were infected with HCV and 260 healthy individuals. Genotyping of the polymorphisms was performed using the technique of amplification refractory mutation system PCR (ARMS-PCR) for regions of the IL-10 gene promoter (-1082 G/A, -819 C/T, -592 C/A). The frequencies of alleles and genotypes related to polymorphisms in the IL-10 gene promoter showed a higher frequency of the G allele and genotype GG in the -1082 region between the infected group and the control group (p = 0.005 and p = 0.001, respectively), whereas the AA genotype was significantly more frequent in the control group. The frequencies of the haplotypes GTA and GCC were higher in the group of infected individuals, whereas the haplotype ATA was more frequent in the healthy group (p < 0.006). It was also observed that the genotypes GG and AG in the region -1082 were significantly more frequent among patients infected with HCV who were in advanced stages of fibrosis and cirrhosis (p = 0.042). No association was observed between polymorphisms of IL-10 and sustained virologic response (SVR).     

Association of tumor necrosis factor alpha, interferon gamma and interleukin 10 gene polymorphisms with peripheral neuropathy in South Indian patients with type 2 diabetes

Diabetic peripheral neuropathy (DPN) is a major global health threat and a common complication of diabetes. Peripheral nerve complications due to irregular cytokine production are eminent factors in many inflammatory diseases. The present study focused on gene polymorphisms of pro and anti-inflammatory cytokines that may be responsible for nerve damage in diabetic neuropathy. We examined three common functional SNPs primarily at the positions on genes of tumor necrosis alpha (TNFα) −308G/A, interferon gamma (IFNγ) +874A/T and interleukin (IL) 10 −1082G/A in order to establish their association with peripheral neuropathy in type 2 diabetes. Results: Genotypic frequencies obtained from TNFα −308G/A gene analysis in DPN group comprised 86.4% of G/A, 10.6% of G/G and 3% of A/A genotype, where as the control group had 94% of G/A, 2% of G/G and 4% of A/A which could not reach the statistical significance with the disease after Bonferroni correction. The IFNγ +874 A/T polymorphism in patient group revealed 33.3% of A/A, 47.5% of A/T and 19.2% of T/T genotype. The A/A genotype had attained statistical significance of P = 0.04 (P corrected); OR 2; 95% CI 1.14–3.64 when compared to controls. The IL10 −1082 G/A polymorphism in the patient group has showed 62.6% of A/A, 21.2% of G/A, 16.2% of G/G genotype, revealing significant association with G/G genotype (P < 0.01, OR 2.9; 95% CI 1.47–5.84) when compared to controls. Conclusion: Our findings indicate that the tested markers within the IFNγ and IL-10 genes, but not the TNFα gene, are significantly associated with peripheral neuropathy in South Indian type 2 diabetic patients. The study shows that the ‘high-producer’ IL-10 −1082 G/G genotype and the ‘low-producer’ IFNγ +874 A/A genotype may be responsible for the down regulation of immune response leading to inflammation in this setting.     

Associations between interleukin-10 polymorphisms and susceptibility to juvenile idiopathic arthritis: a systematic review and meta-analysis

Background

Cytokine genes, including interleukin-10 (IL-10), are known to play important roles in the pathogenesis of juvenile idiopathic arthritis (JIA). This study aims to determine whether the IL-10 polymorphisms confer susceptibility to JIA.

Methods

A meta-analysis was performed on the associations between the IL-10-1082 G/A, -592 C/A, and -819 C/T polymorphisms and JIA. A total number of 7 studies involving 1,785 patients and 6,142 controls were considered in the meta-analysis.

Results

Meta-analysis of the IL-10-592 C/A and -819 C/T polymorphisms showed no association with JIA in the study participants, or in Caucasian or Middle Eastern participants. Meta-analysis of the IL-10-1082 A allele in all study participants, Caucasian and Middle Eastern, showed significant associations with RA (overall ORs were 1.17, 1.15, and 1.41, respectively). Meta-analysis of the AA versus GG genotype of the IL-10-1082 G/A polymorphism revealed significant associations with JIA (OR = 3.66, 95% CI = 1.44-9.29, P = 0.006) in participants from Middle Eastern countries. Additionally, meta-analysis of the GG versus AA+GA genotypes of the IL-10 -1082 G/A polymorphism revealed the GG genotype as the protective factor against JIA in the Middle Eastern subgroup (OR = 0.44, 95% CI = 0.20-0.94, P = 0,04). Moreover, meta-analysis of the IL-10 -1082 A allele in 4 studies on Hardy-Weinberg equilibrium showed a significant association with JIA (OR = 1.17, 95% CI = 1.07-1.28, P = 0.0009). No association was found between the IL-10 (-1082, -819, -592) ACC, ATA, and GCC haplotypes and JIA.

