Biomedical subjects

George Füst

Publications and source records attributed to George Füst.

At least 37 records · Page 2Linked to original sources

PubMed2004

Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior.

The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.

Adult↗

PubMed2004

Association of high serum concentration of the third component of complement (C3) with pre-existing severe coronary artery disease and new vascular events in women.

Atherosclerosis is an inflammatory disease. The complement system plays an important role in the atherosclerotic process. However, lesser data is available on the possible role of C3 as a risk factor for atherosclerosis. Therefore, in a follow up study we determined C3 levels in 266 patients with pre-existing severe coronary artery disease (CAD) and compared their serum C3 concentrations with the cause of the disease. We investigated whether C3 levels predict the major complications of severe CAD during a 5-year long follow up period in patients, who have received an aorto-coronary bypass graft surgery. C3 concentrations were elevated in the patients with severe CAD compared to 182 healthy controls, and women had higher C3 concentrations than men. Pathological C3 levels (C3> or =1.8 g/L) were able to predict major complications of atherosclerosis (death by cardiac events, new acute myocardial infarction, stroke, carotid surgery and peripheral arterial disease) that developed during the follow up period only in women (OR: 4.1, 95% C.I. 1.23-13.61, p = 0.0249) independent of other risk factors for atherosclerosis. Our data supports the assumption that high C3 indicates the progression of atherosclerosis as a special marker of chronic inflammation.

Arteriosclerosis↗

PubMed2004

Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond.

Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.

Angioedema↗

PubMed2004

Knock-out of the histidine decarboxylase gene modifies the repertoire of natural autoantibodies.

Natural antibodies (NA) are antibodies produced in the absence of known immunization with specific antigens. NA are found in the blood of healthy humans and mice. Histamine influences many aspects of the immune response, including antibody production. However, the role of histamine in the generation of NA has not yet been studied. In this work, we used an ELISA assay to characterize the self-antigen binding repertoires of NA in wild type (WT) mice and in histidine decarboxylase knock-out (HDC-KO) mice, unable to synthesize histamine. We now report that HDC-KO and WT mice differed in the patterns of autoreactivity of their IgM and IgG NA. The NA in HDC-KO sera manifested a larger repertoire of IgM autoantibodies than did the WT sera. The self-antigens bound by IgM from HDC-KO mice included structural proteins, enzymes associated with cellular metabolism, double-stranded and single-stranded DNA, and tissue-specific antigens like insulin. There were relatively fewer differences in the NA repertoire of IgG autoantibodies of the mice: notably, the HDC-KO sera reacted with glutamic acid decarboxylase (GAD), an antigen associated with autoimmune diabetes. These results demonstrate that endogenous histamine can influence the self-reactivity of the NA repertoire.

Amino Acid Sequence↗

PubMed2004

Immunological aspects of heat-shock proteins-the optimum stress of life.

This review summarizes the complex role of heat-shock proteins (Hsp) in immune reactions, especially the cellular effects of heat-shock proteins during the recognition processes by innate immunity. The role of heat-shock proteins in the pathogenesis of two multifactorial diseases, i.e. inflammatory bowel disease (IBD) and atherosclerosis is highlighted. A new hypothesis on "immunodeficiency burden" is presented. According to this hypothesis, susceptibility to any multifactorial disease in any given subject and in the presence of specific environmental factors is the aggregate effect of polymorphisms resulting in the failure of protective immunity with consequent disease.

Arteriosclerosis↗

PubMed2004

Paradoxical alteration of acute-phase protein levels in patients with chronic hepatitis C treated with IFN-alpha2b.

