Genetic factors predisposing to a chronic course of virus hepatitis and liver fibrosis

The IL4 C(?590)T, IL4RA Ile50Val, and TNF G(?308)A polymorphisms were tested for association with the chronic development of virus hepatitis, the extent of which was inferred from the liver fibrosis stage. The frequency of allele A of the TNF G(?208)A polymorphism in patients with mild fibrosis was higher (24.5%) than in patients with moderate or severe fibrosis (13.4%) or cirrhosis (8.7%). The frequency of heterozygous genotype CT of the IL4 C(?590)T polymorphism significantly differed between cirrhosis (68.2%) and moderate or severe fibrosis (39.1%).     

Association of immune system gene polymorphisms with quantitative features which are pathogenetically important in chronic viral hepatitis

Association study was performed for genetic polymorphisms IL4 C(-590)T, IL4RA Ile50Val, TNF G(-308)A, to estimate their effect on quantitative features which are pathogenetically important for chronic viral hepatitis course, i.e. levels of IL4, IL10, IL12, tumor necrosis factor alpha, fibronectin, collagenase, protease inhibitors, macroglobulines, elastases, free and protein-bound hydroxyproline. It has been shown that A allele of TNF G(-308)A polymorphism is associated with decreased TNF-alpha, increased IL4 and IL12, as well as with low level of protein-bound hydroxyproline. In addition, association of CT genotype of IL4 C(-590)T polymorphism and high level of protein-bound hydroxyproline has been identified.     

Mortality in adult intensive care patients with severe systemic inflammatory response syndromes is strongly associated with the hypo-immune TNF −238A polymorphism

The systemic inflammatory response syndrome (SIRS) is associated with activation of innate immunity. We studied the association between mortality and measures of disease severity in the intensive care unit (ICU) and functional polymorphisms in genes coding for Toll-like receptor 4 (TLR4), macrophage migratory inhibitory factor (MIF), tumour necrosis factor (TNF) and lymphotoxin-alpha (LTA). Two hundred thirty-three patients with severe SIRS were recruited from one general adult ICU in a tertiary centre in the UK. DNA from patients underwent genotyping by 5′ nuclease assay. Genotype was compared to phenotype. Primary outcome was mortality in ICU. Minor allele frequencies were TLR4 +896G 7%, MIF 173C 16%, TNF ?238A 10% and LTA +252G 34%. The frequency of the hypoimmune minor allele TNF ?238A was significantly higher in patients who died in ICU compared to those who survived (p?=?0.0063) as was the frequency of the two haplotypes LTA +252G, TNF ?1031T, TNF ?308G, TNF ?238A and LTA +252G, TNF?1031T, TNF?308A and TNF?238A (p?=?0.0120 and 0.0098, respectively). These findings re-enforce the view that a balanced inflammatory/anti-inflammatory response is the most important determinant of outcome in sepsis. Genotypes that either favour inflammation or its counter-regulatory anti-inflammatory response are likely to influence mortality and morbidity.     

The association between proinflammatory cytokine polymorphisms and cerebral palsy in very preterm infants

