Association between interleukin-10 gene promoter polymorphisms and susceptibility to liver cirrhosis

We conducted a case-control study to investigate the association between three common SNPs in IL-10 gene (rs1800896, rs1800871 and rs1800872) and the development of liver cirrhosis in a Chinese population. Between January 2013 and December 2014, a total of 318 patients with liver cirrhosis and 318 health control subjects were enrolled into our study. The IL-10 rs1800896, rs1800871 and rs1800872 polymorphisms were analyzed using polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By multivariate logistic regression analysis, we found that individuals with the AA genotype and GA+AA genotype of IL-10 rs1800896 were more likely to have an increased risk of liver cirrhosis when compared with the GG genotype, and the ORs (95% CI) for the AA genotype and GA+AA genotype were 2.04 (1.20-3.50) and 1.41 (1.02-1.96), respectively. We found that the GA+AA genotype of IL-10 rs1800896 had higher risk of liver cirrhosis in individuals with chronic hepatitis B when compared with the GG genotype (OR = 1.95, 95% CI = 1.01-3.59). In conclusion, we found that IL-10 rs1800896 polymorphism was correlated with an increased risk of liver cirrhosis, especially in individuals with chronic hepatitis B.     

白细胞介素10启动子基因多态性与强直性脊柱炎的易感性

背景：在强直性脊柱炎患者中,基因多态性很可能影响细胞因子的分泌模式。 目的：在中国胶东半岛地区汉族人强直性脊柱炎患者中,探讨白细胞介素10启动子基因的单核苷酸多态性和单体型与强直性脊柱炎易感性的相关性。 方法：用酶联免疫吸附测定法测定血清中白细胞介素10的水平,用聚合酶链反应和限制性片段长度多态性方法对白细胞介素10基因启动子中的-1082A/G、-819C/T和-592C/A位点的单核苷酸多态性进行分析。 结果与结论：收集了110例强直性脊柱炎患者和120例同种族的健康人,强直性脊柱炎患者组血清中白细胞介素10水平明显高于健康对照组(Z=10.9,P < 0.001),单核苷酸多态性分析显示：在强直性脊柱炎患者组和健康对照组之间-592A/C位点基因型分布和等位基因频率没有明显差异,该研究中没有发现-1082GG基因型。强直性脊柱炎患者-1082G等位基因频率较健康对照组增加(P=0.047),通过logistic回归分析,强直性脊柱炎患者-1082AG基因型的比值比为1.993(95%CI：1.046-3.800,P=0.034 ),而-819CC基因型的比值比为3.125(95%CI：1.246-7.836,P=0.015),此外,单体型分析显示与ATA 基因型相比,GCC基因型显著增加了患强直性脊柱炎的风险(OR=2.19,95%CI：1.13- 4.26,P= 0.020)。结果表明白细胞介素10的基因单体型与中国胶东半岛地区汉族人强直性脊柱炎的易感因素相关。     

Genetic association of Fc receptor-like 3 polymorphisms with susceptibility to primary biliary cirrhosis: ethnic comparative study in Japanese and Italian patients

A functional variant in the Fc receptor-like 3 (FCRL3) gene is associated with the susceptibility to several autoimmune diseases. In this study, we examined whether the FCRL3 is associated with susceptibility to primary biliary cirrhosis (PBC) by comparing the two different ethnic groups, Japanese and Italians. We enrolled 232 patients with PBC and 230 controls in Japanese, and 216 PBC and 180 controls in Italians. Minor allele frequency of fcrl3_3 (-169 T>C) in the patients with PBC and controls was 0.20 and 0.09 in Japanese and 0.24 and 0.21 in Italians, respectively. We found a significant association of fcrl3_3 with PBC only in Japanese (P = 9.64 × 10(-7) ). These findings support the presence of common FCRL3-related pathological pathways in several autoimmune diseases, especially in Asians.     

