HLA class I and II polymorphisms and trachomatous scarring in a Chlamydia trachomatis-endemic population

Immune responses to Chlamydia trachomatis contribute to protection from infection and to immunopathologic disease. To test whether subjects' HLA class I (A, B, and Cw) or class II (DRbeta1 and DQbeta1) types influence risk of trachomatous scarring from chronic infection with C trachomatis, 153 cases and pair-matched controls in Gambia were studied. No HLA type was associated with protection from scarring, indicating that protective immune responses are not limited to only one or a few HLA-restricted epitopes in C. trachomatis antigens. One class I antigen, HLA-A28, was significantly more common among cases than controls (25.8% vs. 15.9%, respectively; McNemar's odds ratio [OR], 1.88; 95% confidence interval [CI] = 1.01-3.49; P = .046). In DNA subtyping of the A28 specificity, the A*6801 allele was equally common among cases and controls, but the A*6802 allele was significantly overrepresented among cases (McNemar's OR, 3.14; 95% CI = 1.32-7.44; P = .009). This association may be due to an immunopathologic HLA-A*6802-restricted cytotoxic T lymphocyte response.     

On the coordination and oxidation states of the active-site copper ion in prokaryotic Cu,Zn superoxide dismutases

Cytokines such as TNF-alpha and interferon gamma (IFN-gamma) are important for the elimination of infected hepatocytes during acute hepatitis B virus (HBV) infection. Two G versus A transitions in the TNF-alpha promoter region at positions -308 and -238 possibly influence TNF-alpha expression. We investigated these TNF-alpha polymorphisms in 71 patients with chronic HBV infection, in 32 subjects that had spontaneously recovered from acute HBV infection, and in 99 healthy controls. The -238 A promoter variant was present in 18 (25%) of 71 patients with chronic HBV infection compared with two (6%) of 32 subjects with acute infection (P<0.04), and seven (7%) of 99 controls (P<0.003). By contrast, the prevalence of the variant at position -308 was similar in all investigated groups. The observed differences could not be explained by linkage disequilibrium to HLA-B or -DRB1* alleles. These findings suggest an association between the TNF-alpha promoter polymorphism at position -238 and the development of chronic HBV infection. This promoter variant appears to be linked to defective viral clearance.     

Use of statistical programs for nonparametric tests of small samples often leads to incorrect P values: examples fromAnimal Behaviour

To determine if serum antibody response to the 60-kDa chlamydial heat-shock protein (Chsp60) was associated with scarring trachoma, responses to Chlamydia trachomatis and to Chsp60 from 148 Gambian subjects with trachomatous scarring and from 148 controls without clinical evidence of disease from trachoma-endemic communities were characterized. Chsp60 response was found in 32% of cases and 16% of controls (P < .001). Although C. trachomatis titer was also higher in cases than controls, the prevalence of Chsp60 response between the 2 groups remained significantly different after stratifying for C. trachomatis titer (weighted odds ratio [OR] = 2.1, P = .02). Chsp60 response and C. trachomatis serovar A titer of > or =128 were independently associated with scarring trachoma. The presence of HLA class II allele DRB1*0701 was positively correlated with Chsp60 response (OR = 2.6, P = .02), and DQB1*0301 and DQB1*0501 were negatively associated (OR = 0.42, P < .001; OR = 0.55, P = .46, respectively).     

HLA-DRB1*03, but not the TNFA -308 promoter gene polymorphism, confers protection against fistulising Crohn's disease

