Association between TNFA polymorphism and the development of asthma in the Japanese population

Tumor necrosis factor (TNF) is a proinflammatory cytokine that participates in the inflammatory reaction in patients with asthma. The TNFA and TNFB genes, which encode TNF-alpha and TNF-beta, respectively, are located within the region encoding the human major histocompatibility complex on chromosome 6p21.3, which showed linkage to atopic asthma in our genome-wide search. To determine whether polymorphisms in the 5' flanking region of the TNFA gene (-1031C/T, -863C/A, and -857C/T) and an NcoI polymorphism in the TNFB gene (LTA NcoI) are associated with the development of asthma, we performed transmission disequilibrium tests of families identified through children with atopic asthma. Genotypes of families were determined by polymerase chain reaction-based restriction fragment length polymorphism or SNaPshot analysis. Transmission disequilibrium tests of 144 asthmatic families revealed that transmission of the -857C allele and the -1031T-863C-857C haplotype in the TNFA gene to asthma-affected offspring occurred more frequently than expected (-857C allele, p = 0.0055; -1031T-863C-857C haplotype, p = 0.0002). Our results suggest that TNFA or nearby genes, including those in the major histocompatibility complex region, may contribute to the development of asthma in the Japanese population.     

Different effects of polymorphisms of tumor necrosis factor-alpha and interleukin-1 beta on development of peptic ulcer and gastric cancer

BACKGROUND AND AIM: In Western countries, polymorphism of pro-inflammatory cytokine genes is associated with the development of gastric cancer and duodenal ulcer. The aim of this study was to clarify the association of polymorphisms of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha with susceptibility to peptic ulcer diseases and gastric cancer in Japan. METHODS: The IL-1beta-511/-31 and TNF-alpha-308/-857/-863/-1031 genotypes were determined in Helicobacter pylori-positive patients with gastritis only (n = 164), gastric ulcers (n = 110), duodenal ulcers (n = 94), or gastric cancers (n = 105), and in H. pylori-negative controls (n = 172). RESULTS: Carriage of the alleles TNF-alpha-857 T (odd ratio [OR], 1.826; 95% confidence interval [CI], 1.097-3.039), TNF-alpha-863 A (OR, 1.788; 95% CI, 1.079-2.905) and TNF-alpha-1031 C (OR, 1.912; 95% CI, 1.152-3.171) was associated with increased risk for gastric ulcer development. Carriage of the alleles TNF-alpha-857 T (OR, 1.686; 95% CI, 1.003-2.832), TNF-alpha-863 A (OR, 1.863; 95% CI, 1.118-3.107) and TNF-alpha-1031 C (OR 2.074; 95% CI, 1.244-3.457) was also associated with increased risk of gastric cancer development. There was no relationship between the development of H. pylori-related diseases and polymorphisms of IL-1beta-511/-31 and TNF-alpha-308. The simultaneous carriage of three different high-producer alleles of TNF-alpha-857/-863/-1031 significantly increased the risk of gastric ulcer (OR, 6.57; 95% CI, 2.34-18.40) and gastric cancer (OR, 5.20; 95% CI, 1.83-14.78). CONCLUSIONS: Polymorphisms in TNF-alpha rather than IL-1beta are associated with increased risk for gastric ulcers and gastric cancer in Japan. The simultaneous carriage of more than one high-producer allele of TNF-alpha further increased the risks for gastric ulcer and cancer.     

Association of TNF-alpha promoter polymorphisms with the outcomes of hepatitis B virus infection in Chinese Han population