Association analysis of toll-like receptor 4 polymorphisms in Japanese primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts that often result in liver failure. Toll-like receptor (TLR) 4 recognizes lipopolysaccharides of Gram-negative bacteria. Infectious agents have been suspected to play a crucial role in PBC pathogenesis since TLR4 expression was found in bile duct epithelial cells and periportal hepatocytes in liver tissues of PBC. To assess the potential contribution of TLR4 SNPs to the development of this disease, we genotyped five SNPs in TLR4 in 261 PBC patients and 359 controls using a TaqMan assay. No significant positive associations with either PBC susceptibility or progression were uncovered. These results indicate that TLR4 polymorphisms do not play a prominent role in the development of PBC in Japanese patients.     

Single nucleotide polymorphisms of the mannose-binding lectin are associated with susceptibility to primary biliary cirrhosis.

Although the immunopathogenesis of primary biliary cirrhosis (PBC) remains unknown, familial clustering of patients with PBC suggests an important role for genetic factors. In addition, recent data support the thesis that the mucosal immune response against intraluminal pathogens may be involved with the onset of PBC. Mannose-binding lectin (MBL) is a key factor in innate mucosal defenses and has several key single nucleotide polymorphisms (SNPs). To study whether MBL gene SNPs are associated with susceptibility to PBC, we studied 65 patients with PBC and 218 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequence specific priming-polymerase chain reaction (SSP-PCR) to examine four polymorphic loci: two (H/L and X/Y) within the promoter region and the other two (P/Q and A/B) within exon-1. We also analyzed serum MBL concentrations. Interestingly, the prevalence of haplotype HYPA, leading to hyper-production of MBL, as well as HYPA/HYPA genotype were significantly increased in PBC compared to controls (0.53 vs. 0.44, P=0.031; 33.9%vs. 17.0%, P=0.003, respectively). Furthermore, individuals homozygous for HYPA had a significantly increased risk for PBC (odds ratio (OR)=2.51, 95% confidence interval (CI)=1.34-4.66). Our results demonstrate that the MBL genotype can be significantly associated with increased risk for PBC, and further, that increased production of MBL plays a critical role in immunopathogenesis.     

Association of single nucleotide polymorphisms of DNA repair gene and susceptibility to pancreatic cancer

We conducted a case-control study to assess the XRCC4 genes polymorphism and development of pancreatic cancer. A case-control study including 248 cases and 496 controls was conducted in a Chinese population. Genotypes of XRCC4 rs2075685, rs10040363, rs963248 and rs1805377 were determined using Polymerase Chain Reaction combined with a restriction fragment length polymorphism (PCR-RFLP) assay (Applied Biosystems, Foster City, CA, USA). Pancreatic cancer cases were more likely to have a history of diabetes, a higher BMI, family history of cancer and a habit of alcohol drinking when compared with control. Conditional logistic regression analysis showed that individuals carrying TT genotype of XRCC4 rs2075685 was associated with increased risk of pancreatic cancer when compared with GG genotype, and the OR (95% CI) was 1.62 (1.04-2.52). Individuals with GT+TT genotype of XRCC4 rs2075685 were significantly associated with increased risk of pancreatic cancer in those with ever tobacco smoking habit, and the OR (95% CI) was 1.77 (1.07-2.98). In conclusion, our results suggest that XRCC4 rs2075685 polymorphism plays an important role in the risk of pancreatic cancer in a Chinese population, especially in tobacco smokers.     