Crohn's disease (CD) appears in forms so diverse that it has been hypothesized CD might be a syndrome, with different pathogenic mechanisms leading to the various clinical phenotypes. This may plausibly explain the conflicting and inconclusive results with regard to HLA associations in unselected groups of patients. The power of these association studies may increase when disease heterogeneity is taken into account. As fistulising CD has been proposed as a separate subgroup of patients with CD, we studied the carrier frequencies (CF) of the DRB1 alleles in 35 unrelated Caucasian Dutch CD patients with proven peri-anal fistulas. A striking decrease in the frequency of the DRB1(*)03 allele was found in those patients with peri-anal fistulas when compared with a panel of 2400 healthy controls (HC) (3% vs 25%; P = 0.005; Odds Ratio [OR] = 0.09). The DRB1(*)03 allele is in strong linkage disequilibrium with a polymorphism at position -308 in the promoter region of the gene encoding TNFalpha (TNFA-308(*)2). We investigated whether this allele frequency was decreased as well. Surprisingly, the CF of TNFA-308(*)2 was 29%, not different from the CF of 98 HC (34%; P = 0. 7; OR = 0.8). This study is the first showing a significant negative association between DRB1(*)03 and a particular subgroup of CD patients. Thus, patient selection may largely determine the outcome of genetic association studies in CD, as we previously observed no association with this allele in an unselected population of CD patients. As DRB1(*)03 frequency, but not the closely linked TNFA-308(*)2, was decreased, this suggests recombination between the DRB1 and TNFA loci in this group of patients, and may help to define the biological basis of fistula formation.     

Genetic and immunological markers in pouchitis

OBJECTIVES: Previous studies of the interleukin-1 receptor antagonist (IL-1RN) have found an increased frequency of the associated variable number tandem repeat (VNTR) allele 2 for ulcerative colitis (UC) and further evidence has been reported that this allele is associated with increased severity of several other inflammatory conditions. The HLA type of UC patients has also been implicated in the extent of disease as has the presence of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). We therefore decided to test the hypothesis that the p-ANCA, HLA type or the presence of the IL-1RN allele 2 in patients who received a restorative proctocolectomy for UC had an effect on the risk of developing pouchitis. PATIENTS: We determined the genotypes of the IL-1RN and HLA DR beta and DQ beta loci for 28 subjects with previous UC and a pouch with no evidence of pouchitis for a minimum of 2 years after formation of an ileo-anal reservoir (mean 6.3 years; range 2-17 years) and 25 subjects with previous UC and pouchitis confirmed by strict histological examination of pouch mucosal biopsy. The IL-1RN genotypes were also determined for 86 healthy controls and 61 unrelated patients with familial adenomatous polyposis (FAP). The p-ANCA status was determined for all 25 pouchitis subjects but only 23/28 non-pouchitis subjects, with 15 unaffected subjects as a negative control. METHODS: The HLA haplotypes of the UC groups were determined by polymerase chain reaction sequence-specific primer (PCR-SSP) typing and the IL-1RN genotypes were determined by PCR and agarose gel electrophoresis. The p-ANCA status was determined by indirect immunofluorescence. RESULTS: A chi 2 of 5.686 with 1 degree of freedom and a P value of 0.0171 using Yates' correction was obtained by comparing the IL-1RN allele frequencies of the combined UC groups to the FAP controls, and a chi 2 of 6.801 with 1 degree of freedom and a P value of 0.0091 comparing the pouchitis group to the FAP controls. The HLA haplotype frequencies did not vary significantly between groups nor did they correlate with p-ANCA status. There were also no significant associations of the p-ANCA status and pouchitis. CONCLUSION: There is an increased frequency of IL-1RN allele 2 in UC, with the majority of the association arising from the pouchitis group, suggesting that the presence of allele 2 in patients with UC affects the disease outcome. However, the HLA frequencies and p-ANCA status do not have any significant associations.     

Distinct associations of HLA class II genes with inflammatory bowel disease

BACKGROUND: There are relatively few studies of HLA class II association either with Crohn's disease (CD) or ulcerative colitis (UC). The few available association studies have been carried out by serological techniques, and the results from these studies are inconclusive. METHODS: The association between HLA class II genes was studied using molecular genotyping in combination with allele-specific oligonucleotide hybridization by polymerase chain reactions. RESULTS: In UC (n = 74), we observed a positive association with the HLA DR2 allele (P = 0.008) and negative associations with the DR4 (P = 0.018) and DRw6 (P = 0.028) when compared with ethnically matched controls (n = 77). No associations were observed with any DQ alleles. In contrast, in CD (n = 95) we observed a positive association with the combination of DR1 and DQw5 alleles (P = 0.021). Furthermore, stratifying DR1 and DQw5 alleles indicated that neither allele was independently associated with CD, suggesting that the association was with the haplotype rather than either of the alleles individually. A suballele of DQw5, DQB1*0501, contributed this haplotypic association (P = 0.012). CONCLUSIONS: DR and DQ molecules firmly separate UC and CD on genetic grounds, suggesting that the contribution of the HLA class II genes to the disease susceptibility is quite different for the two disorders.     

Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves' disease: replication using a population case control and family-based study

Early case control studies found association of the DRB1 allele, DR3, with Graves' disease (GD). Recent reports, claim the DQA1 allele, DQA1*0501, to be the primary susceptibility determinant within the human leukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB1*0304 (47% vs. 24%; pc < 1.4 x 10(-5)), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10(-3)) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10(-6)). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10(-5); odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (chi2 = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; chi2 = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.     

The Gln-Arg191 polymorphism of the human paraoxonase gene (HUMPONA) is not associated with the risk of coronary artery disease in Finns

The human paraoxonase gene (HUMPONA) is codominantly expressed as alleles A and G. The A allele codes for glutamine (A genotype) and the G allele for arginine (B genotype) at position 191 of the paraoxonase enzyme. This genetic polymorphism has been suggested to be associated with the predisposition to coronary artery disease (CAD). We investigated the frequency of paraoxonase A and G alleles in 380 well-characterized CAD patients and in 169 controls. The most common genotype in both the patients with CAD (211/380) and in healthy Finnish individuals (87/169) was AA (Gln/Gln). The heterozygous AM (Gln/Arg) genotype was present in 140 of the patients and in 75 controls. The frequency of the A allele was 0.74 in both patients and controls. The genotype distribution between the two groups did not differ (P = 0.12, chi2 test). The genotype distributions were also similar to those reported earlier in other caucasoid populations. In conclusion, we found no association between the Gln-Arg 191 polymorphism of the human paraoxonase gene and coronary artery disease in Finns.     

An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele

The role of inflammatory T cells in Crohn's disease suggests that inherited variations in major histocompatibility complex (MHC) class II genes may be of pathogenetic importance in inflammatory bowel disease. The absence of consistent and strong associations with MHC class II genes in Caucasian patients with inflammatory bowel disease probably reflects the use of less precise typing approaches and the failure to type certain loci by any means. A PCR-sequence-specific oligonucleotide-based approach was used to type individual alleles of the HLA class II DRB1, DRB3, DRB4, and DRB5 loci in 40 patients with ulcerative colitis, 42 Crohn's disease patients, and 93 ethnically matched healthy controls. Detailed molecular typing of the above alleles has previously not been reported in patients with inflammatory bowel disease. A highly significant positive association with the HLA-DRB3*0301 allele was observed in patients with Crohn's disease (P = 0.0004) but not in patients with ulcerative colitis. The relative risk for this association was 7.04. Other less significant HLA class II associations were also noted in patients with Crohn's disease. One of these associations involved the HLA-DRB1*1302 allele, which is known to be in linkage disequilibrium with HLA-DRB3*0301. These data suggest that a single allele of an infrequently typed HLA class II locus is strongly associated with Crohn's disease and that MHC class II molecules may be important in its pathogenesis.     

Contribution of HLA genes to genetic predisposition in diffuse panbronchiolitis

Diffuse panbronchiolitis (DPB) in East Asia is a distinctive chronic obstructive pulmonary disease of unknown etiology. We hypothesize that the disease susceptibility is due to genetic predisposition unique to Asians. Association between human leukocyte antigen (HLA)-Bw54 and the disease was previously reported. In the present study, using newly developed polymerase chain reaction (PCR)- based methods, we directly analyzed HLA class I and II alleles in 76 Japanese patients. HLA-A, -B, and -C antigens were screened by the conventional typing method, and then B22-group alleles including HLA-B54 were genotyped by single-strand conformation polymorphism analysis. Alleles of HLA-DRB1 gene were fully determined by the microtiter plate hybridization method. Thirty-seven percent of the patients possessed HLA-B*5401 allele conserved predominantly in East Asians, as compared with 15% of 110 healthy volunteers (chi2 = 12.4, p = 0.0004). In addition, 4% of the patients possessed B*5504 also unique to Asians but a rare allele which was not found in normal control subjects in this study. Typing of HLA-DRB1 class II gene did not demonstrate strong positive association with the disease. A33, B44, and DRB1*1302 showed negative association with the disease. We conclude that distinctive molecular structure of HLA-B alleles or a closely linked gene in the HLA region contributes to genetic predisposition in diffuse panbronchiolitis. This may partly explain why this disorder is found primarily in Asians.     