Previously we observed elevation of the serum concentration of two acute-phase protein (AFP) complement components (C9 and C1-inhibitor) in patients with chronic hepatitis C who responded (R) to IFN-alpha therapy, but not in non-responders (NR). In the present study we investigated the effect of high-dose IFN-alpha therapy on serum concentrations of two positive [orosomucoid (OROSO) and C-reactive protein (CRP)] and two negative [transferrin (TF) and fetuin/alpha2HS-glycoprotein (AHSG)] AFP in an outpatient setting. We investigated blood samples of 40 patients with chronic hepatitis C at the onset and at the end of a 3-month treatment with high-dose IFN-alpha2b (5 MIU/day for 6 weeks, followed by 5 MIU t.i.w.) and of 52 healthy individuals. Serum concentrations of OROSO, TF and AHSG were measured by radial immunodiffusion; CRP levels were determined by immunotubridimetry. Compared to controls, patients with chronic hepatitis C had significantly lower OROSO and CRP, and higher AHSG levels. By the end of treatment, OROSO concentration increased in R (P = 0.0054), but not in NR patients. In contrast, TF levels decreased in R (P = 0.0040), but did not change in NR patients. Similarly, in R patients, AHSG levels tended to decrease (P = 0.0942) following IFN-alpha treatment. We conclude that the acute-phase reaction is suppressed in patients with chronic hepatitis C that may be potentially related to the responsiveness to IFN-alpha therapy.

Acute-Phase Proteins↗

PubMed2003

Significant decrease of the enhancement/neutralization index in HIV patients during highly active antiretroviral therapy (HAART).

Authors studied the effect of highly active antiretroviral therapy (HAART) on balance of the antibodies that enhance or neutralize growth of HIV-1(IIIB) strain in MT-4 cells in the presence or absence of human complement. Sequential serum samples were collected from 28 patients in advanced stage of HIV disease before and during HAART. The balance of the enhancing and neutralizing antibodies was expressed by an index value (E/N I). Samples with an E/N I of <0.5 (twofold decrease in virus production) were considered as neutralizing, whereas samples with an E/N I>2.0 (twofold increase in virus production) were considered as enhancing. At the beginning of HAART serum samples from eight patients enhanced, and samples from only two patients neutralized the virus in the presence of complement, median (25th-75th percentile) value of E/N I was 1.32 (0.79-2.29). E/N I significantly (P<0.0001) dropped to 0.37 (0.19-0.57) during the follow-up period of 18.5 (10.5-23.5) months under HAART. Similar changes were detected when serum samples were tested with no complement added. The E/N I values were also markedly decreased when cultures inoculated with mixtures of HIV and purified IgG prepared from serum pools taken before and during HAART, respectively, were compared. In the last samples of 20/28 patients, neutralization was measured even in the presence of complement while enhancement was found with none of these samples. These findings suggest that HAART results in disappearance of enhancing antibodies and switches the E/N I toward neutralization.

Antibodies, Blocking↗

PubMed2003

Diversity in intrinsic strengths of the human complement system: serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index.

Among the genes and proteins of the human immune system, complement component C4 is extraordinary in its frequent germline variation in the size and number of genes. Definitive genotypic and phenotypic analyses were performed on a central European population to determine the C4 polygenic and gene size variations and their relationships with serum C4A and C4B protein concentrations and hemolytic activities. In a study population of 128 healthy subjects, the number of C4 genes present in a diploid genome varied between two to five, and 77.4% of the C4 genes belonged to the long form that contains the endogenous retrovirus HERV-K(C4). Intriguingly, higher C4 serum protein levels and higher C4 hemolytic activities were often detected in subjects with short C4 genes than those with long genes only, suggesting a negative epistatic effect of HERV-K(C4) on the expression of C4 proteins. Also, the body mass index appeared to affect the C4 serum levels, particularly in the individuals with medium or high C4 gene dosages, a phenomenon that was dissimilar in several aspects from the established correlation between body mass index and serum C3. As expected, there were strong, positive correlations between total C4 gene dosage and serum C4 protein concentrations, and between serum C4 protein concentrations and C4 hemolytic activities. There were also good correlations between the number of long genes with serum levels of C4A, and the number of short genes with serum levels of C4B. Thus, the polygenic and gene size variations of C4A and C4B contribute to the quantitative traits of C4 with a wide range of serum protein levels and hemolytic activities, and consequently the power of the innate defense system.

