Interleukin-18 promoter -607 C/A and -137 G/C polymorphisms and susceptibility to type 1 diabetes: A meta-analysis

ObjectiveThe aim of this study was to determine whether the functional interleukin-18 (IL-18) promoter -607 C/A (rs1946518) and -137 G/C (rs187238) polymorphisms are associated with susceptibility to type 1 diabetes (TID).MethodsA meta-analysis was conducted to assess the associations between the IL-18 -607 C/A and -137 G/C polymorphisms and T1D in overall and by ethnic group.ResultsA total of 6075 cases and 5744 controls from ten studies were considered in this meta-analysis. In all study subjects, the meta-analysis showed no association between T1D and the IL-18 -607 C allele (OR = 1.083, 95% CI = 0.930–1.260, p = 0.307). However, stratification by ethnicity indicated an association between the IL-18 -607 C allele and T1D in Asians (OR = 1.506, 95% CI = 1.172–1.936, p = 0.001), but not in Europeans (OR = 0.988, 95% CI = 0.808–1.209, p = 0.907). Analysis using recessive and dominant models and homozygote contrast showed the same -607 C allele pattern in Asians and Europeans. Meta-analysis of the IL-18 -137 G/C polymorphism showed no association between T1D and the IL-18 -137 G allele in all study subjects (OR = 1.066, 95% CI = 0.926–1.2289, p = 0.375). Stratification by ethnicity indicated no association between the IL-18 -137 G allele and T1D in Europeans and Asians (OR = 1.021, 95% CI = 0.961–1.085, p = 0.504; OR = 0.851, 95% CI = 0.5821–1.245, p = 0.406).ConclusionsOur meta-analysis demonstrates that the IL-18 -607 C/A polymorphism may be associated with susceptibility to T1D in Asians, but not in Europeans.     

Interleukin IL-18 gene promoter polymorphisms in adult patients with type 1 diabetes mellitus and latent autoimmune diabetes in adults

Interleukin-18 (IL-18) gene promoter polymorphism is known as a genetic risk factor for child type 1 diabetes mellitus development. To test the role of IL-18 gene polymorphism in predisposition to adult type 1 diabetes (T1DM) and latent autoimmune diabetes in adults (LADA), we analysed SNPs at position -607 (C/A) and -137 (G/C) in the promoter region of IL-18 gene by sequence-specific PCR in 49 T1DM, 66 LADA patients and 139 healthy controls. We found differences in allele, genotype or haplotype distribution in tested patients when compared to frequencies found in control group but these differences did not reach statistical significance. However, there was a difference in -607 (C/A) allele and genotype distribution found in LADA and T1DM patients that reached statistical significance. These results suggest that the IL-18 gene promoter polymorphisms are not associated with adult type 1 diabetes or LADA susceptibility, and according to our findings genes involved in onset and progression of LADA and T1DM are probably different.     

Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes

Interleukin-18 (IL-18) is a potent proinflammatory cytokine which is strongly associated with the development of diabetes in NOD mice. To test the putative involvement of IL-18 gene polymorphism in predisposition to human type 1 diabetes, the SNPs at position -607 (C/A) and -137 (G/C) in the promoter region of IL-18 gene were analyzed by sequence-specific PCR in 116 patients with type 1 diabetes and 114 normal controls. A linkage disequilibrium found only three of the four possible haplotypes defined by these SNPs. The distribution of the IL-18 gene genotypes at position -607 was significantly different between patients with type 1 diabetes and normal controls (P=0.023). Furthermore, there was a significant increase in haplotype 1 (-607C/-137G) in the patients compared with controls (P=0.006). The association study of the susceptible CTLA-4 genotype (GG at nucleotide position 49 in exon 1) or HLA-DR4-DQB1*0401 and type 1 diabetes showed that the predisposing IL-18 gene haplotype modulates the risk on CTLA-4 GG genotype, but not on HLA-DR4-DQB1*0401 haplotype. Among subjects carrying the CTLA-4 GG genotype, the frequency of IL-18 haplotype 1 in patients with type 1 diabetes was significantly higher than that in controls (91% vs. 71%, P=0.012). However, IL-18 haplotype 1 was not frequent in patients who do not exhibit the CTLA-4 high-risk genotype. These results suggest that the IL-18 gene polymorphism is associated with a type 1 diabetes susceptibility, and there might be a gene-gene interaction between IL-18 gene with susceptible CTLA-4 gene.     