Cerebral palsy (CP) is a nonprogressive motor disorder caused by white matter damage in the developing brain and is often accompanied with cognitive and sensory disabilities. The risk of CP is higher among infants born preterm than in more mature infants. Intrauterine infection/inflammation, activation of the cytokine network and elevated levels of proinflammatory cytokines in neonatal blood or in amniotic fluid to which the preterm infant is exposed, has been identified as the most common cause of preterm delivery, periventricular leukomalacia (PVL) and CP. The aim of our study was to evaluate the possible association of four TNFα promoter single nucleotide polymorphisms (SNPs) (-1031 T/C, -857 C/T, -308 G/A and -238 G/A), two IL1β SNPs (-511 C/T and +3954 C/T) and one IL6 (-174 C/G) polymorphism with susceptibility to CP in very preterm infants. Statistically significant association between TNFα -1031 T/C high expression genotypes (TC and CC) (OR, 2.339; p=0.016) as well as between TNFα -1031 C high expression allele (OR, 2.065; p=0.013) and risk of CP was observed. In addition, statistically significant association was found between TNFα TC, CC, GG, GG -1031/-857/-308/-238 genotypes combination (OR, 3.286; p=0.034) and risk of CP. Statistically significant association between IL1β TT, CC -511/+3954 genotypes combination and risk of CP (OR, 4.000; p=0.027) was also found. In CP patients with cystic PVL (cPVL) statistically significant association was found between TNFα -1031 T/C high expression genotypes (TC and CC) (OR, 2.361; p=0.038), IL1β -511 C/T high expression genotype TT (OR, 3.215; p=0.030) as well as IL1β -511 T high expression allele (OR, 1.956; p=0.019) and risk of CP. Statistically significant association was also found in patients with cPVL between TNFα TC, CC, GG, GG -1031/-857/-308/-238 genotypes combination (OR, 4.107; p=0.024), as well as IL1β TT, CC -511/+3954 genotypes combination (OR, 7.333; p=0.005) and risk of CP. Our results suggest the role of TNFα and IL1β polymorphisms which have previously been associated with higher circulating levels of these cytokines in genetic susceptibility to white matter damage and consequently CP in very preterm infants.     

Tumour necrosis factor -308 and -238 promoter polymorphisms are predictors of a null virological response in the treatment of Brazilian hepatitis C patients

Certain host single nucleotide polymorphisms (SNPs) affect the likelihood of a sustained virological response (SVR) to treatment in subjects infected with hepatitis C virus (HCV). SNPs in the promoters of interleukin (IL)-10 (-1082 A/G, rs1800896), myxovirus resistance protein 1 (-123 C/A, rs17000900 and -88 G/T, rs2071430) and tumour necrosis factor (TNF) (-308 G/A, rs1800629 and -238 G/A, rs361525) genes and the outcome of PEGylated α-interferon plus ribavirin therapy were investigated. This analysis was performed in 114 Brazilian, HCV genotype 1-infected patients who had a SVR and in 85 non-responders and 64 relapsers. A significantly increased risk of having a null virological response was observed in patients carrying at least one A allele at positions -308 [odds ratios (OR) = 2.58, 95% confidence intervals (CI) = 1.44-4.63, p = 0.001] or -238 (OR = 7.33, 95% CI = 3.59-14.93, p < 0.001) in the TNF promoter. The risk of relapsing was also elevated (-308: OR = 2.87, 95% CI = 1.51-5.44, p = 0.001; -238: OR = 4.20, 95% CI = 1.93-9.10, p < 0.001). Multiple logistic regression of TNF diplotypes showed that patients with at least two copies of the A allele had an even higher risk of having a null virological response (OR = 16.43, 95% CI = 5.70-47.34, p < 0.001) or relapsing (OR = 6.71, 95% CI = 2.18-20.66, p = 0.001). No statistically significant association was found between the other SNPs under study and anti-HCV therapy response.     

Genetic polymorphisms of cytokine genes and risk for trichloroethylene-induced severe generalized dermatitis: a case-control study.

Trichloroethylene (TCE)-induced severe generalized dermatitis (SGD) is considered to be a contact allergic disease and is dependent on a cell-mediated immune response. Little is known about its pathogenesis. Several lines of evidence suggest that tumour necrosis factor (TNF) and interleukin 4 (IL-4) are involved in the immunological and inflammatory reactions. To investigate the relation between polymorphisms of TNF and the IL-4 gene and the risk of TCE-induced SGD, a case-control study was conducted consisting of 111 patients diagnosed with SGD and 152 TCE-exposed workers without SGD. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the polymorphisms of TNF-alpha (G-238A, G-308A), TNF-beta (intron 1) and IL-4 (C-590T). Logistic regression was applied to calculate the odds ratios (OR) and 95% confidence intervals. The results reveal that the frequency of TNF alpha-308 wild allele in cases was significantly higher than that in control subjects (p=0.049). Individuals with a heterozygous genotype of TNF alpha-308 were associated with the decreased risk of TCE-induced SGD relative to the homozygous genotype (OR=0.398, 95% CI=0.164-0.967). No significant differences in the allele and genotype frequencies could be demonstrated at any other polymorphic loci among both groups. The finding of a possible contribution of a TNF-alpha genetic polymorphism is a primary result because the pathogenesis of TCE-induced SGD is complex and likely to involve the interaction of a number of genes. A further study should be conducted to illustrate the influence of a link between certain relevant alleles in the assessment of genetic susceptibility     

