Gene Polymorphisms In Japanese Patients Research Articles

Serum amyloid A1 (SAA1) gene polymorphisms in Japanese patients with adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder in which inflammasome activation plays a pathophysiological role. In view of the inflammatory nature of AOSD, we investigated whether serum amyloid A (SAA) gene polymorphisms affect the susceptibility of patients with AOSD.Eighty-seven Japanese patients with AOSD and 200 healthy Japanese subjects were recruited in this study. The genotypes of the -13C/T SNP in the 5′-flanking region of the SAA1 gene (rs12218) and two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined using polymerase chain reaction fragment length polymorphism (PCR-RFLP) assay in all subjects. In AOSD patients, exons 1, 2, 3, and 10 of the MEFV gene were also genotyped by direct sequencing.The frequency of the SAA1.3 allele was increased in AOSD patients compared with that in healthy subjects (43.1% versus 37.5%), but the difference was not significant. The −13T allele was more frequently observed in AOSD patients than in healthy subjects (50.6% versus 41.0%, P = .0336). AOSD patients with the −13T allele had been treated with immunosuppressants more frequently than those without this allele. MEFV mutations were detected in 49 patients with AOSD (49/87, 57.3%). AOSD patients with MEFV variants frequently exhibit macrophage activation syndrome, but the difference was not significant (34.7% versus 18.4%, P = .081). Also, there was no significant difference in SAA1 -13C/T allele frequency between AOSD patients with and without MEFV mutations.Our data shows a significant association between T allele of rs12218 and AOSD in Japanese population.

Association of autoimmune hepatitis with Src homology 2 adaptor protein 3 gene polymorphisms in Japanese patients.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. The Src homology 2 adaptor protein 3 (SH2B3) gene is a member of the SH2B family of adaptor proteins that has been implicated in the integration and regulation of multiple signaling events. SH2B3 is involved in cytokine signaling pathways and serves as a negative mediator of T-cell receptor signaling. Genome-wide association analyses in Caucasians have linked a missense mutation at rs3184504 in SH2B3 with AIH. Accordingly, four selected single-nucleotide polymorphisms (SNPs) in the SH2B3 gene were genotyped in 158 patients with AIH, 327 patients with primary biliary cholangitis, 160 patients with autoimmune pancreatitis, and 325 healthy subjects of Japanese descent. Although the functional rs3184504 was non-polymorphic in 952 subjects, the frequency of the minor rs11065904 T allele was significantly decreased in AIH patients compared with healthy controls (odds ratio (OR)=0.68; corrected P=0.025). Haplotype 2 (rs2238154 A, rs11065904 T and rs739496 G) was associated with resistance to AIH (OR 0.67, P=0.021) as well as to autoimmune pancreatitis (OR=0.70, P=0.035). Our findings suggest that an SNP and haplotype in SH2B3 are associated with AIH.

Hypothetical Mechanism of Aspirin-Exacerbated Respiratory Disease Based on Recent Investigations of Gene Polymorphisms in Japanese Patients

Aspirin-exacerbated respiratory disease (AERD) is characterized by severe asthmatic attack after taking aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs). The typical patient with AERD is an adult who develops refractory chronic rhinitis in the third or fourth decade of life. Natural history and clinical features of AERD indicates that during the evaluation of chronic rhinitis persistent bronchial asthma develops, and finally after exposure to NSAID acute respiratory reactions begin to occur. The inhibitory action of aspirin and/or NSAIDs on cyclooxygenase activity may cause diversion to the 5-lipoxygenase pathway, which leads to the overproduction of cysteinyl leukotrienes (LTs). Thus, a general consensus exists that increased levels of cysteinyl LTs are key inflammatory mediators in AERD. As aspirin intolerance is found in a specific population, genetic predisposition has been considered as a crucial determinant. Investigations on candidate genes have been concentrated especially on cysteinyl LTs-related genes, however conflicting results have been reported. So, future areas of investigations need to focus on comprehensive approaches towards other genetic biomarkers. We’ve recently reported possible presence of other gene polymorphisms in Japanese patients with AERD. The natural history and clinical characteristics of AERD indicate that the respiratory mucosal inflammatory process in AERD begins and continues in the absence of ongoing or even intermittent exposure to NSAIDs. So, in this review, we propose a hypothetical progress of AERD over time based on mainly the results of our investigations, and present a schematically sketching the course of NSAIDs-triggered hypersensitivity with genes, such as asthma-associated genes, that may initiate susceptibility to AERD, and that may accelerate pathogenesis and induce onset of AERD. The findings of our studies were based on small-sized samples from a Japanese population, and future validation studies in independent populations are required to provide reassurance about our hypothesis.