Tumor necrosis factor-alpha gene promoter -308G/A and -238G/A polymorphisms in Mexican patients with type 2 diabetes mellitus

The association between some Tumor necrosis factor-alpha (TNF-α) promoter polymorphisms and Type 2 diabetes mellitus (T2DM) remains controversial. Ethnic differences may play a role in these conflicting results. The aim of this study was to investigate the association between -308G/A and -238G/A polymorphisms located in the promoter region of the TNF-α gene and T2DM in Mexican mestizo patients. Nine hundred four individuals (259 patients with T2DM and 645~controls) were genotyped for the -308G/A and -238G/A polymorphisms by PCR--RFLP. We found that the -238A allele increased the risk of developing T2DM in Mexican patients (OR=1.57, 95% CI: 1.07-2.29; p=0.018). Moreover, we found that the frequency of the GA haplotype (created by the -308G and -238A alleles) was significantly increased in patients with T2DM when compared with controls (OR =1.56, 95% CI: 1.05-2.31; p=0.026). Our results suggest that the -238G/A polymorphism and a specific haplotype (GA) are genetic risk factors for the development of T2DM in Mexican population.     

中国南方妇女AhR和ARNT基因多态性与子宫内膜异位症的相关性

目的 探讨中国南方汉族妇女芳香烃受体(arylhydrocarbon receptor,AhR)基因和芳香烃受体核转位子(arylhydroarbon nuclear translocator,ARNT)基因多态性与子宫内膜异位症的相关性.方法 收集经手术证实的431例子宫内膜异位症患者和499名对照人群外周血,采用高分辨率熔解曲线技术检测AhR及ARNT基因多态性.结果 病例组和对照组妇女AhR 1661G/A位点AA、AG、GG基因型频率分别为9.7%、44.6%、45.7%和12.0%、41.9%、46.1%,两组的基因频率差异无统计学意义(χ2=0.234,P=0.629);A和G等位基因频率为32.0%、68.0%和33.0%、67.0%,两组差异无统计学意义(χ2=0.189,P=0.664).病例组和对照组妇女ARNT 567G/C位点GG、GC、CC基因频率分别为13.5%、47.8%、38.7%和15.6%、51.7%、32.7%,两组差异无统计学意义(χ2=0.194,P=0.659);C、G等位基因频率为62.6%、37.4%和58.5%、41.5%,两组差异无统计学意义(χ2=3.30,P=0.07).2组间AhR1661G/A和ARNT 567G/C联合基因型频率分布差异亦无统计学意义(χ2=11.20,P=0.191).结论 中国南方妇女外周血AhR 1661G/A及ARNT 567G/C基因多态与子宫内膜异位症的发病无明显相关.     