Association of immune system gene polymorphisms with quantitative traits pathogenetically important for chronic virus hepatitis

The IL4 C(?590)T, IL4RA Ile50Val, and TNF G(?308)A polymorphisms were tested for association with quantitative traits important for chronic virus hepatitis, including the levels of IL4, IL10, IL12, TNF-α, fibronectin, collagenase, the proteinase inhibitor, macroglobulin, and free and protein-bound (PBO) oxyproline. Allele A of the TNF G(?308)A polymorphism was associated with a lower TNF-α production by mononuclear cells, a higher production of IL4 and IL12, and a lower PBO level. The genotype CT of the IL4 C(?590)T polymorphism was associated with a high PBO level.     

TNF promoter ?308 A/G and ?238 A/G polymorphisms and juvenile idiopathic arthritis: a meta-analysis

The aim of this study was to determine whether the tumor necrosis factor (TNF) promoter polymorphisms confer susceptibility to juvenile idiopathic arthritis (JIA). A meta-analysis was conducted on the A allele of the TNF -308 A/G and -238 A/G polymorphisms. The nine comparison studies including 1,132 JIA patients and 1,663 controls were included in the meta-analysis and consisted of 7 European, 1 Mexican, and 1 Turkish population. No association was found between JIA and the TNF -308 A allele and the TNF -238 A allele (odds ratio [OR] = 1.211, 95 % confidence interval [CI] = 0.917-1.598, P = 0.177; OR = 1.135, 95 % CI = 0.603-1.861, P = 0.615, respectively). Stratification by ethnicity did not show the association of the TNF -308 and -238 polymorphisms with JIA in Europeans. Mexicans were found to have lower prevalences of A alleles (2.9, 4.1 %) of the TNF -308 A/G and -238 A/G polymorphisms than any other population studied, and the Turkish population the highest (31.2, 26.9 %). This meta-analysis shows no association between the A alleles of the TNF -308 A/G or -238 A/G polymorphisms and JIA in Europeans, but that the prevalences of these alleles are ethnicity dependent.     

Association between interleukin-6 polymorphism and age-at-onset of type 1 diabetes. Epistatic influences of the tumor necrosis factor-alpha and interleukin-1beta polymorphisms

Multiple immune mediators have been mentioned as playing a role in the pathomechanism of type1 DM. Interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha play a central role in the autoimmune destruction of pancreatic beta-cells, whereas IL-6 inhibits TNF-alpha secretion, and may have some protecting effects. In our study, we aimed to investigate the association between these three cytokines' single nucleotide polymorphisms (IL-6 gene G(-174)C, TNF-alpha gene G(-308)A and IL-1beta gene C(3954)T polymorphisms) and age-at-onset of type 1 diabetes mellitus (T1DM) in 165 diabetic children (median age: 17 years). Polymorphisms were determined using the PCR-RFLP method. We found that the age-at-onset of T1DM was significantly different in patients with a different IL-6 genotype (median age-at-onset of T1DM was: 8, 6 and 4.5 years in children with the (-174)GG, GC and CC genotypes, respectively; p < 0.01). Adjusted for TNF-alpha and IL-1beta polymorphisms, patients with a IL-6 (-174)CC genotype have a 3.0-fold (95% CI: 1.2-7.1) increased risk of developing diabetes before the age of 6 years than (-174)G allele carrier patients. However, we found this association to be present only in patients who carried the TNF-alpha (-308)A or IL-1beta (3954)T allele, i.e. in patients with high TNF-alpha and high IL-1beta producer genotypes. We suppose that in the case of high TNF-alpha and IL-1beta producer genotypes, elevated proinflammatory cytokine levels result in a higher production of IL-6 in (-174)G allele carrier patients. This elevated IL-6 level may have a protective effect against the development of T1DM and may delay the destruction of pancreatic beta-cells.     