Solute Carrier Family 6 Member 12 Gene Polymorphisms in Japanese Patients with Aspirin-Exacerbated Respiratory Disease

Background: Betaine/gamma-aminobutyric acid (GABA) signaling pathway in the airway epithelium has been revealed to play a critical role in bronchial asthma. To elucidate any genetic influence of the GABAergic in aspirinexacerbated respiratory disease (AERD), we investigated the association of solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in Japanese patients with AERD. Methods: DNA specimens were obtained from 103 AERD patients, 300 patients with aspirin-tolerant asthma (ATA) and 100 normal controls. Allelic discrimination assay for two single nucleotides polymorphisms in SLC6A12 gene (rs499368 and rs557881) was carried out. Results: The minor allele frequencies in SLC6A12 intron 2 A>T genotype (rs49936) were higher in AERD patients than in normal controls, and that in SLC6A12 exon 4 T>C genotype (rs557881) were higher in AERD patients than in ATA patients and normal controls. The frequencies of the combined TC/CC genotype group of SLC6A12 exon 4 T>C were higher than those of the TT genotype in AERD patients compared with those in ATA patients (P=0.021; odds ratio, 1.724; 95% confidence interval, 1.087-2.732). In male patients with AERD, frequencies of the TC/CC genotype group were higher than those of the TT genotype compared with male patients with ATA (P = 0.010; odds ratio, 3.177; 95% confidence interval, 1.311-7.699). Forced expiratory volume in one second (percentage predicted) in AERD patients with the TC/CC genotype group of the SLC6A12 exon 4 T>C gene was lower than that in the patients with the TT genotype (P=0.039). Conclusion: This is the first Japanese study to investigate the SLC6A12 intron 2 A>T and SLC6A12 exon 4 T>C genotype polymorphisms in patients with AERD. Our findings suggest that the association between SLC6A12 intron 2 A>T and exon 4 T>C gene sequence variations might be implicated in the development of AERD in a Japanese population.

Retinal angiomatous proliferation associated with risk alleles of ARMS2/HTRA1 gene polymorphisms in Japanese patients

BackgroundThe purpose of this study was to investigate the association between ARMS2/HTRA1, CFH, and C3 gene polymorphisms and retinal angiomatous proliferation (RAP), an infrequent and severe form of exudative age-related macular degeneration, which is characterized by intraretinal neovascularization.MethodsDiagnosis of RAP was based on fundus photographs, images of fluorescein and indocyanine green angiographies, and optical coherence tomography findings. Six single nucleotide polymorphisms (SNPs), A69S (rs10490924) in ARMS2, rs11200638 in HTRA1, I62V (rs800292) in CFH, Y402H (rs1061170) in CFH, R80G (rs2230199) in C3, and rs2241394 in C3, were genotyped in eight Japanese patients with RAP.ResultsThe two SNPs in the ARMS2/HTRA1 were in complete linkage disequilibrium. The frequency of the risk T allele in ARMS2 (the risk A allele in HTRA1) was 93.8% in the RAP patients. The frequency of homozygosity for the risk genotype TT of ARMS2 (the risk genotype AA of HTRA1) was 87.5%. The frequency of the non-risk allele (A) of I62V was 100%. The frequencies of risk alleles of Y402H, R80G, and rs2241394 were 12.5%, 0%, and 18.8%, respectively.ConclusionOur results suggest that the risk alleles of the ARMS2/HTRA1 SNPs may be associated with development of RAP and play a major role in the pathogenesis of intraretinal angiogenesis.