中国南方妇女AhR和ARNT基因多态性与子宫内膜异位症的相关性

目的 探讨中国南方汉族妇女芳香烃受体(arylhydrocarbon receptor,AhR)基因和芳香烃受体核转位子(arylhydroarbon nuclear translocator,ARNT)基因多态性与子宫内膜异位症的相关性.方法 收集经手术证实的431例子宫内膜异位症患者和499名对照人群外周血,采用高分辨率熔解曲线技术检测AhR及ARNT基因多态性.结果 病例组和对照组妇女AhR 1661G/A位点AA、AG、GG基因型频率分别为9.7%、44.6%、45.7%和12.0%、41.9%、46.1%,两组的基因频率差异无统计学意义(χ2=0.234,P=0.629);A和G等位基因频率为32.0%、68.0%和33.0%、67.0%,两组差异无统计学意义(χ2=0.189,P=0.664).病例组和对照组妇女ARNT 567G/C位点GG、GC、CC基因频率分别为13.5%、47.8%、38.7%和15.6%、51.7%、32.7%,两组差异无统计学意义(χ2=0.194,P=0.659);C、G等位基因频率为62.6%、37.4%和58.5%、41.5%,两组差异无统计学意义(χ2=3.30,P=0.07).2组间AhR1661G/A和ARNT 567G/C联合基因型频率分布差异亦无统计学意义(χ2=11.20,P=0.191).结论 中国南方妇女外周血AhR 1661G/A及ARNT 567G/C基因多态与子宫内膜异位症的发病无明显相关.

Abstract：

Objective To explore the association between the arylhydrocarbon receptor gene (AhR)1661G/A or arylhydrocarbon nuclear translocator gene (ARNT) 567G/C polymorphism and endometriosis in southern Han Chinese women. Methods The polymorphisms of AhR gene 1661G/A and ARNT gene 567G/C in 431 cases of endometriosis and 499 healthy women were genotyped by fluorescence quantitative PCR-based high resolution melting. Results The frequencies of genotypes AA, AG, GG and alleles A and G in controls were 12.0%, 41.9%, 46. 1%, 33.0% and 67.0%, respectively, which were not significantly different from those in patients with endometriosis (9. 7%, 44. 6%, 45. 7%, 32. 0% and 68. 0%,respectively). The genotype frequencies of GG, GC, CC and alleles C and G in controls (15.6 %, 51.7 %,32. 7%, 58. 5%, 41. 5%) were not significantly different from those in patients with endometriosis (13.5%, 47.8%, 38. 7%, 62. 6%, 37. 4%), either. And no interaction of AhR 1661G/A and ARNT 567G/C on endometriosis was found. Conclusion No association between AhR 1661G/A and ARNT 567G/C genetic polymorphisms and endometriosis was found in the southern Han Chinese women in this study.     

中国南方妇女AhR和ARNT基因多态性与子宫内膜异位症的相关性

目的 探讨中国南方汉族妇女芳香烃受体(arylhydrocarbon receptor,AhR)基因和芳香烃受体核转位子(arylhydroarbon nuclear translocator,ARNT)基因多态性与子宫内膜异位症的相关性.方法 收集经手术证实的431例子宫内膜异位症患者和499名对照人群外周血,采用高分辨率熔解曲线技术检测AhR及ARNT基因多态性.结果 病例组和对照组妇女AhR 1661G/A位点AA、AG、GG基因型频率分别为9.7%、44.6%、45.7%和12.0%、41.9%、46.1%,两组的基因频率差异无统计学意义(χ2=0.234,P=0.629);A和G等位基因频率为32.0%、68.0%和33.0%、67.0%,两组差异无统计学意义(χ2=0.189,P=0.664).病例组和对照组妇女ARNT 567G/C位点GG、GC、CC基因频率分别为13.5%、47.8%、38.7%和15.6%、51.7%、32.7%,两组差异无统计学意义(χ2=0.194,P=0.659);C、G等位基因频率为62.6%、37.4%和58.5%、41.5%,两组差异无统计学意义(χ2=3.30,P=0.07).2组间AhR1661G/A和ARNT 567G/C联合基因型频率分布差异亦无统计学意义(χ2=11.20,P=0.191).结论 中国南方妇女外周血AhR 1661G/A及ARNT 567G/C基因多态与子宫内膜异位症的发病无明显相关.     