Host genetic factors and environment factors including hepatitis B virus (HBV) genotypes are widely studied for the different outcomes of HBV infection. Recent studies suggest that tumour necrosis factor-alpha (TNF-alpha) plays a pivotal role in the viral clearance and host immune response to HBV, and the capacity for TNF-alpha production in individuals is influenced by a major genetic component. In this study, we aimed to explore whether the single-nucleotide polymorphisms (SNPs) of TNF-alpha promoter are associated with the outcomes of HBV infection in the Chinese Han population. One hundred and forty-three spontaneously recovered HBV subjects and 196 chronic hepatitis B patients were recruited in this case-control study in the Beijing area of China. Polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) and sequence-specific primer-PCR (SSP-PCR) were used to detect the SNPs of five sites in the TNF-alpha promoter (-238G/A, -308G/A, -857C/T, -863C/A, -1031T/C). The frequency distributions of genotypes and haplotypes in two groups were analysed by EPI and EH programs. The presence of the -238GG genotype was significantly correlated with persistence of HBV infection (OR = 4.08, P = 0.02), and -857TT genotype appeared in relation to the spontaneous clearance of HBV (OR = 0.47, P = 0.03). Frequency of haplotype GGCCT (-238/-308/-857/-863/-1031) in the chronic HB group was significantly lower than that in spontaneously recovered group (P = 0.03), and frequencies of haplotypes GGCAT and GGTAT in the chronic HB group were significantly higher than those in the spontaneously recovered group (P = 0.0001, P = 0.0004). In conclusion, TNF-alpha promoter polymorphisms are independently associated with different outcomes of HBV infection.     

H pylori seropositivity and cytokine gene polymorphisms

AIM: To investigate whether the pro- and anti-inflammatory cytokine gene polymorphisms, IL1B-511C/T, IL1B-31C/T, IL6-634C/G, TNF-1031T/C, TNF-857C/T, and IL10-1082A/G, interact with smoking and drinking habits to influence infection with H pylori.METHODS: The subjects were 410 Japanese transit company employees. C-reactive protein and conventional cardiovascular risk factors were evaluated. Serum anti-H pylori antibodies were measured. The genotypes of IL1B-511C/T, IL1B-31C/T, IL6-634C/G, TNF-1031T/C, TNF-857C/T, and IL10-1082A/G polymorphisms were determined by allelic discrimination using fluorogenic probes and a 5′nuclease assay.RESULTS: In gender- and age-adjusted logistic analyses, the subjects with TNF-857T/T had a significantly lower odds ratio (OR) for H pylori seropositivity (reference -857C/C; OR = 0.15, 95% CI: 0.03-0.59, P = 0.007). After stratification according to smoking and drinking status, among never-smokers, the subjects with IL1B-511C/T had a significantly lower OR (reference -511C/C; OR = 0.30, 95% CI: 0.10-0.90, P = 0.032). Among drinkers in the 1-5 times/wk category, the subjects with IL1B-511T/T had a significantly lower OR (reference C/C; OR = 0.38, 95% CI: 0.16-0.95, P = 0.039), and the subjects with IL1B-31C/T and T/T had a significantly higher OR (reference C/C; C/T: OR = 2.59, 95% CI, P = 0.042: 1.04-6.47; C/C: OR = 3.17, 95% CI: 1.23-8.14, P = 0.017). Among current smokers, the subjects withIL6-634C/G had a significantly higher OR (reference C/C; OR = 2.28, 95% CI: 1.13-4.58, P = 0.021). However, the interactions terms between the aforementioned genotypes and lifestyles were not statistically significant.CONCLUSION: Contrary to previous findings, the results herein suggest that the TNF-857T/T genotype may be protective against chronic infection with H pylori. Drinking and smoking habits may influence the effect of cytokine gene polymorphisms. Further studies are required to clarify the effects of the pro- and anti-inflammatory cytokine polymorphisms and gene-environmental interactions on H pylori infection.     

Association between hepatocellular carcinoma and tumor necrosis factor alpha polymorphisms in South Korea