AB0113 Association between functional fc receptor-like 3 (fcrl3) -169 c/t polymorphism and susceptibility to seropositive rheumatoid arthritis: a meta-analysis

BackgroundThe Fc receptor-like 3 gene (FCRL3) is located on chromosome 1q21, a region implicated in susceptibility to several autoimmune diseases by whole-genome linkage studies. The FCRL3 protein is an orphan...

Heat Shock Protein 70 Gene Polymorphisms in Japanese Patients With Aspirin-Exacerbated Respiratory Disease

BackgroundAspirin-exacerbated respiratory disease (AERD) is nonatopic asthma, and the role of heat shock protein (HSP) 70 in AERD remains unknown. We analyzed HSP70 gene polymorphisms in Japanese patients with AERD.MethodsThe...

Association between bevacizumab-related hypertension and vascular endothelial growth factor (VEGF) gene polymorphisms in Japanese patients with metastatic colorectal cancer

Bevacizumab, a monoclonal antibody that binds to VEGF, has a well-known toxic effect of hypertension. We studied possible associations between bevacizumab-related hypertension and gene polymorphisms to assure safer cancer therapy. We retrospectively studied 60 Japanese patients with metastatic colorectal cancer who had received bevacizumab-based chemotherapy. Genotypes were determined for five well-known functional single-nucleotide polymorphism of the VEGF gene at positions C-2578A, T-1498C, G-1154A, G-634C, and C936T. Hypertension was graded according to CTCAE v4.0 on the basis of home blood pressure. The VEGF-2578 C/C and -1498 T/T genotypes were associated with significantly less hypertension during the first 2 months of bevacizumab-based chemotherapy (p = 0.004, p = 0.025, respectively). During the treatment period as a whole, the VEGF-2578 C/C and 936 C/C genotypes were associated with less hypertension (p = 0.031, p = 0.043, respectively). Preexisting hypertension was not associated with bevacizumab-related hypertension. This study demonstrated a significant relation between a lower incidence of grade 2 or higher bevacizumab-related hypertension and the VEGF-2578 C/C genotype for the entire treatment period in Japanese patients with metastatic colorectal cancer. This genotype might be useful for ensuring safer treatment of patients who receive bevacizumab-based chemotherapy.

IL-13 and IL-17A gene polymorphisms in Japanese patients with aspirin-exacerbated respiratory disease

The role of interleukin (IL) 13 and IL-17A in aspirin-exacerbated respiratory disease (AERD) remains unknown. To analyze the IL-13 and IL-17A gene polymorphisms in Japanese patients with AERD. The single-nucleotide polymorphisms in each gene were examined in patients with AERD, patients with aspirin-tolerant asthma (ATA), and healthy controls. Frequencies of the TT/CT genotype of the IL-13 -1111C>T gene were higher than frequencies of the CC genotype in AERD patients compared with ATA patients (P < .001). In female patients with AERD, frequencies of the TT/CT genotype were higher than those of the CC genotype compared with female patients with ATA (P < .001). However, genotype frequencies of IL-13 Arg110Gln did not differ between AERD and ATA patients. Frequencies of the CC genotype of the IL-17A -737C>T gene were higher than those of the TT/CT genotype in AERD patients compared with ATA patients (P = .02). In female patients with AERD, frequencies of the CC genotype were higher than those of the TT/CT genotype compared with female patients with ATA (P = .03). Forced expiratory volume in 1 second (percentage predicted) in AERD patients with the CC genotype of the IL-13 -1111C>T gene was lower than that in the patients with the TT/CT genotype. AERD patients with the TT/CT genotype of the IL-17A -737C>T gene had a higher peripheral total eosinophil count compared with the patients with the CC genotype. The comparison of the clinical characteristics according to the IL-13 Arg110Gln gene polymorphism showed no difference. These findings suggest that the IL-13 -1111C>T and IL-17A -737C>T gene sequence variations might have a role in the development of AERD.