Conclusions

These results suggest that the IL-10-1082 G/A polymorphism confers susceptibility to JIA.

     

Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether the interleukin-10 (IL-10) polymorphisms confer susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the IL-10 −1082 G/A, −592 C/A, −892 C/T and IL-10.R polymorphisms and RA using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 16 studies (19 comparisons) involving 2647 RA patients and 3383 controls were considered in the meta-analysis. Meta-analysis of the IL-10 −1082 G/A polymorphism showed no association with RA in the study subjects, or in European or Asian subjects. However, meta-analysis of the −1082 G allele in 4 studies in Hardy–Weinberg equilibrium showed a significant association with RA (OR = 1.217, 95% CI = 1.027–1.442, P = 0.0236). In contrast, meta-analysis of the C allele, the CC genotype, and of the CC versus the AA genotype of the IL-10 −592 C/A polymorphism showed significant associations with RA. The overall ORs of the associations between the C allele and RA were 0.684 and 0.758 (95% CI = 0.494–0.946, P = 0.022; 95% CI = 0.475–1.210, P = 0.045) in all study subjects and Asians. Meta-analysis of the CC + CT versus TT genotype and of the CC versus TT genotype of the IL-10 −892 C/T polymorphism revealed significant associations with RA. The overall OR of the association between the C allele carrier and RA was 0.552 (95% CI = 0.375–0.812, P = 0.003). No association was found between the IL10.R2 alleles and RA. This meta-analysis suggests that the IL-10 −592 C/A polymorphism confers susceptibility to RA in Asians and that the IL-10 −1082 G/A and −892 C/T polymorphisms are associated with RA susceptibility. These findings suggest the IL-10 genes confer susceptibility to RA.     

Liver Fibrosis,Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients

Objective

To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism).

Patients and Methods

A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, −238 TNF-α and −592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count.

Results

Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of −238 TNF-α genotype GG was detected in patients with significant liver fibrosis.

Conclusions

In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a −238 TNF-α polymorphism in these patients.     

HLA polymorphisms are associated with Helicobacter pylori infected gastric cancer in a high risk population, China

Helicobacter pylori is one of the most common bacterial infections associated with an increased risk of gastric cancer, but its association with host factors, particularly polymorphisms of the immune response genes, such as human leukocyte antigen (HLA) genes, is still unclear. To investigate the role of HLA polymorphisms in the risk of gastric cancer among subjects with H. pylori infection, a case-control study involving 52 gastric cancer patients and 139 non-cancer controls was conducted in Linqu County, China, an area with a high incidence of gastric cancer. Polymorphisms of HLA class I and class II alleles were determined by PCR with sequence-specific primers (PCR-SSP). The information about H. pylori infection was obtained from previous records. Among 48 class I and 19 class II HLA alleles detected in this study, two alleles, CW*03 and DRB1*01, were found to be distributed significantly differently between patients and controls [odds ratio(OR)=1.95, 95% confidence interval (CI)=1.13–3.35, P=0.017 and OR=4.39, 95% CI=1.39–13.84, P=0.012, respectively). The OR of gastric cancer risk in individuals carrying CW*03/CW*03 or CW*03/CW*N was 2.06, 95% CI=1.05–4.02, P=0.035, while the OR was 3.49, 95% CI=1.0–12.4, P=0.04 for DRB1*01/DRB1*01 or DRB1*01/DRB1*N carriers. The analysis of the interaction between H. pylori infection and HLA risk genotypes of CW*03 or DRB1*01 revealed that the effect of CW*03 and DRB1*01 genotypes on gastric cancer risk was manifested stronger in H. pylori-positive individuals (OR=5.30, 95% CI=1.73–16.29, P=0.004 and OR=13.38, 95% CI=2.52–70.98, P=0.002, respectively) than in H. pylori-negative ones (OR=1.25, 95% CI=0.25–6.12, P=0.785 and OR=2.26, 95% CI=0.18–28.88, P=0.531, respectively). The combined effect of the two risk HLA genotypes on gastric cancer risk was also analysed. The result showed that the individuals carrying both the CW*03 and DRB1*01 alleles could only be found in cancer patients (5/52), and not in controls (0/139), further suggesting that CW*03 and DRB1*01 are risk alleles advancing the progression of tumorigenesis. These observations demonstrate that host HLA genotypes may play an important role in the risk of gastric cancer, especially among persons with H. pylori infection.     

CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis

Several reports demonstrate association between variants of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune diseases. CTLA-4 may generate autoimmunity by immune dysregulation, making CTLA-4 an attractive candidate gene for systemic lupus erythematosus (SLE) susceptibility. Previous CTLA-4 association studies with SLE, however, have produced inconsistent results. We have performed a meta-analysis to better assess the purported associations. A total of 14 independent studies (to July 2004) testing association between one or more CTLA-4 polymorphisms and SLE were used in this analysis. We have compared allele and genotype frequencies at four polymorphic sites found in exon-1 (at +49), the promoter region (at –318 and –1722), and the 3 untranslated region (3UTR) (dinucleotide repeat). We have evaluated both fixed and random effect models, depending on the presence of between-study heterogeneity. The data demonstrate that the exon-1 +49 polymorphism is significantly associated with SLE susceptibility. The overall risk, measured by odds ratio (OR), for exon-1 +49 GG genotype is 1.287 [95% confidence interval (CI)=1.031–1.562, P=0.011]. Stratification by ethnicity indicates the exon–1 +49 GG genotype is associated with SLE, at least in Asians (OR=1.293, 95% CI=1.031–1.620, P=0.026). European-derived populations have an effect of similar magnitude (OR=1.268, 95% CI=0.860–1.870, P=0.230), though not significant. Similar trends are found in allele-specific risk estimates and disease association. The OR for the exon-1 +49 risk allele (G) in Asians is 1.246 (95% CI=1.057–1.469, P=0.009), while Europeans have no evidence of allelic association (OR=0.978, 95% CI=0.833–1.148, P=0.780). In conclusion, this meta-analysis supports the CTLA-4 exon-1 +49 (A/G) polymorphism influencing the risk for developing SLE, especially in Asians.     

Alleles and haplotypes of the interleukin 10 gene polymorphisms are associated with risk of developing acute coronary syndrome in Mexican patients

Inflammation plays an important role in the pathogenesis of atherosclerosis and acute coronary syndromes (ACS). Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that mediates the inflammatory process. The objective of the present study was to evaluate the role of IL-10 gene polymorphisms as susceptibility markers for ACS in Mexican patients. IL-10 promoter polymorphisms (positions -1082, -819, and -592) were analyzed by 5' exonuclease TaqMan genotyping assays in 389 ACS patients and 302 healthy controls. ACS patients showed increased frequencies of IL-10-592 C allele and CC genotype when compared to healthy controls (pC=0.0006, OR=1.48 and pC=0.022, OR=1.56, respectively), whereas the frequencies of the A allele and AA genotype were decreased in patients (pC=0.0006, OR=0.68 and pC=0.006, OR=0.57, respectively). When the distribution of IL-10-592 genotypes was analyzed separately in women and men (patients and healthy controls), a different distribution of alleles and genotypes was observed only in the group of men. In this case, increased frequency of C allele (pC=0.004, OR=1.46) and decreased frequencies of A allele (pC=0.004, OR=0.68) and AA genotype (pC=0.023, OR=0.56) were observed in the group of patients when compared to healthy controls. Multiple logistic analyses by gender showed that male individuals with IL-10-592CC+AC genotypes had 3.54-fold increased risk of developing ACS than individuals with AA genotype (p<0.001). The analysis of linkage disequilibrium showed one (ACC) increased haplotype in patients as compared to healthy controls. The results suggest that IL-10 gene polymorphisms could be involved in the risk of developing ACS in the Mexican population.     

IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection

BACKGROUND: In hepatitis C virus infection an inappropriate ratio of pro-inflammatory and anti-inflammatory cytokines may either determine different outcomes of the infection or affect the benefit of antiviral treatment. Given that polymorphisms in regulatory regions of cytokine genes influence cytokine production, we determined frequency of polymorphisms of IL-10, IFNgamma, and TNFalpha genes in HCV-infected patients and healthy controls, and investigated their association with either ongoing or cleared HCV infection, or with response to treatment. METHODS: Genomic DNA from 270 patients and 145 controls sharing the same ethnic background was studied by polymerase chain reaction, restriction enzyme digestion, direct sequencing, and microsatellite analysis. RESULTS: The IL-10 ATA haplotype was more frequent in patients with spontaneous HCV RNA clearance (36.0%) than in patients with persistent infection (23%) (p=0.009, p corrected = 0.036). Neither TNF -308 and -238 polymorphisms nor IFNgamma alleles variability were associated with different HCV outcome. However, the combination of ATA homozygous state and IFNgamma 119 allele was more frequent in patients with spontaneous HCV clearance than in patients with ongoing disease (p=0.012; p corrected = 0.048). We could not confirm the reported effect of genetic influence on the response to treatment. CONCLUSIONS: Our findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining a spontaneous favourable outcome of HCV infection.     

Association between CXCL10 and DPP4 Gene Polymorphisms and a Complementary Role for Unfavorable IL28B Genotype in Prediction of Treatment Response in Thai Patients with Chronic Hepatitis C Virus Infection

Pretreatment serum levels of interferon-γ-inducible protein-10 (IP-10, CXCL10) and dipeptidyl peptidase-4 (DPP IV) predict treatment response in chronic hepatitis C (CHC). The association between functional genetic polymorphisms of CXCL10 and DPP4 and treatment outcome has not previously been studied. This study aimed to determine the association between genetic variations of CXCL10 and DPP4 and the outcome of treatment with pegylated interferon-α (PEG-IFN-α) based therapy in Thai patients with CHC. 602 Thai patients with CHC treated using a PEG-IFN-α based regimen were genotyped for CXCL10 rs56061981 G>A and IL28B rs12979860 C>T. In addition, in patients infected with CHC genotype 1, DPP4 (rs13015258 A>C, rs17848916 T>C, rs41268649 G>A, and rs 17574 T>C) were genotyped. Correlations between single nucleotide polymorphisms, genotype, and treatment response were analyzed. The rate of sustained virologic response (SVR) was higher for the CC genotype of IL28B rs12979860 polymorphisms than for non-CC in both genotype 1 (60.6% vs. 29.4%, P < 0.001) and non-genotype 1 (69.4% vs. 49.1%, P < 0.05) CHC. SVR was not associated with the CXCL10 gene variant in all viral genotypes or DPP4 gene polymorphisms in viral genotype1. Multivariate analysis revealed IL28B rs12979860 CC genotype (OR = 3.12; 95% CI, 1.72–5.67; P < 0.001), hepatitis C virus RNA < 400,000 IU/ml (OR = 2.21; 95% CI, 1.22–3.99, P < 0.05), age < 45 years (OR = 2.03; 95% CI, 1.11–3.68; P < 0.05), and liver fibrosis stage 0–1 (OR = 1.64; 95% CI, 1.01–2.65, P < 0.05) were independent factors for SVR. Unfavorable IL28B rs12979860 CT or TT genotypes with the CXCL10 rs56061981 non-GG genotype were associated with a higher SVR than GG genotype (66.7% vs. 33.0%, P = 0.004) in viral genotype 1. In Thai CHC genotype 1 infected patients with an unfavorable IL28B rs12979860 CT/TT genotype, the complementary CXCL10 polymorphism strongly enhances prediction of treatment response.     

Relationship of Epstein-Barr Virus and Interleukin 10 Promoter Polymorphisms with the Risk and Clinical Outcome of Childhood Burkitt Lymphoma