AIM: To investigate associations between the tumor necrosis factor alpha(TNF-α)-1031 TC,-863 CA,-857 CT,-308 GA,and-238 GA polymorphisms and HCC in Korea.METHODS: Hepatocellular carcinoma(HCC) cases were diagnosed at CHA Bundang Medical Center from June 1996 to August 2008. The association between TNF-α polymorphisms and HCC was analyzed in 157HCC patients and 201 controls using a polymerase chain reaction-restriction fragment length polymorphism assay. We investigated five TNF-α polymorphisms,which are TNF-α-1031 TC,-863 CA,-857 CT,-308 GA,and-238 GA. The TNF-α genotype frequencies,genotype combinations and haplotypes were analyzed to disclose the association with HCC.RESULTS: None of the TNF-α polymorphisms was significantly associated with HCC. However,nine genotype combinations had associations with increased likelihood of HCC. Among them,TNF-α-1031/-857/-238 TT/CC/GA(AOR = 18.849,95%CI: 2.203-161.246,P = 0.007),TNF-α-1031/-308/-238 TT/GG/GA(AOR = 26.956,95%CI: 3.071-236.584,P = 0.003),and TNF-α-1031/-238 TT/GA(AOR = 21.576,95%CI: 2.581-180.394,P = 0.005) showed marked association with HCC. There were five haplotypes of TNF-α polymorphisms which were significantly associated with HCC. They are TNF-α-1031/-863/-857/-308/-238 T-C-C-G-A(OR = 25.824,95%CI: 1.491-447.223,P = 0.0005),TNF-α-1031/-857/-308/-238 T-C-G-A(OR = 12.059,95%CI: 2.747-52.950,P 0.0001),TNF-α-1031/-857/-238 T-C-A(OR = 10.696,95%CI: 2.428-47.110,P = 0.0001),TNF-α-1031/-308/-238 T-G-A(OR = 7.556,95%CI: 2.173-26.280,P = 0.0002) and TNF-α-1031/-238 T-A(OR = 10.865,95%CI: 2.473-47.740,P = 0.0001). Moreover,HCC Okuda stage Ⅲ cases with the TNF-α-1031 CC genotype had better survival than those with the TT genotype(AOR = 5.795,95%CI: 1.145-29.323). CONCLUSION: Although no single TNF-α polymorphism is associated with HCC in this study,some TNF-α genotype combinations and haplotypes are associated with HCC. In addition,HCC Okuda stage Ⅲ cases with the TNF-α-1031 TT genotype may have a better prognosis than those with the CC genotype.     

Host TNF-alpha-1031 and -863 promoter single nucleotide polymorphisms determine the risk of benign ulceration after H. pylori infection

OBJECTIVES: This study tested whether host genotypes of the tumor necrosis factor-alpha (TNF-alpha) promoter single nucleotide polymorphism (SNP) could determine clinical and histological outcomes after Helicobacter pylori infection. METHODS: A total of 524 dyspeptic patients, 424 with and 100 without H. pylori infection, were checked for TNF-alpha promoter SNP over the locus on -1031(T/C), -863(C/A), -857(C/T), -806(C/T), and -308(G/A) by sequence-specific oligonucleotide probe. Each patient received panendoscopy to take gastric biopsy to detect H. pylori infection and its related histology using the updated Sydney's system. Gastric TNF-alpha expressions were stained by immunohistochemistry. RESULTS: In H. pylori-infected patients, -1031C or -863A carriers of TNF-alpha promoter had more severe gastric neutrophil infiltration and TNF-alpha gastric staining than individuals with -1031TT or -863CC genotype, respectively (p<0.05). The multivariate logistic regression verified both -1031C and -863A carriers were independent risk factors to have duodenal ulcers and gastric ulcer without IM in the H. pylori-infected hosts (p<0.05). As compared to -863CC and -1031TT genotype combinations, the ulcer risk after H. pylori infection was 2.46 (95% CI: 1.32-4.59, p相似文献   

Lack of association of interleukin-18 gene polymorphisms with susceptibility of Japanese populations to Graves' disease or Graves' ophthalmopathy.

OBJECTIVE: To investigate whether polymorphisms of interleukin (IL)-18 gene confer susceptibility to Graves' disease (GD) and Graves' ophthalmopathy (GO). DESIGN: We performed a case control study on polymorphisms of IL-18 gene in Japanese patients with GD (n = 435), and healthy control subjects without antithyroid autoantibodies or family history of autoimmune disorders (n = 255). The C-4675G, C-607A, and G-137C polymorphisms in the promoter region and A105C (exon 5) polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using restriction enzymes, sequence-specific PCR, and PCR-direct sequencing methods. RESULTS: None of the polymorphisms in the IL-18 gene were associated with development of Graves' disease. The CC genotype and C allele frequencies of IL-18 gene G-137C polymorphism tended to be greater in patients with ophthalmopathy than in patients without evident ophthalmopathy. However, the differences were not statistically significant. Although there were three major haplotypes, none of the haplotypes were statistically associated with susceptibility to GD or ophthalmopathy. CONCLUSIONS: These results suggest that IL-18 gene polymorphisms are not major genetic factors for susceptibility to GD in a Japanese population. Further studies with adequate sized data set in the subset analyses for GO are needed.     