A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity

We explored the role of the adiponutrin (PNPLA3) nonsynonymous-rs738409 single nucleotide polymorphism (SNP) in genetic susceptibility to nonalcoholic fatty liver disease (NAFLD) and whether this SNP contributes to the severity of histological disease. Two hundred sixty-six individuals were evaluated in a case-control association study, which included 172 patients with features of NAFLD and 94 control subjects. The rs738409 G allele was significantly associated with NAFLD (P < 0.001; OR 2.8 95%, CI 1.5-5.2), independent of age, sex, body mass index (BMI), and Homeostasis Model Assessment (HOMA) index. When we tested the hypothesis of a relation between the SNP and the histological spectrum of NAFLD, a significant association was observed [chi2 19.9, degree of freedom (df): 2, P < 5 x 10(-5), adjusted for HOMA and BMI]. The degree of liver steatosis, as evaluated by liver biopsy, was significantly associated with the rs738409 G allele. Patients with CC genotype showed a lower steatosis score (14.9% +/- 3.9) in comparison with the CG genotype (26.3% +/- 3.5) and GG genotype (33.3% +/- 4.0) (P < 0.005). The proportion of the total variation attributed to rs738409 genotypes was 5.3% (beta 0.23 +/- 0.07; P < 0.002). Our data suggest that the rs738409 G allele is associated not only with fat accumulation in the liver but also with liver injury, possibly triggered by lipotoxicity.

Assessment of 14 functional gene polymorphisms in Japanese patients with oral lichen planus: a pilot case-control study

Oral lichen planus (OLP) is a refractory mucosal disease. Its pathogenesis is thought to involve immunologic and genetic alterations. To gain a better understanding of the genetic risk factors, the authors evaluated associations between 14 functional gene polymorphisms and OLP. 32 Japanese patients with OLP and 99 unrelated healthy Japanese controls were genotyped for 14 single nucleotide polymorphisms (SNPs) of genes that regulate host immune responses. Genotyping was performed with a modified version of the serial invasive signal amplification reaction. A trend towards over-representation of tumor necrosis factor receptor 2 (TNFR2) +587 G allele was found in the patients compared with the controls (allele frequency: P=0.049). The other 13 SNPs were unassociated with OLP. These results suggest that TNFR2 +587 gene polymorphism may be associated with susceptibility to OLP.

Influence of adiponectin gene polymorphisms in Japanese patients with non-alcoholic fatty liver disease

Single nucleotide polymorphisms (SNPs) of the adiponectin gene have been reported to be associated with insulin resistance and the prevalence of type-2 diabetes. We investigated the SNPs of adiponectin in non-alcoholic fatty liver disease (NAFLD) patients. One hundred nineteen patients histologically diagnosed as having NAFLD and 115 control subjects were examined. Adiponectin SNP sites were investigated at +45 of exon 2 and at +276 of intron 2; these sites have been thought to be associated with diabetes or insulin resistance. Regarding the +276 SNP, the frequency of G/G tended to be higher in NAFLD patients than in controls, but not significantly. Among females only, however, the G/G frequency was significantly higher in NAFLD patients. As for the +45 SNP, in the severe fibrosis group, the frequency of G/G homozygotes was significantly higher than that in the mild fibrosis group, and G/G homozygotes of the +45 SNP proved by multivariate analysis to be an independent factor in severe fibrosis. In NAFLD patients with adiponectin +45 G/G, homeostasis model assessment-insulin resistance was significantly higher than in NAFLD patients without adiponectin +45 G/G. Adiponectin SNPs were found to be associated with the progression of liver fibrosis and insulin resistance, suggesting that adiponectin SNPs might play roles in the occurrence and progression of NAFLD.