Adult↗

PubMed2003

Relationship between the tumor necrosis factor alpha polymorphism and the serum C-reactive protein levels in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, including ulcerative colitis (UC) and Crohn's disease (CD). The aim of the study was to determine the prevalence of the tumor necrosis factor alpha (TNF-alpha) promoter polymorphisms at positions -238 and -308, and to measure the serum CRP levels in CD and UC patients and in a healthy population. The TNF-alpha gene polymorphisms were determined by the PCR-RFLP method. Samples of 74 CD and 50 UC patients and 138 healthy Hungarian volunteers were examined. The G-->A substitution at position -308 (designated the TNF2 allele) was significantly less frequent among IBD patients than in the control group (P=0.0009); 15% of the CD patients and 18% of the UC patients carried the mentioned allele, which was significantly less frequent compared with the healthy population (33%, P=0.0035 and P=0.036, respectively). No difference in the G-->A substitution at position -238 was observed. We found the median CRP levels to be significantly higher in the active phase of the disease than in the inactive phase among the -308A allele carriers (P=0.002), while this difference was not significant when the CRP levels in the active and inactive phases were compared among the -308GG homozygous patients (P=0.084). The decreased frequency of the TNF2 allele (known to be associated with elevated TNF-alpha production) in IBD may determine the severity of IBD through its interaction with plasma CRP levels, and may modify the pathogenesis of this chronic inflammatory disease.

Adult↗

PubMed2003

Elevated levels of antibodies against 70 kDa heat shock proteins in the sera of patients with HIV infection.

Heat shock proteins (Hsp), especially 70 kDa heat shock protein (Hsp70) play an important role in the life cycle of HIV-1 virus. Hsp70 is overexpressed in HIV-infected cells and this is the most abundant Hsp associated with HIV virions. The aim of our study was to investigate whether HIV infection increases the extent of specific humoral immune response against Hsp70. The serum concentration of anti-Hsp70 IgG antibodies was measured in 47 HIV-infected patients, and 62 healthy, HIV-seronegative persons. Nineteen patients on highly active anti-retroviral therapy (HAART) were followed for 24 months in a longitudinal study. Anti-Hsp70 antibodies were measured by ELISA, using recombinant human Hsp70. Levels of anti-Hsp70 antibodies were significantly (P < 0.0001) higher in the HIV-infected patients (median: 1409 (25th-75th percentile: 1031-2214) AU/ml) than in healthy control subjects (626 (429-970) AU/ml). In 19 HIV patients, serum levels of anti-Hsp70 antibodies significantly (P < 0.001) decreased during 24 (11-41) months HAART (1309 (887-2213) AU/ml before and 640 (386-959) AU/ml during HAART), accompanied by viral load reduction and CD4+ count elevation. It is concluded that HIV-infection induces a marked increase in the anti-Hsp70 antibody levels, which is consistent with the enhanced expression of Hsp70 on the surface of HIV-infected cells and/or incorporation of the protein into the membrane of HIV virions.

Adolescent↗

PubMed2003

Studies on the mechanisms of allergen-induced activation of the classical and lectin pathways of complement.

Allergen extracts are efficient activators of the complement system trough the classical pathway. Involvement of the lectin pathway was not previously studied. To further examine the mechanism of complement activation by allergens, in vitro experiments, which covered early steps both of classical and lectin pathways, were performed. Two types of allergens used in these studies: parietaria (PA) and house dust (HD) mite extracts. These allergen extracts bound to the globular head of C1q and interacted with purified mannan-binding lectin (MBL) as measured by solid-phase ELISA. None of the allergen extracts was able to activate human C1 in vitro, as measured by the determination of the split products of C1s in a reconstituted precursor C1 preparation. Neither the HD nor the PA extracts induced C4d generation above background in the serum of three subjects with hypogammaglobulinaemia but normal complement haemolytic activity. After reconstitution to normal level with purified human IgG, allergen extracts induced C4d formation above control at a level comparable to that measured in normal serum incubated with the same amounts of the extracts. HD-induced C4d generation was about the same comparable in MBL-depleted serum and in normal sera. In contrast PA induced no C4d formation in the MBL-depleted serum, whereas reconstitution with purified MBL restored C4d generation. These in vitro findings indicate that although the allergen extracts can bind purified C1q and MBL, they require IgG for efficient complement activation. Depending on the allergens, this activation may be initiated through C1, MBL, or both.

Agammaglobulinemia↗

PubMed2003

Relationship between complement components C4A and C4B diversities and two TNFA promoter polymorphisms in two healthy Caucasian populations.