Immunogenetic features in 120 Japanese patients with idiopathic inflammatory myopathy

OBJECTIVE: To examine the role of HLA-DRB1 and tumor necrosis factor (TNF) promoter genotypes in the development and the autoantibody profiles of idiopathic inflammatory myopathy (IIM) in Japanese patients. METHODS: HLA-DRB1 and TNF promoter genotypes were determined, and serum antinuclear autoantibodies were identified in 120 adult Japanese patients with IIM [72 with dermatomyositis (DM), 30 with polymyositis (PM), 18 with myositis overlapping with other collagen vascular diseases], as well as in 265 controls. RESULTS: Forty-two patients (35%) were positive for myositis-specific autoantibodies (MSA), including 37 (31%) for anti-aminoacyl-tRNA synthetase (ARS) autoantibodies. Allele carrier frequency of HLA-DRB1*0803 was increased in the patients with IIM [p = 0.02, corrected p (pc) NS, 23% vs 14%, odds ratio (OR) = 1.9 (95% confidence interval, CI = 1.1-3.2)], with PM [p = 0.006, pc NS, 33%, OR 3.1 (95% CI 1.3-7.1)], and with anti-ARS autoantibodies [27%, p = 0.04, OR 2.3 (95% CI 1.0-5.1)] compared with controls. DRB1*0405 was increased in patients with anti-ARS autoantibodies compared with controls [41% vs 25%, p = 0.04, pc NS, OR 2.1 (95% CI 1.0-4.3)]. TNF promoter genotype was associated with the presence of interstitial lung disease (ILD). The carriage of a TNF-a haplotype formed by -1031C, -863A, and -857C was increased in the patients with ILD versus those without ILD [33% vs 18%, p = 0.05, pc NS, OR 2.3 (95% CI 0.94-5.5)]. CONCLUSION: HLA-DRB1 alleles were associated with development of IIM and MSA in a Japanese population.     

Polymorphisms of tumor necrosis factor-�� promoter region for susceptibility to HLA-B27-positive ankylosing spondylitis in Korean population

This study designed to assess the relationship between tumor necrosis factor (TNF)-?? promoter polymorphisms and disease susceptibility to human leukocyte antigen (HLA)-B27-positive ankylosing spondylitis (AS). One hundred and nineteen HLA-B27⁺ AS patients, 95 HLA-B27⁺ healthy controls, and 135 random healthy controls were enrolled in this study. Six single nucleotide polymorphisms (SNPs) of the TNF-?? promoter at positions ?C1031T/C, ?C863C/A, ?C857C/T, ?C646G/A, ?C308G/A, and ?C238G/A were analyzed. Differences between groups were evaluated using the chi-square test or Fisher??s exact test. Haplotypes from each SNP were constructed, and differences in haplotypic frequencies between groups were evaluated. There were significant differences in the allelic and genotypic frequencies of 1031T/C, ?C863C/A, and ?C857C/T TNF-?? promoters polymorphisms between HLA-B27⁺ AS patients and random controls, but not between patients with AS and HLA-B27⁺ healthy individuals. TNF-?? polymorphisms did not influence the extra-spinal clinical features in patients with AS. The haplotypic sequence ?C1031T/?C863C/?C857C/?C308G increased the risk of susceptibility to AS compared to random controls (P _corr?<?0.001, OR?=?2.756, 95% CI?=?1.894?C4.010), whereas the sequence ?C1031C/?C863A/?C857C/?C308G appeared to be associated with decreased susceptibility to AS compared to random controls (P _corr?=?0.006, OR?=?0.396, 95% CI?=?0.231?C0.679). This study indicates that TNF-?? promoter polymorphism between controls and AS patients with HLA-B27⁺ genetic background is not associated with susceptibility to AS. However, TNF-?? polymorphism, irrespective of HLA-B27, increases risk of susceptibility to AS in general population.     