Association of cytokines genes (ILL, IL1RN, TNF, LTA, IL6, IL8, IL0) polymorphic markers with chronic obstructive pulmonary disease

The purpose of this study was to investigate the possible roles of the cytokines genes in the development of chronic obstructive pulmonary disease (COPD). Polymorphisms in the genes encoding IL1B, IL1RN, TNFA, LTA, IL6, IL8 H IL10 were investigated in COPD patients (N = 319) and healthy individuals (N = 403) living in Ufa, the Republic of Bashkortostan. We observed that IL1RN*2/IL1RN*2 genotype of ILRN gene was associated with susceptibility for COPD (9.8% vs. 4.67%; chi(2)= 5.45, df= 1, P = 0.02; OR = 2.21). Analysis of the LTA gene polymorphic locus A252G showed that in patients with COPD, the frequency of the GG genotype was significantly higher than that in the control group (7.84% vs. 3.72%; chi(2) = 5.00, df= 1, P = 0.025). The increase of this genotype was significant in case of stage IV of COPD (11.18% vs. 4.79%; chi(2) = 3.075, df= 1, P = 0.07). Frequency of genotype combination TNFA-308 G/G and LTA252 A/A significantly decreased in COPD group (38.55% vs. 46.93% in control group; chi(2) = 8.82, df= 1, P = 0.0039). The frequency of GG genotype of the IL6 gene was higher in the patients with stage IV of COPD (43.75% vs. 31.54%, chi(2) = 4.14, P = 0.041). Our results indicate that the genotype frequency of the T(-511)C, T3953C of IL1B, G(-308)A of TNFA, G(-1 74)C of IL6, A(-251)C of IL8 and C(-627)A of ILl0 genes polymorphisms was similar in COPD and healthy control groups.     

Genetic polymorphisms of cytokine genes and risk for trichloroethylene-induced severe generalized dermatitis: A case-control study

Trichloroethylene (TCE)-induced severe generalized dermatitis (SGD) is considered to be a contact allergic disease and is dependent on a cell-mediated immune response. Little is known about its pathogenesis. Several lines of evidence suggest that tumour necrosis factor (TNF) and interleukin 4 (IL-4) are involved in the immunological and inflammatory reactions. To investigate the relation between polymorphisms of TNF and the IL-4 gene and the risk of TCE-induced SGD, a case-control study was conducted consisting of 111 patients diagnosed with SGD and 152 TCE-exposed workers without SGD. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the polymorphisms of TNF-α (G-238A, G-308A), TNF-β (intron 1) and IL-4 (C-590T). Logistic regression was applied to calculate the odds ratios (OR) and 95% confidence intervals. The results reveal that the frequency of TNF α-308 wild allele in cases was significantly higher than that in control subjects (p=0.049). Individuals with a heterozygous genotype of TNF α-308 were associated with the decreased risk of TCE-induced SGD relative to the homozygous genotype (OR=0.398, 95% CI=0.164–0.967). No significant differences in the allele and genotype frequencies could be demonstrated at any other polymorphic loci among both groups. The finding of a possible contribution of a TNF-α genetic polymorphism is a primary result because the pathogenesis of TCE-induced SGD is complex and likely to involve the interaction of a number of genes. A further study should be conducted to illustrate the influence of a link between certain relevant alleles in the assessment of genetic susceptibility.     