Epstein-Barr virus (EBV) is an important environmental factor associated to the development of Burkitt lymphoma (BL) in endemic and intermediate risk regions. However, little is known about the contribution of genetic constitution to the development and clinical response of the disease. The aim of this work was to investigate the role of EBV and Interleukin 10 (IL10) single nucleotide polymorphisms (−1082A/G, −819C/T, −592C/A) and microsatellites (IL10.R and IL10.G) in susceptibility and clinical outcome in pediatric BL patients, in a region with intermediate EBV association frequency. The frequencies of IL10 promoter Single nucleotide polymorphisms −1082A/G, −819C/T, −592C/A, and IL10.R and IL10.G microsatellites were compared in 62 pediatric patients and 216 healthy donors. IL10 −1082GG and GCC/GCC genotypes were more frequent in patients than in controls, and associated to a higher risk of BL development (GG genotype OR 2.62, 95% CI, 1.25–5.51; P = 0.008; Pc = 0.024). EBV was detected in tumor samples by EBER-ISH in 54.1% of cases. EBV+ patients exhibited a better event free survival (EFS) (P = 0.019) than EBV− patients. Carriers of IL10 R3-GCC had worse EFS (P = 0.028). Our results suggest a risk effect and an independent prognostic value of IL10 polymorphisms and EBV in childhood BL patients.     

IL-10 promoter single nucleotide polymorphisms are significantly associated with resistance to leprosy

The minor haplotype −3575A/-2849G/-2763C in IL-10 promoter has been defined as a marker of disease resistance to leprosy and its severity in Brazilian population. Our investigation of six single-nucleotide polymorphisms (SNPs) in IL-10 promoter in 282 Indian leprosy patients and 266 healthy controls by direct PCR sequencing, however, showed that the extended haplotype: −3575T/-2849G/-2763C/-1082A/-819C/-592C was associated with resistance to leprosy per se and to the development of severe form of leprosy, using either a binomial (controls vs cases, P=0.01, OR=0.58, CI=0.37–0.89) or ordinal (controls vs paucibacillary vs multibacillary, P=0.004) model. Whereas, IL-10 haplotype −3575T/-2849G/-2763C/-1082A/-819T/-592A was associated with the risk of development of severe form of leprosy (P=0.0002) in contrast to the minor risk haplotype −3575T/-2849A/-2763C in the Brazilian population. The role of IL-10 promoter SNPs in Brazilian and Indian population strongly suggests the involvement of IL-10 locus in the outcome of leprosy.     

Polymorphisms of CYP1B1 and COMT in Breast and Endometrial Cancer

CYP1B1 and COMT code for the key enzymes of catecholestrogen biosynthesis and metabolism, and their polymorphisms determine the variation of enzyme activities. RFLP analysis was used to study the allele and genotype frequency distributions of CYP1B1 polymorphisms Arg48Gly, Ala119Ser, and Val432Leu, and COMT polymorphism Val158Met among 210 breast cancer patients, 138 endometrial cancer patients, and 152 healthy women. The COMT polymorphism showed no significant association with breast or endometrial cancer. For the first time, such association was observed for the CYP1B1 polymorphisms. CYP1B1 allele C (Arg48), which codes for the enzyme more active in estradiol 4-hydroxylation, was associated with higher risk of breast (OR = 3.22, CI 2.34–4.43, P = 0.000) and endometrial (OR = 2.43, CI 1.72–3.44, P = 0.000) cancer. Similar data were obtained for CYP1B1 allele G (Ala119): OR = 2.18, CI 1.58–3.01, P = 0.000 in breast cancer and OR = 2.52, CI 1.78–3.56, P = 0.000 in endometrial cancer. Risk of endometrial but not breast cancer was significantly higher in carriers of CYP1B1 genotype Val432/Val. This was explained by stronger estrogen dependence and, consequently, higher estrogen responsiveness of the endometrium as compared with the mammary gland.     

Influence of Hepatitis C Virus and IL28B Genotypes on Liver Stiffness

Objective

Liver fibrosis has been associated with hepatitis C virus (HCV) genotype and genetic variation near the interleukin 28B (IL28B) gene, but the relative contribution is unknown. We aimed to investigate the relation between HCV genotypes, IL28B and development of liver stiffness.

Patients and Methods

This cross-sectional study consists of 369 patients with chronic hepatitis C (CHC). Liver stiffness was evaluated using transient elastograhy (TE). Factors associated with development of liver fibrosis were identified by logistic regression analysis.