Polymorphism in the tumor necrosis factor-alpha promotor region and in the heat shock protein 70 genes associated with malignant tumors

BACKGROUND: Tumor necrosis factors (TNFs) and heat shock protein 70 (hsp70) are determining factors in immunologic mechanisms to tumor cells. The authors designed a case-controlled study to investigate the potential association of the polymorphisms of TNF-alpha and of hsp70-2 and hsp70-hom genes with malignant tumors. METHODS: The authors used an allele specific polymerase chain reaction to characterize the variation of the TNF-alpha promotor region in 124 unrelated Tunisian patients with malignant tumors (non-Hodgkin's lymphoma, breast carcinoma, and other tumors) and 106 healthy control subjects. Using polymerase chain reaction and restriction enzyme digestion, polymorphic analysis of hsp70-2 and hsp70-hom genes was performed in patients with non-Hodgkin's lymphoma, in those with breast carcinoma, and in control subjects. RESULTS: Analysis of TNF-alpha polymorphism in patients with malignant tumors and in control subjects demonstrated a high relative frequency of the TNF2 allele in the cancer patients. The relative risk (RR) of lymphoma was especially high in association with TNF1/TNF2 heterozygotes (RR = 6.7; P < or = 0.0001). Polymorphism analysis of the hsp70-2 and hsp70-hom genes in patients with lymphoma and in those with breast carcinoma revealed that these patients had highly significant differences in the genotypic distribution of these biallelic loci compared with the control subjects. Homozygosity for one hsp70-2 allele was significantly associated with lymphoma (RR = 18.2; P < or = 0.0001) and with breast carcinoma (RR = 16.3; P < or = 0.001). CONCLUSIONS: Tunisian persons carrying the TNF2 allele may have an increased risk of cancer. In this study, non-Hodgkin's lymphoma and breast carcinoma were significantly associated with polymorphism in hsp70 genes.     

HLA-DRB1*0701 and DRB1*1401 are associated with genetic susceptibility to psoriasis vulgaris in a Taiwanese population

We analysed the allelic frequencies of class II human leucocyte antigen (HLA)-DRB1, DQA1, DQB1 and DPB1 by polymerase chain reaction/sequence-specific oligonucleotide probe hybridization typing in 76 Taiwanese psoriasis vulgaris (PSV) patients and 238 Taiwanese non-psoriatic controls. The analysis revealed the following: (i) the DRB1*0701 allele was positively associated with PSV (relative risk, RR = 6.4, corrected P-value, Pc < or = 0.001); (ii) the DRB1*1401 allele was positively associated with type I PSV (age at onset < 40 years) (RR = 3.5, Pc < or = 0.001); (iii) the DQA1*0501 allele was negatively associated with PSV (RR = 0.4, Pc < or = 0.001); (iv) there was no significant association of HLA-DP genes with PSV; and (v) there was a strong association of beta-chain phenylalanine at position 37 (Phe 37) and glutamate or glutamine at position 74 (Glu 74/Gln 74) with PSV (RR = 3.5, Pc < or = 0.001 for the association of Phe 37 with PSV: RR = 2.2, Pc < or = 0.001 for the association of Glu 74/Gln 74 with PSV). The positive association between PSV and the DRB1*0701 allele is consistent with previous reports. The negative association of the DQA1*0501 allele is reported only in Finland, whereas the positive association between PSV and the DRB1*1401 allele has never been described before. Trans-racial studies may shed further light on the association of class II HLA alleles or other closely linked genes with the development of PSV. Phe 37 (a large, non-polar amino acid) and Glu 74/Gln 74 (both negatively charged amino acids) were the polymorphic residues in pockets 9 and 4, respectively, of the beta-chain, which may have increased their affinity for the small non-polar amino acids and basic amino acids of the psoriatic antigen peptide, thereby activating the T lymphocytes. This finding may facilitate the identification of a psoriatic antigen.     

Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis

Airway inflammation is an important pathologic feature in chronic bronchitis, and we hypothesized that individuals with greater inflammatory responses may be more likely to acquire the disease. A polymorphism at -308 position of the tumor necrosis factor-alpha (TNF-alpha) gene has been described, with the rarer allele, TNF2, demonstrated to have higher inducibility in vitro. We investigated the distribution of this polymorphism in a case-control study. The genotype was determined in 42 male patients with chronic bronchitis, 42 sex-, age-, and smoking index-matched control subjects, and 99 random-sampled schoolchildren. We report here that the TNF2 allele is overrepresented in the patient group. The allele frequency of TNF2 is 5.1% in the schoolchildren, 2.4% in the control group, and 19% in the bronchitis group (p < 0.01). Carriage of the TNF2 allele confers a higher risk to the development of chronic bronchitis (odds ratio = 11.1, 95% CI = 2.89-42.57). The results demonstrate the important pathologic role of TNF-alpha in chronic bronchitis and suggest that greater inflammatory response may predispose an individual to this disease.     

HLA-C genes and susceptibility to type 1 autoimmune hepatitis

Susceptibility to autoimmune hepatitis (AIH) is associated with the HLA A1-B8-DR3 haplotype, DR4 antigen, and, more specifically, the HLA DRB3*0101, DRB1*0301, and DRB1*0401 alleles. Few investigators, however, have examined the HLA C locus in AIH, which warrants detailed study in view of its recently described roles in immunoregulation. Eighty-seven adult, white patients with well-characterized type 1 AIH and 100 controls were studied. HLA C and HLA DRB1 alleles were assigned by polymerase chain reaction (PCR)-based genotyping. HLA A and B antigens were determined by standard microlymphocytotoxicity assay. Extended haplotypes were constructed according to known patterns of linkage disequilibrium. Only one HLA C locus allele, Cw*0701, which was present in 54% of patients versus 34% of controls (P = .006; relative risk [RR] = 1.54) was associated with AIH. The overall increase in the frequency of the Cw*07 gene (70.1% of patients vs. 54% of controls; P = .024; RR = 1.3) was due entirely to inheritance of the Cw*0701 allele rather than the other Cw*07 alleles, Cw*0702, *0703, and *0704. The RR for Cw*0701 (RR = 1.54) is greater than that for HLA A1 (RR = 1.33) and DRB1*0301 (RR = 1.49), but less than that for HLA-B8 (RR = 1.75). The present findings suggest that the gene or genes conferring susceptibility to AIH lie in the region centromeric to the HLA A locus between HLA C and DRB1. Although linkage disequilibrium with both B8 and DRB1*0301 may account for our finding of an increased frequency of Cw*0701, it is also possible that this allele contributes to disease susceptibility, perhaps by interaction with natural killer cells or cytotoxic T lymphocytes.     

bcl-2/bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with prostate cancer

This study examines in detail the HLA associations of 74 patients (40 women and 34 men) with bullous pemphigoid (BP) and compares their immunogenetic profile with that of 604 unrelated control subjects (238 women and 366 men). Correlations were sought between HLA antigens and the various BP disease parameters investigated. The presence of milia was the only clinical or laboratory finding which was linked with a specific HLA antigen, HLA-DQ6, in both men and women with BP (P < 0.01). BP has previously been linked with the HLA-DQ7 antigen and this association was confirmed in 39 of our patients (14 women and 25 men). Twelve of these patients (four women and eight men) were homozygous for HLA-DQ7. The association of HLA-DQ7 with BP was gender-restricted and only significant for men (P < 0.01). No equivalent HLA disease susceptibility risk factor could be identified for our female BP patients. This difference in HLA association between men and women with BP has not been reported previously, and its significance for disease pathogenesis is not known. No specific link could be found between HLA-DQ7 and BP for any of the clinical, immunofluorescence, western blotting, treatment or prognostic disease factors studied.     