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.     

Association of TNF-alpha serum levels and TNFA promoter polymorphisms with risk of myocardial infarction

Elevated levels of tumor necrosis factor-alpha (TNF-alpha), and presence of polymorphisms of the TNFA gene have been implicated in cardiovascular disease pathogenesis. We explored the relationship between polymorphisms in the TNFA gene (-1031C/T, -863C/A -857T/C, -308G/A, -238G/A), protein levels of TNF-alpha and their association to myocardial infarction (MI) using a sample of 1213 post-MI patients and 1561 healthy controls. MI risk was higher among men with elevated TNF-alpha levels, with the highest compared to the lowest TNF-alpha quartile giving a 70% risk increase (OR [95% CI]: 1.7 [1.1; 2.6]). Obese subjects who also had elevated TNF-alpha levels were at even higher risk for MI (OR [95% CI]: 3.4 [2.1; 5.6]). Higher TNF-alpha levels were seen among smokers (but not among non-smokers) carrying the -857T allele. Furthermore, a rare haplotype occurred more frequently among the cases than the controls. Elevated TNF-alpha levels are associated with increased MI risk. Obese subjects with elevated TNF-a levels, and carriers of polymorphisms in or near TNFA are particularly susceptible to the hazards of smoking, results which may have implications for cardiovascular preventive measures.     

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.     

Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5'-flanking region of the TNFalpha gene and HLA genes

OBJECTIVE: To study polymorphisms in the 5'-flanking promoter/enhancer region of the tumor necrosis factor alpha (TNFalpha) gene and in the coding regions of HLA class I and class II genes, in order to better understand the genetic background of juvenile rheumatoid arthritis (JRA). METHODS: One hundred eleven Japanese JRA patients (50 with systemic disease, 29 with pauciarticular disease, and 32 with polyarticular disease) and 575 healthy Japanese subjects were examined for the allele frequencies of the TNFalpha, HLA-A, and HLA class II (DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1) genes, by DNA typing using the polymerase chain reaction-sequence-specific oligonucleotide probe method. RESULTS: The frequencies of the polymorphic allele at positions -1,031 (T to C substitution, termed -1,031C), -863 (C to A, termed -863A), and -857 (C to T, termed -857T) of the TNFalpha gene in patients with systemic JRA, but not in those with polyarticular or pauciarticular JRA, were significantly higher than in the healthy controls. The allele frequencies of DRB1*0405 and DQB1*0401 in systemic JRA, but not in the other JRA types, were significantly higher than in controls. Linkage analysis showed that the presence of both the TNFalpha -857T allele and DRB1*0405 yielded a significantly increased odds ratio (3.84), while the presence of only 1 of them did not yield a high odds ratio (0.87 and 1.58). CONCLUSION: The -1,031C/-863A allele and the -857T allele of the TNFalpha gene, both of which are related to high production of tumor necrosis factor alpha, are associated with systemic JRA. The -857T allele may enhance the effect of the DRB1*0405/DQB1*0401 haplotype in predisposing to development of systemic JRA.     

无关供者异基因造血干细胞移植中急性移植物抗宿主病与肿瘤坏死因子基因多态性的关系

目的 探讨无关供者异基因造血干细胞移植(allo-HSCT)患者及其干细胞供者的肿瘤坏死因子(TNF)单核苷酸多态性(SNP)与急性移植物抗宿主病(aGVHD)之间的关系.方法 回顾性分析浙江大学医学院附属第一医院移植中心接受无关供者allo-HSCT患者及其供者,共76对,采用多重单碱基延伸SNP分型技术检测TNF基因5个位点的SNP(TNFα-238、TNFα-857、TNFα-863、TNFα-1031、TNFβ+252),分析与aGVHD的发生风险、临床严重程度之间的关系.结果 在23例发生Ⅱ-Ⅳ度aGVHD患者中,其干细胞供者基因型TNFα-857 CC的频率(91.3%)高于基因型CT(8.7%)(P=0.039);TNFβ+252(A/G)位点未检出从基因型,19例患者为GA基因型(82.6%),4例患者为GG基因型(17.4%),3组之间比较差异有统计学意义(P=0.006).而患者与干细胞供者TNFα-238(G/A)、TNFα-863(C/A)和TNFα-1031(T/C)位点的基因多态性均未发现与aGVHD的发生风险相关.结论 干细胞供者TNFα-857 CC基因型与Ⅱ～Ⅳ度aGVHD的发生密切相关,而TNFβ+252为AA基因型的患者不易发生Ⅱ～Ⅳ度aGVHD.     