E-钙黏蛋白基因多态性与上皮性卵巢癌发病风险关系的研究

目的 探讨E-钙黏蛋白基因(E-cadherin gene,CDH1)单核苷酸多态性(single nucleotide polymorphism,SN-P)与上皮性卵巢癌发病风险的关系.方法 采用聚合酶链反应-限制性片段长度多态性方法分析207例上皮性卵巢癌患者和256名健康对照的CDH1基因启动子区-160C/A、-347G/GA和3′UTR+54C/T3个SNP位点基因型频率分布;采用免疫组织化学方法检测携带3′UTR+54C/T SNP位点不同基因型的卵巢癌患者癌组织CDH1基因的表达情况.结果 CDH1基因-160C/A和-347G/GA 2个SNP位点的基因型和等位基因频率分布在患者组与健康对照组间差异无统计学意义(P＞0.05).3′UTR+54C/T SNP 位点的基因型与等位基因频率分布在患者与健康对照组间差异有统计学意义,患者组中CC基因型和C等位基因频率(65.2%,89.1%)明显高于对照组(52.7%,64.5%)(P＜0.01);CC基因型可能显著增加上皮性卵巢癌的发病风险(比值比为1.85,95%可信区间为1.27～2.69);且免疫组化研究表明CC基因型患者癌组织CDH1基因的表达明显低于T等位基因(CT+TT)携带者(P＜0.05).采用2LD软件分析显示-160C/A、-347G/GA两位点间存在连锁不平衡(D′=0.999 582),-160A/-347GA单倍型仅在患者组中检测到(5.1%),-160C/-347GA单倍型可能明显降低卵巢癌的发病风险(比值比为0.66,95%可信区间为0.45～0.96).结论 CDH1基因-160C/A、-347G/GA SNP可能与上皮性卵巢癌的发病风险无关,但两位点的单倍型可能改变上皮性卵巢癌的发病风险.3′UTR+54C/T多态CC基因型可能成为上皮性卵巢癌发病的潜在危险因素.     

Proximal interleukin-10 gene polymorphisms in Italian patients with systemic sclerosis

Interleukin-10 (IL-10) can favour the development of fibrosis by promoting a relative shift towards T helper 2 responses. Three single base pair substitutions in the 5' flanking region of the IL-10 gene (G/A -1082, C/T -819 and C/A -592) influence the amount of IL-10 secreted in cell cultures: the GCC haplotype is associated with an increased production, while the ACC and the ATA haplotypes are associated with intermediate and decreased production. Accordingly, three phenotypes have been individuated: high producers (GCC+/GCC+), medium producers (GCC+/GCC-) and low producers (GCC-/GCC-). We hypothesised that IL-10 haplotypes and genotypes are differently expressed in patients with systemic sclerosis (SSc) with the limited cutaneous SSc (lcSSc) subset or the diffuse cutaneous SSc (dcSSc) subset. One hundred and sixty-one unrelated Italian patients with SSc and 94 controls have been included. Their DNA was extracted and stored before being analysed by polymerase chain reaction with sequence-specific primers. The GCC haplotype is overrepresented in patients with SSc; subjects with dcSSc were the primary contributors to these results (dcSSc: 52.2% vs controls: 37.2%; chi2= 8.519, 2 d.f., corrected P= 0.04). In Scl70-positive patients, the GCC haplotype increased the likelihood of presenting the dcSSc subset [chi2= 12.56, P < 0.0005; odds ratio (OR) = 3.89, 95% confidence interval (CI(95)) = 1.69-9.08]; these results were confirmed at the phenotypic level (chi2= 11.67, 2 d.f., P= 0.003). In Scl70-positive patients, the high-producing phenotype was associated with poor survival, independently from disease subset and gender (hazard ratio = 9.9, CI(95)= 1.6-61.27, P < 0.05). The IL-10 haplotype and genotype associated with high IL-10 production may alter the susceptibility to SSc and/or its expression, increasing the prognostic value of other well-known markers of disease severity.     

Association of interleukin-15 single nucleotide polymorphisms with resistance to brucellosis among Iranian patients

Interleukin (IL)-15, a Th1-related cytokine, triggers inflammatory cells' recruitment and increases the expression of interferon gamma (IFN-γ), which is an important cytokine in the immunity against brucellosis. Different single-nucleotide polymorphisms (SNPs) have been observed in the IL-15 gene, so this study aimed to investigate the probable association between these SNPs and susceptibility to brucellosis among Iranian patients. A total of 190 patients with brucellosis and 83 healthy milk farmers who consumed contaminated raw milk and dairy products from animals involved with brucellosis were included in this study. All the patients and the controls were genotyped for four IL-15 polymorphisms at positions 267, 367, 13687 and 14035 using polymerase chain reaction-restriction fragment length polymorphisms. The 267C and 13687A alleles, haplotypes CGCT and CAAA and the 267CC and 13687AA genotypes were significantly more frequent in the controls than in the patients (P = 0.014, 0.03, 0.006, 0.024, 0.026 and 0.01, respectively), so the variation in the IL-15 gene may be one of the factors affecting the resistance to brucellosis. In contrast, the frequency of haplotypes CGCA and TACT was significantly higher in patients compared with controls (P = 0.015 and 0.007, respectively), and interestingly the last one was observed only in the patients; therefore, it may serve as a predictive factor for brucellosis. In conclusion, it could be suggested that IL-15 genetic variants can affect resistance or susceptibility to human brucellosis among Iranian patients.     