The RP-C4-CYP21-TNX (RCCX) modules and the tumor necrosis factor (TNF) gene cluster are probably the most polymorphic genomic regions in the human central major histocompatibility complex (MHC). Using definitive methods for genotypic and phenotypic analyses of complement components C4A and C4B, determination of the RCCX length variants, and SSP-PCR/RFLP analyses of TNFA promoter polymorphisms at positions -308 and -238, we studied the complex relationships between the C4 and TNFA polymorphisms in two normal Caucasian populations. The patterns of the RCCX modular structures and the allelic frequency of -308A TNFA (TNF2) were similar between the Budapest (n = 125) and the Ohio (n = 80) Caucasians. However, the frequency of the -238A allele was significantly higher in the Ohio (11.3%) than in the Budapest (1.6%) study population (p < 0.0001). Marked features were found in the RCCX length variants in the TNF2 carriers and noncarriers. Strong associations were found between the C4AQ0 B1 haplotype from the monomodular short (mono-S) RCCX structure and the TNF2 allele, and between the C4A6 B1 haplotype from the bimodular long-short (LS) structure of the RCCX and the TNFA -238A allele. However, 36%-46% of the TNF2 carriers did not associate with a mono-S in both study cohorts, and 57.1% of the TNFA -238A carriers in Ohio did not associate with C4A6, which has a defective complement C5 convertase activity. The carriers of TNF2 allele had significantly lower C4A serum concentration (0.17 +/- 0.08 g/l) than noncarriers (0.23 +/- 0.09 g/l) (p < 0.001). The lowest C4A serum levels were found in TNF2 carriers with mono-S structures (0.14 +/- 0.06 g/l). In essence, our results demonstrated the heterogeneities of the TNFA promoter polymorphisms, and the linkage disequilibrium of TNFA -308A and -238A alleles with complement C4A deficiency and impaired C4A protein function, respectively.

Blotting, Southern↗

PubMed2003

High normal serum levels of C3 and C1 inhibitor, two acute-phase proteins belonging to the complement system, occur more frequently in patients with Crohn's disease than ulcerative colitis.

Few data are available on measurements of serum concentrations of complement proteins in inflammatory bowel disease (IBD). Therefore we measured serum levels of C3, C4, and C1-esterase inhibitor (C1-INH) as well as C-reactive protein (CRP) in 167 patients with Crohn's disease (CD) and 111 patients with ulcerative colitis (UC). Median serum concentrations of C3 and C1-INH were significantly higher in CD than in UC. According to multiple logistic regression analysis adjusted to age, sex, activity of disease, and presence of extraintestinal manifestations, IBD patients with high-normal (> or = 128%, > or = 75th percentile ) C1-INH concentrations had significantly (0.0275) higher odds ratio to have a diagnosis of CD than UC. Patients with high-normal C3 (> or = 1.40 g/liter) and high (> or =20 mg/liter) CRP concentrations had an even higher odds ratio of a CD diagnosis (P = 0.0132). Our findings indicate that measurement of C3, C1-INH, and CRP can be used as an additional marker to pANCA/ASCA for distinguishing patients with CD and UC.

Adult↗

PubMed2003

Serum anti-cholesterol antibodies in chronic hepatitis-C patients during IFN-alpha-2b treatment.