Possible involvement of cytokine gene polymorphisms in fulminant hepatitis

BACKGROUND AND AIM: Host genetic factors have been reported as influencing the progress to fulminant hepatitis (FH). Our previous data showed the serum level of tumor necrosis factor (TNF)-alpha influenced by gene polymorphisms to be markedly increased. It was investigated whether polymorphisms in the IL-10 gene, in addition to TNF-alpha and -beta gene polymorphisms, might contribute to the pathogenesis of FH. METHODS: We analyzed 42 patients with FH, 78 patients with acute hepatitis (AH), and 149 healthy subjects (control). IL-10 polymorphism sites at promoter regions -1028, -819, -592; TNF-alpha polymorphism sites at promoter regions -1031, -863, -857, -308, -238; and TNF-beta first intron Nco1 sites were studied. IL-10 gene polymorphisms were classified into three groups: low IL-10-producing haplotypes (ATA/ATA), intermediate haplotypes (ATA or CCA/CCA), and high haplotypes (ATA/ATG or CCG). RESULTS: The allelic frequency of B2 in the TNF-beta gene was significantly higher in FH patients compared with the control group. The three groups showed no differences in polymorphisms of positions -1031, -863, -857, -308 and -238 in the TNF-alpha gene. The frequency of low IL-10-producing haplotypes tended to be higher in FH patients compared with control and that of high IL-10-producing haplotype tended to be lower in FH patients compared with control. The carrier rate with both the IL-10 haplotype and the TNF-beta gene B2/B2 was significantly higher than control. CONCLUSION: Variations of cytokine polymorphisms including IL-10 and TNF-beta genes may be attributable to the pathogenesis of FH.     

Association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors with Graves' ophthalmopathy in European and Japanese populations

OBJECTIVE: The development and severity of Graves' ophthalmopathy (GO) may result from a complex interplay of genetic and environmental factors. The aim of this study was to investigate the association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors (age, sex, cigarette smoking) with GO in two different populations, Polish-Caucasians and Japanese. DESIGN: We investigated the distribution of CTLA-4 A49G polymorphism in 264 Caucasian patients with Graves' disease (GD), of which 95 had clinically evident GO (NOSPECS class >or=3) and 319 Japanese patients with GD, of which 99 had ophthalmopathy. The control groups consisted of healthy Polish adults (n=194), Polish centenarians (n=51) and Japanese adults (n=112). RESULTS: Allele G and G/G genotype were significantly increased in Caucasian patients with GD (48% and 25% respectively) and in Japanese patients with GD (69% and 47% respectively) compared with control groups. There were no significant differences in the G allele and G/G genotype frequencies in GO patients compared with GD patients without ophthalmopathy. Multiple logistic regression analysis demonstrated that cigarette smoking (P=0.03, odds ratio (OR)=1.7) and age of onset of GD over 42 Years (P=0.08; OR=1.6) were contributing factors associated with susceptibility to GO in Polish patients. In Japanese patients, a younger age of onset of GD had an effect on the development of GO (P=0.02, OR=1.8). CONCLUSIONS: (i) Allele G and G/G genotype confer genetic susceptibility to GD; (ii) CTLA-4 A49G polymorphism is not associated with the development of GO; (iii) different non-genetic factors may contribute to GO in different populations.     