Association of single nucleotide polymorphisms in the eosinophil peroxidase gene with Japanese cedar pollinosis

BACKGROUND: Japanese cedar pollinosis is the most common form of hay fever in spring in Japan. We have previously demonstrated that single nucleotide polymorphism Pro358Leu of exon 7 in the eosinophil peroxidase (EPO) gene is associated with cedar pollinosis, although the association has not been confirmed by analysis of the whole gene in a different population. METHODS: We sequenced all exons of the EPO gene in 60 children with pollinosis and their parents using the PCR-restriction fragment length polymorphism method. RESULTS: We found 8 polymorphisms, Ile40Met, Gln122His, Arg202Arg (A660G), Asn303Asn (C909T), Arg326Pro, Arg326His, Pro358Leu, and Asn572Ty, in the EPO gene. As a result of the transmission disequilibrium test, we recognized significant transmissions of 202Arg (660G) in exon 6 in addition to 358Leu of exon 7 in the EPO gene of affected children. CONCLUSIONS: Our results might indicate that polymorphisms of the EPO gene are associated with Japanese cedar pollinosis.     

Interleukin-18基因启动子区单核苷酸多态性与肝细胞癌遗传易感性关系的研究

目的探讨白细胞介素18(IL-18)基因启动子区-607C/A(rs1946518)和-137G/C(rs187238)单核苷酸多态性(SNP)与肝细胞癌(肝癌)遗传易感性的关系。方法应用序列特异性引物-聚合酶链反应(PCR-SSP)技术,检测228例肝癌患者和300例健康对照者IL-18基因启动子-607C/A(rs1946518)、-137G/C(rs187238)单核苷酸多态性位点基因型,分析肝癌患者和对照组基因型频率和等位基因频率分布。结果肝癌组SNP位点rs187238 G等位基因的频率明显高于对照组(OR=1.1891,95%CI=1.0106-1.5633,P=0.026)。携带rs187238 GG基因型的肝癌患者较多(OR=1.5168,95%CI=1.1490-1.8322,P=0.010)。分层分析发现,rs1946518位点上AA基因型与肝癌发病的关联在饮酒的肝癌患者中更加显著(P=0.024),而且rs187238位点上GC/CC基因型与肝癌发病的关联在出现肝癌复发的患者中更加显著(P=0.005)。结论 IL-18基因启动子区-137G/C(rs187238)GG基因型与肝癌遗传易感性有关联。而rs1946518位点AA基因型和rs187238位点GC/CC基因型分别与肝癌患者饮酒和肝癌复发有关联。     

骨保护素基因单核苷酸多态性与类风湿关节炎发病的相关性研究

 目的：探讨骨保护素（OPG）基因163A/G及245T/G单核苷酸多态性（SNPs）与我国汉族人群类风湿关节炎（RA）发病的相关性。方法：采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术检测我国南方汉族正常人群及RA患者的OPG 163A/G 和245T/G 2个SNP位点;进行Hardy-Weinberg平衡检验;计算基因型和等位基因频率,及这2个位点的连锁关系,并分析这2个SNP位点与RA的关系。结果：所研究基因分布符合Hardy-Weinberg平衡,163A/G 位点基因型AA、AG、GG分布频率在2组比较有显著差异（P<0.05）;等位基因A、G分布比较在2组有显著差异（P<0.05）,携带163GG基因型者发生RA的危险性是非携带者的1.219倍（OR=1219, 95％CI：1066~2.339, P<0.05)。但245T/G位点各基因型及等位基因频率在2组中均未见差异（P>005）。结论：OPG 基因 163A/G SNP可能与我国汉族人群RA发病相关,携带G等位基因可能是发病的危险因素。     