汉族人白细胞介素-18基因启动子多态性与慢性乙型肝炎的相关性研究

目的 探讨中国汉族人白细胞介素-18（interleukin-18,IL-18）基因启动子单核苷酸多态性及其与慢性乙型肝炎易感性之间的关系。方法 应用序列特异性引物一聚合酶链反应技术，检测231例慢性乙型肝炎患者和300名正常人儿．馏基因启动子-607C/A、-137G／C单核苷酸多态性位点基因型。结果 正常对照组和慢性乙型肝炎组中，IL-18基因启动子-607C/A位点3种基因型频率分别为CC型：0．22（66／300）和0．27（62／231），CA型：0．53（160／300）和0．50（116／231），AA型：0．25（74／300）和0．23（53／231）；IL-18基因启动子-137G／C位点3种基因型频率分别为GG型：0．67（202／300）和0．79（182／231），GC型：0．30（90／300）和0．19（45／231），CC型：0．03（8／300）和0．02（4／231）。经Y0检验，慢性乙型肝炎组IL-18基因启动子-137GG分布频率显著高于正常对照组（X^2=8．55，P=0．003），而-607C／-137C和-607A／-137C单倍型频率显著低于正常对照组。进一步比较慢性乙型肝炎患者儿．馏基因启动子多态性与乙型肝炎病毒（hepatitis Bvirus，HBV）DNA复制的关系，发现高水平HBV—DNA组-607位点AA基因型分布频率明显低于低水平HBV—DNA组（Y2=6．03，P=0．014）。结论 汉族人慢性乙型肝炎与IL-18基因启动子-607C/A、-137G／C单核苷酸多态性相关，其中IL-18基因启动子-137位点C等位基因可能对机体HBV感染有保护作用，而启动子-607位点AA型对感染后HBV—DNA的复制可能有抑制作用。     

TGF-β1基因启动子-800G/A、-509C/T多态性与食管癌的研究

目的研究转化生长因子β1(TGF-β1)基因启动子多态性各等位基因及基因型在食管癌患者中的分布频率,初步分析其基因型及血清水平与食管癌的相关性.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118例食管癌患者和130例正常对照组TGF-β1的基因多态性,包括TGF-β1基因启动子-800G/A、-509C/T位点,同时采用ELISA检测血清TGF-β1水平.结果食管癌患者血清TGF-β1水平显著高于对照组(P＜0.01),TGF-β1基因-800G/A位点多态性在食管癌组和正常人群中的分布差异无显著性(P＞0.05),而TGF-β1基因-509C/T多态性各等位基因及基因型频率在两组人群中的分布差异存在显著性(P＜0.05);等位基因频率的相对风险分析发现,T等位基因携带者患食管癌的风险是C等位基因的1.624倍(OR=1.624,95%CI1.134～2.324),携带T等位基因的食管癌患者血清TGF-β1水平显著高于不携带者(50.97±8.91μg/LVS44.23±8.54μg/L,P＜0.01).结论TGF-β1基因-509C/T多态性与食管癌的发病具有相关性,其中T等位基因可能是食管癌发病的遗传易感基因;携带T等位基因的个体可能通过促进TGF-β1的高度表达进而增加了食管癌的发病风险.     

汉族人群脂联素基因-11377C/G多态性与子痫前期的相关性研究

目的探讨福建莆田地区汉族人群脂联素基因（APN）单核苷酸多态性（SNP）和子痫前期（pre-eclampsi-a）及其血脂水平的关联性。方法研究对象516例,包括对照组260例,子痫前期病例组256例。采用聚合酶链反应一限制性片段长度多态性（PCR-RFLP）法鉴定APN基因启动子-11377C/G单核苷酸多态性并测定血脂水平。结果 APN基因启动子-11377C/G位点G等位基因频率和GG＋CG基因型频率在子痫前期病例组明显升高,差异有统计学意义（P〈0.05）。子痫前期病例组内GG＋CG基因型患者血清甘油三酯（TG）、血浆总胆固醇（TC）和低密度脂蛋白（LDL）值均高于CC基因型（P〈0.05）。结论 APN基因启动子-11377C/G位点GG＋CG基因型与子痫前期及其血浆TG、TC和LDL水平升高关联,C-G多态性提高了子痫前期合并血脂代谢紊乱的风险性。     