Interleukin‐6 (G‐174C) and tumour necrosis factor‐alpha (G‐308A) gene polymorphisms in geriatric patients with chronic periodontitis

doi:10.1111/j.1741‐2358.2009.00291.x
Interleukin‐6 (G‐174C) and tumour necrosis factor‐alpha (G‐308A) gene polymorphisms in geriatric patients with chronic periodontitis Background and objective: Periodontitis is a chronic inflammatory disease, and genetic factors may have an important role in its severity. Polymorphisms in the promoter regions of the interleukin‐6 (IL‐6) and tumour necrosis factor‐α (TNF‐α) genes have been reported to cause changes in the production of these cytokines. The aim of this study was to evaluate the possible role of IL‐6 (G?174C) and tumour necrosis factor (G?308A) polymorphisms, in the severity of chronic periodontitis in an elderly population. Materials and methods: In this study, a group of 65 elderly women, comprising 17 patients with moderate chronic periodontitis, 21 with severe chronic periodontitis and 27 healthy patients were selected. DNA was isolated from all subjects, and polymerase chain reaction was used to study the IL‐6 and TNF‐α gene polymorphisms. Results: The results of this study showed a significant difference in the allele and genotype frequencies of IL‐6 gene polymorphism between patients with periodontal disease and controls. Subjects carrying the G/G genotype of IL‐6 were most severely affected by periodontitis. The TNF‐α gene polymorphism showed no association with chronic periodontitis between patients and controls. Conclusion: The results suggest that the IL‐6 gene polymorphism may be associated with chronic periodontitis, and that TNF‐α gene polymorphism may not be involved in the progression of chronic periodontitis in the population of elderly Brazilian women.     

Cytokine gene polymorphisms in endemic pemphigus foliaceus: a possible role for IL6 variants

Endemic pemphigus foliaceus (EPF) is a complex autoimmune disease characterized by the presence of antibodies against desmoglein 1, which lead to the loss of adhesion among keratinocytes (acantholysis). Variants of HLA class II genes have been the only genetic factors found to modulate susceptibility to EPF. This study aims at investigating the influence of cytokine genetic variants in the pathogenesis of EPF, since they may affect the expression levels of these immunomodulatory molecules. The sample included 168 patients and 189 controls and was comprised of mostly Caucasoids and Mulattos. The approach consisted of a case-control association study and the alleles were identified by mismatched PCR-RFLP. No associations were found with variants of IL1A, IL1B, IL1RN, IL4R and IL10. There was a weak negative association with the haplotype -1082G -592C (OR=0.49) of the IL10 gene in Mulattos. In regard to polymorphism -590 of the IL4 gene, a positive association with the T/T genotype (OR=2.71) and a negative association with the C variant (OR=0.37) were found. Associations with IL6 -174 variants suggest that the C/C genotype has a protective effect (OR=0.13) while carriers of the G allele are more susceptible (OR=7.66) to EPF.     

The association of the carrier state of the tumor necrosis factor-alpha (TNFalpha) -308A allele with the duration of oxygen supplementation in preterm neonates

BACKGROUND: High levels of inflammatory cytokines lead to lung damage in premature newborns. We investigated whether single nucleotide polymorphisms (SNP) of innate immunity cytokine genes influence the length of oxygen supplementation. METHODS: We genotyped 123 very low birth weight (VLBW) infants for the tumour necrosis factor (TNF)- alpha G(-308)A, interleukin (IL)-1beta C(3954)T, IL-6 G(-174)C and IL-10 G(-1082)A SNPs. Genomic DNA was isolated from remnant dried blood samples from the neonates. We tested the association between SNPs and ventilation characteristics using a stepwise multiple regression analysis model. RESULTS: The carrier state of the TNF-alpha G(-308)A allele was associated with a 40-hour longer period of mechanical ventilation (p=0.004) and, on average, an additional 36 hours of oxygen supplementation (p=0.0008). The association was significant after its adjustment for perinatal risk factors for lung damage. CONCLUSIONS:The TNF-alpha G(308)A genotype - which is associated with increased TNF-alpha levels - might influence the supplemental oxygen requirement of VLBW infants.     