IL-10、MD-1基因单核苷酸多态性与哮喘易感性的相关性研究

目的:分析IL-10基因 rs1800896、rs3024492位点和髓样分化蛋白1(Myeloid differentiation 1,MD-1)基因rs7740529、rs2233128位点单核苷酸多态性(Single nucleotide polymorphism,SNP)与哮喘遗传易感性的相关性以及过敏性鼻炎(Allergic rhinitis,AR)对哮喘遗传易感性的影响.方法:应用Sequenom MassARRAY○ R SNP分型技术对141例哮喘患者和145例正常对照的四个SNP位点(rs1800896、rs3024492、rs7740529、rs2233128)进行基因分型,再将哮喘患者中确定有过敏性鼻炎和无过敏性鼻炎者分别与正常对照组比较.χ2检验统计分析病例组和对照组的基因型频率;采用非条件Logistic回归校正年龄、性别影响,计算比数比(OR)和95%可信区间(CI),以此评价各位点多态性与哮喘遗传易感性的相关性以及过敏性鼻炎对哮喘易感性的影响.结果:(1)IL-10 rs1800896多态性位点GG、GA、AA三种基因型分布频率在哮喘组、哮喘和过敏性鼻炎共患组、哮喘而无鼻炎组的分布频率和对照组相比,差异均有统计学意义(P＜0.001),有无过敏性鼻炎对其影响不明显.相较GG或AA基因型,携带基因型GA的个体,哮喘的患病风险明显降低(OR=0.033,95%CI:0.017～0.065).(2)MD-1 rs7740529位点CC、CT、TT三种基因型分布频率在哮喘患者组、哮喘和过敏性鼻炎共患组、哮喘而无鼻炎组的分布频率和对照组相比,差异也均有统计学意义(P≤0.005),有无过敏性鼻炎对其影响不明显.相比较CC或TT基因型,携带基因型CT的个体,哮喘的患病风险明显降低(OR=0.369,95%CI:0.225～0.606).(3)IL-10 rs3024492位点TA、AA基因型和MD-1 rs2233128位点AG、GG基因型在哮喘人群中的分布频率与对照组相比无统计学意义(P＞0.05).结论:IL-10 rs1800896与MD-1 rs7740529位点多态性与哮喘的遗传易感性相关,其杂合型的患病风险均明显降低,且有无过敏性鼻炎对其影响不明显.     

Association of three single nucleotide polymorphisms of the E-cadherin gene with susceptibility to epithelial ovarian carcinoma]

OBJECTIVE: To investigate the association of three single nucleotide polymorphisms (SNPs), i.e. -160C/A, -347G/GA and 3'UTR+ 54C/T, in the promoter region of E-cadherin gene (CDH1) with the risk of epithelial ovarian carcinoma. METHODS: The SNPs of CDH1 gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 207 epithelial ovarian carcinoma patients and 256 unrelated healthy women; immunohistochemistry was used to measure the level of CDH1 in different genotypes of 3'UTR+ 54C/T locus. RESULTS: There were no significant difference in the frequencies between patients and control women in the two loci (-160C/A, -347G/GA) of CDH1 gene (P> 0.05). However, there was significant difference in the frequency of CDH1 3'-UTR+ 54C/T genotypes (CC, CT and TT) between patients and controls (P< 0.05). The frequencies of the CC genotype and the C allele in patients (65.2%, 89.1%) were significantly higher than that in controls (52.7%ì64.5%) (P< 0.01). The CC genotype significantly increased the risk to epithelial ovarian carcinoma, with adjusted odds ratio of 1.85 (95%CI= 1.27-2.69). In the ovarian tissues of patients, the expression of CDH1 from CC genotype was significantly lower than that with the other genotypes (CT+ TT) (P< 0.05). The -160C/A and -347G/GA polymorphisms were in linkage disequilibrium (D'= 0.999582) by analyzing with 2LD software. The -160A/-347GA haplotype was only observed in patients (5.1%), the -160C/-347GA haplotype decreased susceptibility to epithelial ovarian carcinoma, with adjusted odds ratio of 0.66 (95%CI= 0.45-0.96). CONCLUSION: CDH1 -160C/A and -347G/GA polymorphisms were not associated with the risk of epithelial ovarian carcinoma. However, the haplotype may have impact on the risk of epithelial ovarian carcinoma. The CC genotype of 3'-UTR + 54CT may be a potential risk factor for the epithelial ovarian carcinoma.     