Smoking and thyroid disorders--a meta-analysis

BACKGROUND: Smoking has been associated with Graves' disease, but it remains unclear if the association is present in other thyroid disorders. OUTCOME VARIABLES: Graves' disease, Graves' ophthalmopathy, toxic nodular goitre, non-toxic goitre, post-partum thyroid disease, Hashimoto's thyroiditis, or hypothyroidism. MATERIAL AND METHODS: A search of MEDLINE identified 25 studies on the association between smoking and thyroid diseases. RESULTS: In Graves' disease eight studies were available showing an odds ratio (OR) of 3.30 (95% confidence interval (CI): 2.09-5.22) in current smokers compared with never smokers. In ex-smokers there was no significant excess risk of Graves' disease (OR=1.41, 95% CI: 0.77-2.58). The OR associated with ever smoking in Graves' ophthalmopathy (4.40, 95% CI: 2.88-6.73, six studies) was significantly higher than in Graves' disease (1.90, 95% CI: 1.42-2.55, two-sided P-value <0.01). Ever smoking was not associated with toxic nodular goitre (OR=1.27, 95% CI: 0.69-2.33, three studies), while there was an increased risk of non-toxic goitre in smokers if men were excluded (OR=1.29, 95% CI: 1.01-1.65, eight studies). The risk associated with smoking was significantly lower in men than in women for both Graves' disease and non-toxic goitre. Hashimoto's thyroiditis and post-partum thyroid dysfunction were also associated with smoking while the association with hypothyroidism did not reach statistical significance. CONCLUSIONS: Cessation of smoking seems associated with a lower risk of Graves' disease than current smoking. Smoking increases the risk of Graves' ophthalmopathy beyond the risk associated with Graves' disease alone. Smoking cessation may lead to a decrease in morbidity from Graves' disease, especially in women.     

Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis

BACKGROUND/AIMS: Tumor necrosis factor (TNF) is considered to play a role in the second hit of non-alcoholic steatohepatitis (NASH). To clarify the effects of TNF in NASH we investigated TNF gene polymorphisms that might influence TNF production were investigated. METHODS: We analyzed 102 patients with non-alcoholic fatty liver disease (NAFLD; 36 with simple steatosis and 66 with NASH) and 100 control subjects. The serum level of soluble TNF receptor (sTNFR)-2 was measured. The TNF-alpha promoter region positions -1031, -863, -857, -308, and -238 and the TNF-beta gene Nco1 polymorphism site were investigated. RESULTS: The level of sTNFR-2 was significantly higher in NASH patients than in those with simple steatosis or control subjects. In the analysis of TNF gene polymorphisms, there were no significant deviations between the group of all NAFLD patients and the control subjects. The carrier frequencies of polymorphisms at positions -1031C and -863A were significantly higher in patients with NASH than in those with simple steatosis. In the multivariate analysis, TNF-alpha promoter polymorphisms proved to be significant independent factors distinguishing NASH from simple steatosis. CONCLUSIONS: TNF polymorphisms, which influence TNF production, might be associated with the progression of NAFLD.     

Interleukin-12B gene polymorphism does not confer susceptibility to Graves' ophthalmopathy in Japanese population

Graves' disease (GD) is an autoimmune disorder with genetic predisposition and frequently associated with Graves' ophthalmopathy (GO). Interleukin 12 (IL-12) is an important mediator of inflammatory immune responses and is expressed in the thyroid and orbit. IL-12B gene, which encodes the p40 subunit of IL-12, is located at chromosome 5q31-33. The aim of the present study was to investigate whether IL-12B gene polymorphism is associated with the development of GD or GO. IL-12B gene polymorphism was studied in Japanese GD patients (n = 329) and healthy control subjects without anti-thyroid autoantibodies or a family history of autoimmune disorders (n = 226). The A/C polymorphism at position 1188 of the 3' untranslated region (3'UTR) of the IL-12B gene was analyzed using the polymerase chain reaction--restriction fragment length polymorphism method. There was no difference in allele or genotype frequency of the IL-12B gene polymorphism (1188A/C) between GD patients and control subjects. There was no association of the IL-12B gene polymorphism with ophthalmopathy, severity of hyperthyroidism or serum IgE levels. There was no association of the IL-12B gene polymorphism with serum IL-12 levels, which were significantly elevated in hyperthyroid phase of GD. In conclusion, IL-12B gene 1188A/C polymorphism is not associated with GD or GO susceptibility in Japanese.