Effect of interleukin-10 gene promoter polymorphisms -1082 G/A and -592 C/A on response to therapy in children and adolescents with chronic hepatitis C virus infection

Background and aimStudying predictors of response to therapy for hepatitis C virus (HCV) infection in children may help avoid the inappropriate use of currently available costly therapy associated with numerous adverse effects. We tested the hypothesis that inheritance of single nucleotide polymorphisms (SNPs) of the interleukin-10 (IL-10) promoter gene might influence response to HCV treatment.Patients and methodsThe impact of SNPs, -1082 G/A and -592 C/A, in the promoter region of IL-10 gene, on response to HCV therapy was assessed in a cohort of 40 children treated with a combination of pegylated interferon (Peg-IFN) α2b and ribavirin.ResultsSustained virological response was achieved in 48.7%. High viral load was associated with non-response to therapy. There was no association between histopathological degree of inflammation or fibrosis and response to therapy. There was no direct statistically significant association between polymorphisms in the IL-10 gene (-1082G/A and -592 C/A) as regards inflammation or response to therapy in children. As for the SNP -592 C/A; there was a statistically significant association with the score of fibrosis (P < 0.004), concluding that the A allele was protective from moderate and severe fibrosis. Meanwhile the SNP -1082G/A did not show any association with the fibrosis score.ConclusionWe could not associate response to therapy for HCV with IL-10 polymorphisms -1082 G/A and -592 C/A. For the SNP -592 C/A, the A allele protected from moderate and severe fibrosis.     

Promoter region -318 C/ T and -1661 A/G CTLA-4 single nucleotide polymorphisms and type 1 diabetes in North Indians

Single nucleotide polymorphisms (SNPs) of the CTLA-4 gene have been associated with manifestation of type 1 diabetes in several populations. We assessed the association of five SNPs present in the CTLA-4 gene [-318C/T, -1661A/G and -1722C/T in the promoter region, +49A/G in exon 1 and CT60 in the 3' untranslated region (UTR) region] with type 1 diabetes in North Indian subjects. Genotyping was performed in the patients (n = 130) and the healthy control (n = 180) subjects by polymerase chain reaction-fragment length polymorphism analysis using MseI, BbvI, BstEII and NcoI restriction endonucleases for the -318, -1661, -1722, +49 and CT60 SNPs, respectively. The frequency of G alleles at -1661 locus was significantly higher in the patient group compared with the control subjects. Although the frequency of T alleles at -318 SNP was significantly higher in patients with type 1 diabetes compared with the controls, it did not remain significant after Bonferroni correction for the number of alleles tested. The frequencies of C/T alleles and genotypes at -1722C/T and G allele at +49A/G and CT60 SNPs were not significantly different between the patient and the control groups. Of the various possible haplotypes constructed using the five genetic loci tested (-318, -1661, -1722, +49, CT60), the frequency of 'TGTAG' haplotype was significantly higher in the patients when compared with the controls. The results of the present study indicate that the presence of G allele at -1661 locus at the CTLA-4 gene (IDDM12 locus) is associated with increased susceptibility to type 1 diabetes in North Indians, whereas A allele is protective.     

唐山地区汉族人群脑梗死患者IL-6基因-572C/G多态性研究

目的:探讨唐山地区汉族人群脑梗死患者IL-6基因-572C/G多态性及其分布特点。方法:应用聚合酶链反应(PCR)和限制性片段长度多态性(RFLP)方法测定唐山地区汉族人群中157例脑梗死患者的IL-6基因-572C/G的基因多态性。结果:脑梗死患者和健康人群的C等位基因频率均明显高于G等位基因频率(P0.05)。经Hardy-Weinberg吻合度检验,脑梗死人群和健康人群的-572C/G位点基因型个体数的观察值和期望值差异均无显著性(P0.05)。本组脑梗死患者人群和健康人群中不同性别之间IL-6-572C/G的基因型及等位基因频率分布的差异均无统计学意义(P0.05)。结论:唐山地区汉族人群脑梗死患者中可能存在IL-6基因-572C/G多态性,C等位基因可能为常见基因,G等位基因可能为少见基因。     