Previously we detected more than 3 times higher anti-cholesterol antibody (ACHA) levels in HIV positive patients compared to healthy individuals, however, this level significantly decreased during highly active anti-retroviral therapy (HAART). In our present study we examined whether these findings could also be detected in patients with chronic hepatitis C (CHC). We calculated the correlation between the ACHA levels and the C5b-9 complement activation product. 39 patients with CHC were treated with IFN-alpha-2b (Schering-Plough) 5 MU daily for 6 weeks, followed by 5 MU TIW. Serum levels of ACHA and complement activation products were measured with ELISA. Serum HCV RNA was measured by a highly sensitive branched DNA technique before and 3, 6 and 12 months after the beginning of IFN-alpha-2b therapy. 52 healthy persons served as controls. At the onset of treatment ACHA level was significantly (p = 0.0062) higher in patients (40 (24-69) AU/ml) (median (interquartile range)) than in control sera (26 (20-35) AU/ml). In the 26 responder patients ACHA levels decreased to the normal level during the therapy, but no change was observed in the 13 non-responders. In patients with a sustained response ACHA levels remained low till the end of the 12 months IFN treatment. ACHA levels were significantly (p = 0.0422) higher in the patients with low (< 4.0 mmol/l) than in those with normal (> or = 4.0 mmol/l) cholesterol concentrations. The ACHA level before the therapy strongly correlated (r = 0.5499, p = 0.0014) with C5b-9 serum levels. ACHA levels are elevated in CHC, but this elevation is not as high as in HIV. Decrease of viral load by IFN-alpha-2b treatment in the responders results in normalization of ACHA concentration. High ACHA levels in patients with low serum cholesterol concentration suggest that high ACHA levels may contribute to the decrease in cholesterol levels. The correlation between the ACHA and C5b-9 levels indicate, that the ACHA may play a role in the complement activation in CHC.

Adult↗

PubMed2003

Comparative analysis of linear antibody epitopes on human and mycobacterial 60-kDa heat shock proteins using samples of healthy blood donors.

Growing evidence suggests that anti-Hsp60 antibodies might be involved in the pathogenesis of different autoimmune diseases. Attempts were reported also on the characterization of epitope specificity of anti-Hsp60 antibodies in different infectious and autoimmune diseases. However, there is a lack of data on the occurrence and epitope specificity of anti-Hsp60 antibodies in the healthy human antibody repertoire. Therefore, the aim of our study was to demonstrate the presence of anti-Hsp60 antibodies and to investigate the epitope specificity of these antibodies using a large set of synthetic 10 mer peptides covering regions of Hsp60 with high probability of antigenicity. Here we report the identification of several linear epitopes using serum Ig (IVIG) and sera from healthy subjects by ELISA assay. We have identified two epitopes 'specific' for human Hsp60 and two different epitopes 'specific' for Hsp65. In addition, six epitopes were cross-reactive in nature, detected on both proteins. The presence of these 'specific' epitopes may explain the differences in epitope structure between Hsp60 and Hsp65 observed earlier in patients with cardiovascular disease. The binding of the IVIG preparation to Hsp60 epitopes might indicate that anti-Hsp60 autoantibodies are present in the healthy human natural autoantibody repertoire.

Amino Acid Sequence↗

PubMed2003

Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes in adults (LADA) compared with adult-onset type 1 diabetes with rapid progression.

OBJECTIVE: To compare the clinical parameters, C-peptide levels, pattern of islet cell-specific autoantibodies, and prevalence of predisposing genotypes in subjects with latent autoimmune diabetes in adults (LADA) and those with adult-onset type 1 diabetes with rapid progression. RESEARCH DESIGN AND METHODS: We evaluated the clinical parameters, C-peptide levels, and islet cell-specific autoantibodies in 54 LADA, 57 adult-onset type 1 diabetic, and 190 type 2 diabetic patients. Islet cell autoantibodies were also compared between subgroups of newly diagnosed patients with LADA and those with newly diagnosed adult-onset and childhood-onset type 1 diabetes. The genetic study was performed in subjects with LADA and those with adult-onset type 1 diabetes in comparison with a control population. RESULTS: There were no differences in the clinical parameters between LADA and adult-onset type 1 diabetes. Patients with LADA had lower BMI (P < 0.0001), waist-to-hip ratio (0.0029), total cholesterol (P = 0.001), and triglycerides (P = 0.001); higher HDL cholesterol levels (P < 0.0001); and lower prevalence of hypertension (P = 0.0028) compared with patients with type 2 diabetes. C-peptide levels were similar at onset (P = 0.403) but decreased less rapidly in LADA than in adult-onset type 1 diabetes (P = 0.0253). Single-autoantibody positivity was more often seen in LADA than in type 1 diabetes (P = 0.0001). The prevalence of predisposing HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 genotypes and the DR4-DQB1*0302 haplotype were increased in both LADA and adult-onset type 1 diabetic subjects compared with the control population. There were no differences in the frequencies of these risk alleles and haplotypes between the two patient groups. CONCLUSIONS: Subjects with LADA had clinical characteristics similar to those with adult-onset type 1 diabetes with rapid progression. C-peptide levels did not differ at onset but decreased less rapidly in LADA. Patients with LADA rather had single islet cell-specific autoantibody positivity. The prevalence of HLA-DQB1*0302, -DR4, -DR3, and -DR3/DR4 risk alleles and the DR4-DQB1*0302 high-risk haplotype did not differ in the two forms of autoimmune diabetes.