Cytokine single nucleotide polymorphisms in Iranian patients with pulmonary tuberculosis

BACKGROUND: Several genes coding for different cytokines may affect host susceptibility to tuberculosis. METHODS: In the present study, the allele and genotype frequencies of a number polymorphic genes coding for cytokines or cytokine receptors were investigated in Iranian patients with pulmonary tuberculosis (PTB). RESULTS: From the IL-1 cluster, a positive, significant difference was found at position -889, where the T/T genotype was over represented in PTB patients (p = 0.01); a positive, significant increase was found in the IL1R PstI 1970 C/C genotype, where the C allele was over represented in the PTB patients (p = 0.01). A significant negative association at codon 10 TGF-beta, T allele, was shown in our patients and the C allele and C/C genotype were over represented in the PTB patients (P<0.005). For TNF-alpha at position -238, we found a negative association for the G/A genotype and a positive association for the G/G genotype (p = 0.0009). Significant negative associations at position -590 IL-4, T allele and the T/T genotype were shown in our patients (p = 0.0007); also, the C allele and T/C genotype were significantly increased in our patients (P<0.05). With IL-6 at -174, G/G increased and G/C decreased significantly in the patients (P<0.005). CONCLUSION: Pro-inflammatory cytokines such as TNF-alpha and TGF-beta seem to be decreased, and IL-6 increased in PTB patients.     

Interleukin-4 polymorphisms and response to combination therapy in Egyptian chronic hepatitis C patients

In hepatitis C infection, the production of inappropriate cytokines levels may contribute to viral persistence and may affect the response to antiviral therapy. We investigate the effect of IL4 C-590T and C-33T polymorphisms on the response to combination therapy with interferon and ribavirin in chronic HCV patients. These single nucleotide polymorphisms were determined by PCR-RFLP in 235 responder and 210 non-responder to combination therapy. The IL4-590 T/T and -33 T/T genotypes were associated with resistance to the therapy (p<0.001, p=0.001 respectively). Haplotypes T(-590) T(-33) and T(-590) C(-33) were associated with a higher risk in non-responder patients than the responders (p<0.001 for each) while frequency of haplotype C(-590) C(-33) (with all wild alleles) was significantly higher in responders as compared to non-responders (p<0.001). These results suggest that inheritance of the IL4 polymorphisms may be associated with resistance to combined antiviral therapy in Egyptian HCV patients.     

Genetic variability of interleukin4 gene in Taiwanese children with biliary atresia

Biliary atresia (BA) is a neonatal cholangiopathy of unknown etiology that leads to biliary cirrhosis and is the most common cause of liver transplantation in children. A still undetermined hepatobiliary viral infection may elicit an uncontrollable autoimmune response against the biliary epithelial cells in genetically predisposed children and culminates in atresia of the biliary trees. Interleukin 4 (IL4) is crucial for the differentiation of naive T helper cells into the T helper 2 effector cells that promote humoral immunity. This study aims to investigate whether polymorphisms of the IL4 gene are associated with susceptibility to BA. Genomic DNA was extracted from whole blood samples of 53 Taiwanese children with BA and 904 ethnically-matched healthy controls. The IL4 -590 C/T, -33 C/T, and 8375 A/G polymorphisms were genotyped using the Pre-Developed TaqMan Allelic Discrimination Assay in a real-time polymerase chain reaction system. No significant difference between children with BA and healthy controls were found when comparing genotype, allele, carrier, and haplotype frequencies of these IL4 gene variants. These results suggest that the tested polymorphisms of IL4 gene are unlikely to contribute significantly to BA susceptibility in Taiwanese children.     

Interleukin-10-1082 gene polymorphism is associated with papillary thyroid cancer