Results

We identified 369 patients with CHC. 235 were male, 297 Caucasians, and 223 had been exposed to HCV through intravenous drug use. The overall median TE value was 7.4 kPa (interquartile range (IQR) 5.7–12.1). HCV replication was enhanced in patients carrying the IL28B CC genotype compared to TT and TC (5.8 vs. 5.4 log₁₀ IU/mL, p = 0.03). Patients infected with HCV genotype 3 had significantly higher TE values (8.2 kPa; IQR, 5.9–14.5) compared to genotype 1 (6.9 kPa; IQR, 5.4–10.9) and 2 (6.7 kPa; IQR, 4.9–8.8) (p = 0.02). Within patients with genotype 3, IL28B CC genotype had the highest TE values (p = 0.04). However, in multivariate logistic regression, using various cut-off values for fibrosis and cirrhosis, only increasing age (odds ratio (OR) 1.09 (95% confidence interval (CI), 1.05–1.14 per year increment)), ALT (OR 1.01 (95% CI, 1.002–1.011), per unit increment) and HCV genotype 3 compared to genotype 1 (OR 2.40 (95% CI, 1.19–4.81), were consistently associated with cirrhosis (TE>17.1 kPa).

Conclusions

Age, ALT and infection with HCV genotype 3 were associated with cirrhosis assessed by TE. However, IL28B genotype was not an independent predictor of fibrosis in our study.     

Diverse H. pylori strains,IL-10 promoter polymorphisms with high morbidity of gastric cancer in Hexi area of Gansu Province,China

In Hexi area of Gansu Province, people have a higher susceptibility of gastric cancer than people in the rest area of China. There is substantial geographic variation in the incidence of gastric cancer. In this article, the present author explored the roles of H. pylori infection and IL-10 promoter polymorphisms in development of gastric cancer in this area. A total of 304 participants were admitted to our study, and they were divided into two groups: control group and case group. Blood samples from all subjects were collected for gene extraction using DNA extraction kits. IL-10 polymorphisms were determined by SNaPshot Multiplex. To test H. pylori infection and its typing H. pylori antibody Immunoblotting Kits were used. This research suggested that environmental factor played an important role in the pathogenesis of gastric carcinoma in the area, H. pylori infection increased the risk of gastric cancer (OR = 2.612, 95% CI 1.636-4.170) and subject with H. pylori I-type positive was at significantly higher risk for progression to gastric cancer (OR = 4.712, 95% CI 2.656-8.537). For subjects with the ATA/GCC or GCC/GCC haplotype of the IL-10-1082/-819/-592 polymorphism relative to the ATA/ATA haplotype group, the risk of gastric cancer development was significantly increased. It has been demonstrated that the presence of IL-10-819 C alleles and IL-10-592 C alleles was associated with an increased risk for gastric cancer development in H. pylori-infected patients and IL-10 promoter polymorphisms and H. pylori have a synergistic effect on gastric cancer in Hexi population.     

Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: a meta-analysis

A number of studies have tested the association of the complement receptor 1 (CR1) and Interleukin-10 (IL10) polymorphisms with systemic lupus erythematosus (SLE), but reported conflicting results. The aim of the study is to explore whether the CR1 and IL10 genes are associated with SLE susceptibility. We surveyed studies on the CR1 and IL10 polymorphisms and SLE using comprehensive Medline search and review of the references. A meta-analysis was conducted in a fixed effects model or random effects model based on between-study heterogeneity. Eighteen comparisons from 13 studies were included in the CR1 meta-analysis and a total of 16 separate comparisons were used for the IL10 meta-analysis. The CR1 meta-analysis showed no significant association of the CR1 functional polymorphisms with SLE. In contrast, the S structural variant of the CR1 showed a significant association (OR=1.544, 95% CI, 1.217–1.959, P<0.001). Stratification by ethnicity indicated that the CR1 S variant was associated with SLE in Caucasians (OR=1.667, 95% CI, 1.193–2.357, P=0.003). The IL10 meta-analysis showed a significant association between SLE and the G11 allele of IL10.G (OR=1.279, 95% CI; 1.027–1.593, P=0.028) in whole populations, and IL10 promoter −1082G allele was associated with SLE in Asians (OR=1.358, 95% CI; 1.015–1.816, P=0.039). In conclusion, the CR1 meta-analysis revealed the association of the S structural variant of the CR1 with SLE and the IL10 meta-analysis showed the association of IL10.G11 allele and SLE in whole populations and the association between promoter -A1082G polymorphism and SLE in Asians.     