Association of Autoimmune Pancreatitis With Cytotoxic T-lymphocyte Antigen 4 Gene Polymorphisms in Japanese Patients

Autoimmune pancreatitis (AIP) is characterized by high serum IgG4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Although the HLA DRB1*0405-DQB1*0401 haplotype and Fc receptor-like 3 polymorphisms have been associated with AIP, the role of other genetic factors is largely unknown. As cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with several autoimmune diseases, we sought to determine if CTLA4 polymorphisms and serum sCTLA4 levels were associated with AIP as well. Five CTLA4 polymorphisms, located at -1722, -658, and -318 in the promoter, +49 in exon 1, and +6230 in the 3' untranslated region, were genotyped in 59 patients with AIP and 102 healthy subjects. Serum sCTLA4 levels were also determined in cohorts of 52 patients and 32 controls. Compared with healthy subjects, we found a significant increase in the +6230 G/G genotype (64%vs 42%, odds ratio [OR] 2.48, P= 0.011) in AIP patients. Haplotype 2, which had the +6230A, was associated with AIP resistance (OR 0.49, P= 0.011). The +49A/A and +6230A/A genotypes were associated with an enhanced risk of relapse (OR 5.45, P= 0.038 and OR 12.66, P= 0.022). Additionally, median serum sCTLA4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL, P < 0.001). The +6230 G/A polymorphism did not influence sCTLA4 levels in AIP patients. Our findings suggest that AIP is associated with a genetic polymorphism in CTLA4 and is positively correlated with serum sCTLA4 levels.

The Interleukin‐1 and Fcγ Receptor Gene Polymorphisms in Japanese Patients With Rheumatoid Arthritis and Periodontitis

The pathobiology of rheumatoid arthritis (RA) is similar to that of periodontitis in that proinflammatory cytokines and immunoglobulin G Fc receptor (FcgammaR) play an important role. Functional polymorphisms of interleukin (IL)-1 and FcgammaR were shown to be associated with susceptibility to both diseases. Therefore, we evaluated whether the IL-1 and FcgammaR gene polymorphisms represent a common risk factor for RA and periodontitis. The study population consisted of Japanese adults with RA (RA group; N = 100), periodontitis only (P group; N = 100), and healthy individuals with no systemic or oral disease (H group; N = 100). Clinical periodontal condition was defined by measurements of probing depth, clinical attachment level, and bleeding on probing. Genomic DNA was isolated from peripheral blood and analyzed for determination of IL-1 genotypes (IL-1A+4845, IL-1B+3954, and IL-1RN+2028) and FcgammaR genotypes (FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB) by allele-specific polymerase chain reactions. Among 100 patients with RA, 86% showed periodontal tissue destruction. However, the RA group exhibited milder levels of periodontal tissue destruction than the P group (P <0.01). There was a significant difference in the distribution of IL-1B+3954 C/T genotypes between the RA and P groups and between the RA and H groups (P = 0.03 for both comparisons), with enrichment of the T allele in the RA group (P = 0.04; odds ratio, 2.9 for both comparisons). The combination of IL-1A+4845 T and IL-1+3954 T alleles yielded a strong association with RA and periodontitis (RA versus P group: P = 0.00001; RA versus H group: P = 0.00001). These results failed to show that IL-1 and FcgammaR gene polymorphisms constitute a common risk factor for RA and periodontitis. However, it was suggested that the distributions of IL-1B+3954 genotypes and IL-1A+4845 and IL-1B+3954 haplotypes were unique to the patients with RA and periodontitis.

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

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. 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. 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. TNF polymorphisms, which influence TNF production, might be associated with the progression of NAFLD.

Brain‐derived neurotrophic factor gene polymorphisms in Japanese patients with sporadic Alzheimer's disease, Parkinson's disease, and multiple system atrophy

We studied two genetic polymorphisms (240C/T and 480G/A) of the brain-derived neurotrophic factor (BDNF) gene in Japanese patients with Alzheimer's disease (AD, n = 172), Parkinson's disease (PD, n = 327), and multiple system atrophy (MSA, n = 122), as well as controls (n = 275). The distribution of the 240 C/T polymorphism was significantly different between AD patients and controls, whereas there was no difference in the genotype of the two polymorphisms between MSA and controls or between PD and controls. Our data suggest that BDNF might play a role in AD.