The etiopathogenesis of thyroid cancer has not been clearly elucidated although the role of chronical inflammation and the imbalance between pro- and anti-inflammatory cytokines may play a role in the etiology. The aim of the present study was to investigate whether cytokine gene polymorphisms are associated with papillary thyroid cancer (PTC), and to evaluate the relationship between genotypes and clinical/laboratory manifestation of PTC. Tumor necrosis factorα (TNFα) G-308A (rs 1800629), interleukin-6 (IL-6) G-174C (rs 1800795) and IL-10 A-1082G (rs 1800896) single nucleotide polymorphisms in DNA from peripheral blood leukocytes of 190 patients with thyroid cancer and 216 healthy controls were investigated by real-time PCR combined with melting curve analysis. There was no notable risk for PTC afflicted by TNFα-308 and IL-6-174 alone. However, IL-10-1082 G allele frequency were higher among PTC patients than healthy controls (p = 0.009). The patients with IL-10-1082 GG geotype have twofold increased risk of developing thyroid cancer according to AA genotype (OR 2.07, 95 % CI 1.21–3.55). In addition, the concomitant presence of IL-10-1082 G allele (GG + AG genotypes) together with IL-6 -174 GG genotype has a nearly twofold increased risk for thyroid cancer (OR 1.75 with 95 % CI 1.00–3.05, p = 0.049). We suggest that IL-10-1082 G allele is associated with an increased risk of PTC. The polymorphism of IL-10 gene can improve our knowledge about the pathogenesis of PTC, and could provide to estimate people at the increased risk for PTC.     

Racial differences in selected cytokine allelic and genotypic frequencies among healthy,pregnant women in North Carolina

BACKGROUND: Genetic susceptibility to diseases is likely influenced by common DNA variants in the form of single nucleotide polymorphisms (SNPs). The value of SNPs for linkage and association mapping studies may depend on the distribution of SNP allele frequencies across populations. OBJECTIVES: To establish the SNP allelic frequencies among Caucasian and African American women for tumor necrosis factor (TNF)alpha, transforming growth factor (TGF)beta1, interleukin-10 (IL10), interleukin-6 (IL6), and interferon (IFN)gamma. MATERIALS AND METHODS: DNA was extracted from whole blood from 123 healthy, pregnant women. PCR-based genotyping was performed for the genes encoding TNFalpha (-308G/A), TGFbeta1 (codon 10C/T, codon 25C/G), IL10 (-1082A/G, -819T/C, -592A/C), IL6 (-174C/G) and IFNgamma (874T/A). Allele frequencies were determined by Hardy-Weinberg Equilibrium and Linkage Disequilibrium tests. Differences in the SNP allelic frequencies between Caucasians and African Americans were assessed by the chi(2) of Amitage trend test. RESULTS: SNP allelic and genotypic frequencies for IL6 and IFNgamma, but not for TNFalpha, TGFbeta1, and IL10, differed significantly between the Caucasian and African American women. CONCLUSIONS: Recognition of racial differences in SNP allelic and genotypic frequencies for selected cytokines is important for designing and powering future linkage and association mapping studies investigating the role of cytokines in human disease.     

Frequencies of the tumor necrosis factor gene polymorphisms in the Korean population

Tumor necrosis factor (TNF), a potent immuno-modulator and pro-inflammatory cytokine, has been implicated in many pathological processes. The TNFA and the TNFB genes, which encode TNFalpha and TNFbeta, respectively, are both located on the short arm of chromosome 6 between the class I and class II regions of the HLA complex. A striking feature of the entire HLA complex is a high degree of genetic variation. Two biallelic polymorphisms in the TNFA (- 308G/A) and TNFB (+ 252A/G) genes have been reported to be associated with TNF production and with susceptibility to inflammatory diseases. Population information on polymorphisms is essential for the study of genetic diseases. The aim of this study is to obtain accurate information about polymorphisms in the TNF genes in the Korean population. Allele frequencies of TNFA (- 308G/A) and TNFB (+ 252A/G) were measured in 581 unrelated Korean individuals by PCR-RFLP. Allele frequencies of each polymorphism were determined and compared with those previously reported in other populations. A significant difference was found for the allele frequencies of TNFA and TNFB gene in Koreans compared with Europeans. The - 308/A allele in the TNFA gene was very rare in Asians (0.008-0.096). The frequency of the - 308/A allele in Koreans was considerably lower than in Europeans (0.120-0.189). Contrary to lower frequency of the -308/A allele, that of + 252/G allele in the TNFB gene was higher than in Koreans (0.445) compared with Europeans (0.29-0.39). The polymorphisms and allele frequencies obtained in this study will be useful for genetic studies of common inflammatory diseases.