Development of cervical fat pads following therapy with human immunodeficiency virus type 1 protease inhibitors

Several lines of evidence have suggested a possible involvement of neurotrophic factors in the pathogenesis of neurodegenerative disease. We examined whether a missense mutation (Gly[-63]Glu) of the neurotrophin-3 (NT-3) gene is associated with Alzheimer's disease (AD) in a Japanese sample of 123 patients and 215 controls. We found that homozygotes or heterozygotes for the mutated type (Glu[-63]) were significantly more common among the patients than the controls (P = 0.013, odds ratio 1.77, 95% CI 1.12-2.79). The mutated type was more frequent among the patients than the controls (P = 0.011, odds ratio 1.63, 95%CI 1.11-2.38). This association between NT-3 and AD was more prominent among those who did not carry the epsilon4 allele of the apolipoprotein E gene than those who carried the epsilon4 allele. Our results suggest that the Glu(-63) allele of the NT-3 gene by itself or another mutation nearby which would be in linkage disequilibrium to the mutation is a risk factor for AD.     

Prediction of outcome of patients with life-threatening ventricular arrhythmias treated with automatic implantable cardioverter-defibrillators using SPECT perfusion imaging

BACKGROUND: In the present study, we examined the predictors of outcome of 103 patients with coronary artery disease and left ventricular dysfunction who had life-threatening ventricular arrhythmias and were treated with implantable cardioverter-defibrillators with the use of single-photon emission computed tomography (SPECT). METHODS AND RESULTS: During a mean follow-up of 29 months, there were 29 cardiac deaths. In comparison with patients who died, survivors had less diabetes mellitus (45% versus 19%, P < .007), higher left ventricular ejection fraction (23 +/- 9% versus 27 +/- 11%, P = .04), and fewer perfusion defects as determined with stress SPECT (15 +/- 5 versus 12 +/- 5, P < .004). Most of the perfusion defects were fixed, indicative of scarring; the extent of reversible defects did not differ (2 +/- 3 in survivors and 3 +/- 4 in nonsurvivors). Multivariate Cox survival analysis identified the number of fixed defects as the only independent predictor of death (chi 2 = 10, P = .002). There were six deaths among 42 patients (14%) with < 8 fixed defects compared with 23 deaths among 61 patients (38%) with > or = 8 defects (P = .005). The 4-year survival was better in patients with < 8 segmental fixed defects than in those with > or = 8 fixed defects (80% versus 36%) (chi 2 = 8, P = .005). CONCLUSIONS: The myocardial perfusion pattern is an important determinant of outcome in patients with life-threatening ventricular arrhythmias who are treated with a implantable cardioverter-defibrillator. The extent of scarring separates patients into high- and low-risk groups with a 2.7-fold difference in death rate.     

Tumour necrosis factor-alpha (TNF-alpha) in patients who have asbestosis and develop cancer

OBJECTIVES: Concentrations of tumour necrosis factor-alpha (TNF-alpha) were assayed by radioimmunoassay in serum samples collected between 1981 and 1987 from 111 patients with asbestosis who were at a high risk of cancer. Follow up of these patients until 1993 showed that 38 had developed cancer (27 lung, three mesotheliomas, and eight diverse malignancies). RESULTS: The mean serum concentrations of TNF-alpha given in fmol/100 microliters serum in all the cases with cancer (14.1) and the cases with lung cancer (13.6) were significantly higher (P < 0.05) than the mean concentrations in the exposed controls (10.5). A positive increase was considered to be any value that was > 2 SDs above the mean of the exposed controls. 22% (six of 27) of the cases with lung cancer were positive compared with 4% (three of 73) of the exposed controls, a significant difference (P < 0.001). The serum concentrations of TNF-alpha correlated moderately with cancer (r = 0.3), lung cancer (r = 0.3), and Neu oncoproteins and epidermal growth factor receptor (EGFR) (r = 0.3, 0.5 respectively). Also, there was a significant correlation between development of cancer and severity or progression of asbestosis. There was no correlation between the concentrations of TNF-alpha and severity or progression of asbestosis. CONCLUSIONS: These results showed high concentrations of TNF-alpha in the patients who had cancer. TNF-alpha may offer an auxiliary method in early diagnosis of cancers related to asbestosis.