Glutathione‐S‐transferase‐1 and interleukin‐1β gene polymorphisms in Japanese patients with Parkinson's disease

We studied genetic polymorphisms in the glutathione-S-transferase-1 (GST-1) gene region and the interleukin-1beta (IL-1beta) promoter region in patients with Parkinson's disease (PD, n = 361), as well as controls (n = 257). Although we have confirmed the previous results, in a larger sample, that the IL-1beta genotype has affected the age at onset of PD patients, no contribution of the GST-1 gene polymorphism was observed in the allele frequency or the onset age of the disease in Japanese persons.

Serotonin-2A and 2C Receptor Gene Polymorphisms in Japanese Patients with Obstructive Sleep Apnea

The serotonin (5-HT) 2A and 2C receptor subtype plays an important role in the maintenance of upper airway stability and normal breathing in obesity. Polymorphisms in the 5-HT 2A receptor gene (HTR2A) and 5-HT 2C receptor gene (HTR2C) are associated with various diseases. The aim of this study was to investigate whether or not the HTR2A/C genotypes are associated with obstructive sleep apnea (OSA). The PCR-restriction fragment length polymorphism method was used to determine genotypes of the HTR2A/C gene. The genotype distributions and allele frequencies were statistically analyzed. We studied 177 consecutive male patients with excessive daytime somnolence and an apnea plus hypopnea number [apnea-hypopnea index (AHI)] of greater than five per hour of sleep established by full polysomnography. One hundred Japanese men in whom OSA was clinically excluded were randomly selected as a control group. Genotypes and allele frequencies of 102T/C polymorphism of the HTR2A and 796G/C polymorphism of the HTR2C did not differ between controls and patients with OSA. HTR2C polymorphism was considered inappropriate for association studies because of low frequency of the mutant allele. Multiple regression analysis showed that age and body mass index (BMI) were significantly associated with OSA, but HTR2A polymorphisms were not. HTR2A polymorphisms had no significant relationship with AHI or BMI, although further study with more samples will be needed for powerful statistical analyses. These results indicate that age and BMI, not these polymorphisms, are associated with OSA in this population.

Analysis of HLA Class I and Class II Gene Polymorphisms in Japanese Patients with Human T-Cell Lymphotropic Virus Type 1-Associated Uveitis

Purpose: To investigate the immunogenetic background of human T-cell lymphotropic virus type 1 (HTLV-1)-associated uveitis (HAU) that presents immune-mediated reactive changes in the uvea. Methods: HLA class I and class II genes were studied in 51 patients with HAU, 192 asymptomatic HTLV-1 carriers, and 266 HTLV-1-seronegative controls using a high-resolution method of HLA DNA typing. The HLA alleles of HAU were compared with those of HTLV-1 carriers and healthy controls. Results: We identified 62 distinct alleles of HLA-A, HLA-Cw, and HLA-B and 49 distinct alleles of HLA-DRB1 and HLA-DQB1 in patients with HAU, asymptomatic HTLV-1 carriers, and healthy controls. The relative frequencies of these HLA alleles did not differ among the three groups. Conclusion: The results suggest that HLA class I and class II genes do not contribute to susceptibility to HAU.

Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection—association between TGF-β1 polymorphisms and hepatocellular carcinoma

In this study, we determined the frequencies of the genotypes associated with the polymorphism of the cytokines genes, and investigated their association with the risk of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) carriers. Genetic polymorphism in the cytokines TNF-alpha, IFN-gamma, TGF-beta1, IL-6, and IL-10 were studied in 236 Japanese patients with HBV infection. The genetic polymorphisms of these cytokines were analyzed by polymerase chain reaction-sequence-specific primer (SSP). There was no statistically significant difference in the genetic polymorphisms of TNF-alpha, IFN-gamma, and IL-10 genes between HBV carriers with HCC and those without HCC. However, the TGF-beta1+29 (codon 10) C/C genotype was lower in HBV carriers with HCC than in those without HCC (HCC 14.6% vs non-HCC 31.9%). The association of HCC was significantly lower in HBV carriers with C/C genotype than in those with T/C or T/T genotype in position +29 of the TGF-beta1 gene. Our findings suggest that the genetic polymorphism in codon 10 of the TGF-beta1 gene may play a role in HCC development in patients with chronic HBV infection.