Association of single nucleotide polymorphisms in the IL-18 gene with sarcoidosis in a Japanese population

Interleukin-18 (IL-18) and interleukin-12 (IL-12) synergistically stimulate interferon-gamma (IFN-gamma) production from Th1 cells. The levels of serum IL-18 and IFN-gamma and bronchoalveolar lavage fluid IL-18 were elevated in patients with sarcoidosis. The polymorphisms of the IL-18 gene may play a possible role in expression regulation of the gene. We investigated the roles of the polymorphisms in the development of sarcoidosis. We examined two single nucleotide polymorphisms of the IL-18 gene in 119 patients with sarcoidosis and 130 healthy control subjects. Our results showed that the frequency of sarcoidosis patients with the CA genotype at position -607 was significantly higher than that with the AA genotype (OR = 2.200) and a significantly higher proportion of patients had the C allele at -607 compared with that of the controls (OR = 2.123). No significant differences were seen in the distribution of the genotypes or phenotype frequencies at position -137. There was no specific organ involvement associated with a certain genotype or phenotype. In IL-18 gene polymorphisms, the C allele at position -607 might be a genetic risk factor for sarcoidosis in this Japanese population.     

Association of Interleukin-10 gene promoter polymorphisms in Saudi patients with vitiligo

The promoter region of human Interleukin -10 gene is highly polymorphic and has been associated with numerous autoimmune diseases. Recent studies have linked vitiligo with defective autoimmune system. This study is aimed to explore a possible association between IL-10 gene polymorphism and vitiligo in Saudi population. This case control study consisted of 184 Saudi subjects including 83 vitiligo patients (40 males, 43 females mean age 27.85 +/- 12.43 years) and 101 matched controls. Genomic DNA was extracted from the blood samples of healthy controls and Vitiligo patients visiting out patient clinic of Department of Dermatology, Riyadh Armed Forces Hospital, using QIA ampR DNA mini kit (Qiagen CA, USA). Interleukin-10 gene was amplified by polymerase chain reaction (PCR) using Arms primers to detect any polymorphism involved at positions -592, -819 and -1082. The frequencies of GG genotype at -1082, and CC genotype at positions -592 and 819 were significantly higher in vitiligo patients compared to healthy subjects suggesting that GG and CC genotypes might be susceptible to vitiligo in Saudis. On the other hand genotypes -1082 GA, -819 CT, and -592 CA of IL-10 were more prevalent in healthy controls suggesting protective effects of GA, CT and CA genotypes against vitiligo. This study indicates that the IL-10 gene may play a significant role in the etiology of vitiligo among Saudis.     

ATM基因rs227060位点单核苷酸多态性与肺癌易感性的相关性

目的:探讨共济失调毛细血管扩张症突变基因(ataxia telangiectasia mutated,ATM)rs227060位点单核苷酸多态性(single nucleotide polymorphisms,SNPs)与肺癌易感性之间的相关性.方法:采用聚合酶链反应-SNP敏感性分子开关方法,检测225例肺癌患者和128例健康体检者ATM基因rs227060多态位点等位基因以及基因型频率分布特点;并应用非条件Logistic回归法统计分析rs227060单核苷酸多态性与肺癌的相关性.结果:rs227060多态位点共检测出CC,CT,TT三种基因型和C,T两种等位基因,其在肺癌组与对照组的基因型分布频率为:CC基因型17.3％与29.7％、CT基因型61,4％与59.3％、TT基因型21.3％与11％,两组间基因型频率和等位基因频率分布差异均有统计学意义(P＜0.05).在对ATM rs227060基因型的多态性分析过程中发现:吸烟史在肺癌组与对照组相比差异无统计学意义(P＞0.05),而年龄、性别、肿瘤家族史在肺癌组与对照组相比差异均有统计学意义(P＜0.05);且以CC基因型作为对照,携带TT基因型的个体患肺癌的风险是携带CT基因型个体的3.49倍(OR=1.829;95％CI:1.045～3.199).结论:ATM基因rs227060位点单核苷酸多态性与肺癌易感性存在相关性,且携带TT基因型可增加肺癌的发病风险.