IL-10(-1082A/G)基因多态性和乳腺癌的相关性：Meta分析

目的:系统评价IL-10(interleukin-10)-1082A/G基因位点多态性和乳腺癌的相关性。方法:PUBMED和EMBASE文献数据库收集关于IL-10 rs1800896(-1082A/G)基因多态性和乳腺癌危险性的相关文献资料,提取原始数据。采用STATA软件11.0进行统计分析,以OR值和95%CI作为IL-10基因多态性和乳腺癌发病风险的相关性检测指标,并根据对照来源进行分层分析。Q检验和I2统计检测研究的异质性,并进行敏感性分析,Begg's漏斗图和Egger's检验评价发表偏倚。结果:12篇病例对照研究文献纳入本研究,包含5038例乳腺癌病例,5437例对照。GG和AA等位基因相比,OR值为1.134,95%可信区间为1.004-1.280,P0.05。GG和AA+AG相比,OR值为1.131,95%可信区间为1.018-1.257,P0.05,提示存在相关性。在分层分析中,合并以社区来源人群为对照的研究,OR值为1.144,95%可信区间为1.028-1.273,P0.05。结论:IL-10的-1082A/G的GG等位基因和A等位基因相比,可能增加乳腺癌的发生风险。     

HLA-DQB1*03 Confers Susceptibility to Chronic Hepatitis C in Japanese: A Genome-Wide Association Study

Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10^-5). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (P _combined = 3.59 × 10⁻¹⁶, odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.     

Interleukin-8 and -10 gene polymorphisms in irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal diagnoses seen by primary care providers and gastroenterologists. Proinflammatory cytokines interleukin (IL)-6 and IL-8 have been found increased in IBS patients. Cytokine gene single nucleotide polymorphisms (SNPs) of IL-8 and IL-10 have not been assessed in Mexican IBS patients. DNA was extracted from peripheral blood leucocytes of 45 IBS unrelated patients and 137 controls. Allele, genotype, and haplotype frequencies were determined by analyzing SNPs of IL-8 and IL-10 genes. IL-8 + 396 G allele (P = 0.02), IL-8 + 396(G/G) and IL-8 + 781(C/T) genotypes (P < 0.001), IL-10 - 1082A allele and IL-10 - 1082(A/A) genotype (P < 0.001) were significantly increased in the IBS group. Haplotypes IL-8 ATCC (P = 0.03) and IL-10 ACC (P < 0.001) were associated with susceptibility to develop IBS. An association of certain polymorphisms of IL-8 and IL-10 in IBS patients compared to controls was demonstrated, suggesting a role of these cytokine SNPs in the pathophysiology of IBS.     

Role of an intronic polymorphism in the <Emphasis Type="Italic">PDCD1</Emphasis> gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies

Recently, a polymorphism in intron 4 (G/A) of the programmed cell death 1 (PDCD1) gene was shown to be associated with systemic lupus erythematosus (SLE) risk in familial and sporadic patients of European, European American, and Mexican origin. In this investigation, we examined the role of this polymorphism in 311 SLE patients (276 European Americans and 35 African Americans) and 390 age-matched healthy controls (359 European Americans and 31 African Americans). The frequency of the A allele was significantly higher in European American controls than in African American controls (0.107 vs. 0.048; P=0.046). There was no significant difference in the frequency of the A allele between SLE cases and controls in either the European American (0.107 vs. 0.129; P=0.84) or African American (0.048 vs. 0.100; P=0.25) cohort. However, after adjustment for the status of the antiphospholipid antibodies (APA) in the logistic regression analysis, the risk for SLE associated with the PDCD1 polymorphism was statistically significant. The APA-adjusted odds ratio (OR) between A allele carriers (AA + AG genotypes) versus the GG genotype showed a modest association with SLE risk in European Americans (OR=1.52, 95% CI: 1.02–2.27; P=0.039), African Americans (OR=2.89, 95% CI: 0.61–13.76; P=0.183), and the ethnicity-combined sample (OR=1.59, 95% CI: 1.08–2.34; P=0.019). Furthermore, we observed that the A allele carriers were protected against the occurrence of APA in both controls (OR=0.399, 95% CI: 0.19–0.82; P=0.0098) and SLE cases (OR=0.566, 95% CI: 0.32–1.01; P=0.054). Our data indicate polymorphism in intron 4 of the PDCD1 gene affects the occurrence of APA and may slightly modify the risk of sporadic SLE.