Adult↗

PubMed2002

Relationship of anti-60 kDa heat shock protein and anti-cholesterol antibodies to cardiovascular events.

BACKGROUND: Several recent studies have indicated an association between key inflammatory mediators and atherosclerotic diseases. We evaluated whether high levels of antibodies against heat shock proteins and cholesterol (ACHA) predicted cardiovascular (CV) events. METHODS AND RESULTS: We used blood samples from the Heart Outcomes Prevention Evaluation (HOPE) study to conduct a nested case-control study of 386 cases with CV events and 386 age- and sex-matched HOPE study controls without events. We explored the relationship between anti-hsp antibodies, ACHA, and subsequent outcomes (incident myocardial infarction, stroke, or CV death) during a mean follow-up of 4.5 years using conditional logistic regression. High levels of anti-hsp65 antibodies (> or =90th percentile) predicted CV events (OR, 2.1; 95% CI, 1.2 to 3.9, P=0.01). Anti-hsp60 antibodies did not predict any event type, whereas incident stroke developed significantly less frequently in patients with high ACHA levels. Anti-hsp antibodies and ACHA did not correlate with inflammatory (fibrinogen, C-reactive protein, interleukin-6, intracellular adhesion molecule-1) or infectious markers (C pneumoniae or cytomegalovirus antibodies). Anti-hsp65 antibodies (> or =90th percentile) and fibrinogen (highest tertile) had a strong joint effect: patients with high concentrations of both had more CV events (OR, 5.5; 95% CI, 1.8 to 17.5, P=0.004) than patients with low levels of both. A similar joint effect (OR, 2.7; 95% CI, 1.3 to 5.7, P=0.01) was found for high levels of anti-hsp65 and presence of cytomegalovirus antibodies. CONCLUSIONS: Serum antibodies to hsp65 were associated with subsequent CV events in this study of high-risk patients, independent of conventional cardiovascular risk factors and other inflammatory markers.

Aged↗

PubMed2002

Differences in the genetic background of latent autoimmune diabetes in adults (LADA) and type 1 diabetes mellitus.

OBJECTIVES: According to the recent classification of diabetes mellitus the Latent Autoimmune Diabetes in Adults (LADA) belongs to the group of type 1 autoimmune diabetes, as a slowly progressive form. Our aim was to determine (i) the prevalence of HLA-DRB1 and DQB1 genotypes, and (ii) to determine the tumor necrosis factor (TNF) alpha promoter polymorphism at position -308 (the G-->A substitution, designated the TNF2 allele) in patients with type 1 diabetes and with LADA compared with the healthy population. METHODS: The major histocompatibility complex (MHC) II genotypes and the TNF alpha promoter polymorphism were determined by PCR method. We examined 69 type 1 diabetic and 42 LADA patients. As control samples of 336 cadaver kidney donors and 138 volunteers were used. RESULTS: Both type 1 diabetes mellitus and LADA were positively associated with the DRB1*04-DQB1*0302 (DR4/DQ8) haplotype (P=0.00001, and P=0.0005, respectively), and negatively associated with the DRB1*11-DQB1*0301 (DR11/DQ7) haplotype (P=0.00006, and P=0.007, respectively) compared with control population. There were differences between the two disease entities in the frequency of the DRB1*03-DQB1*02 (DR3/DQ2) haplotype (P=0.00008 vs. P=0.177) compared with control group. The presence of the TNF2 allele was significantly lower in LADA than type I diabetes (P=0.022) or control group (P=0.017). CONCLUSION: Our findings indicate that there are marked differences in the genetic background of type 1 diabetes and LADA. The low presence of TNF2 allele (known to be associated with high amount of TNF alpha production) in LADA could be one of the factors responsible for the relatively slow progression.

Adult↗