IFIH1 gene polymorphisms in type 1 diabetes: genetic association analysis and genotype-phenotype correlation in Chinese Han population

The evaluation of susceptibility loci is an important addition to the current predictive and screening models in type 1 diabetes of Chinese Han population. Therefore, the aim of this study is to provide evidence for the association between type 1 diabetes and two polymorphisms (rs3747517, rs1990760) from interferon induced with helicase C domain 1 (IFIH1). Here, 464 Type 1 diabetes patients and 465 control subjects were genotyped for these 2 polymorphisms. The results indicated that the allelic frequencies of rs3747517 revealed a strong association with type 1 diabetes risk (P < 0.001); yet, no significant association was observed on rs1990760(P = 0.76). Furthermore, IFIH1 rs3747517 polymorphism had no influence on the positive rates of pancreatic auto-antibodies, and both of the polymorphisms had no interaction with HLA class I-linked risk or phenotypes. In conclusion, IFIH1 rs3747517, but not rs1990760 polymorphism, plays an important role in type 1 diabetes risk in Chinese Han population.     

MTNR1B基因多态性与2型糖尿病

2型糖尿病是一种与多基因、多因素相关联的具有明显遗传异质性的疾病.全基因组关联分析显示MTNR1B基因变异与胰岛素分泌、葡萄糖水平以及2型糖尿病发病有显著相关性.MTNR1B基因是2型糖尿病重要的易感基因之一,其变异可能通过减少β细胞胰岛素分泌,从而增加2型糖尿病的易感性.     

MTNR1B基因多态性与2型糖尿病

2型糖尿病是一种与多基因、多因素相关联的具有明显遗传异质性的疾病.全基因组关联分析显示MTNR1B基因变异与胰岛素分泌、葡萄糖水平以及2型糖尿病发病有显著相关性.MTNR1B基因是2型糖尿病重要的易感基因之一,其变异可能通过减少β细胞胰岛素分泌,从而增加2型糖尿病的易感性.     

The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population

Background  

The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of Pck1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan.     

Functional polymorphisms of DEFB1 gene in type 1 diabetes Brazilian children

We analyzed three functional 5′ un-translated region β-defensin 1 (DEFB1) single nucleotide polymorphism (SNPs) in a group of 170 type 1 diabetes (T1D) patients. In order to evaluate the SNPs influence on the disease onset and the development of other autoimmune disorder, such as celiac disease (CD) and autoimmune thyroid disease (AITD), patients were stratified according to the presence of AITD, CD, and both AITD and CD. As control group, we studied 191 healthy children and adolescent not presenting a familiar historic of T1D, CD or AITD. DEFB1 SNPs were in Hardy–Weinberg equilibrium both in healthy controls and T1D patients, as well in the T1D patients stratified according to the presence of other autoimmune disorder(s). Allele, genotype, and haplotype frequencies of T1D patients globally considered were comparable to healthy controls ones. No evidence of any association of DEFB1 SNPs with the onset of AIDT, CD, and both AITD and CD on T1D patients was evidenced. Only a minor trend was found for an increased frequency of the ? 20 G allele in T1D patients only presenting AITD vs. T1D patients not presenting AITD or CD, as well as an increase of those haplotypes comprising the ? 20 G allele when compared with the GCA haplotype. We also evaluated the influence of functional DEFB1 SNPs on the age of T1D onset: no significant statistical conclusion was achieved. Further studies are envisaged, in order to elucidate the possible role of functional DEFB1 polymorphisms in the onset of TD1 and other autoimmune-related disorders.