Albert Császár

Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1 -2518 G/G genotype in CAD patients

The central role of chemokines in the pathogenesis of atherosclerosis has been made clear. Recently polymorphisms in the gene regulatory region of MCP-1 and in the promoter region of RANTES have been found, which increase the expression of these chemokines. We investigated the role of these polymorphisms together with the chemokine SDF-1-801A and the chemokine receptors CCR2-64I and CCR5Delta32 mutations in 318 patients with coronary artery disease (CAD) referred to coronary bypass surgery, comparing them with 320 healthy controls. The prevalence of the MCP-1 -2518 G/G homozygotes was significantly higher among CAD patients than among controls (P<0.005; OR=2.2 (95% CI 1.25-3.92). The Lp(a) levels of CAD patients with G/G genotype were significantly higher than those in patients with G/A or A/A genotypes. No CAD patients homozygous for the CCR5Delta32 and CCR2-64I mutations have been found. The genotype distributions of the two alleles deviated from the Hardy Weinberg equilibrium in patients, indicating that the numbers of homozygotes were significantly lower than expected. The MCP-1 -2518G variant in homozygous form appears as a genetic risk factor for severe CAD. This genotype is associated with elevated Lp(a) levels in patients. Individuals homozygous for CCR2-64I or CCR5Delta32 mutations are at reduced risk for severe CAD.

Comparative study on antibodies to human and bacterial 60 kDa heat shock proteins in a large cohort of patients with coronary heart disease and healthy subjects

Background Recent observations indicate an association between antibodies against mycobacterial heat shock protein (hsp65) and coronary heart disease (CHD). Previously, we reported on marked differences in antigen specificity and complement activating ability of anti‐hsp65 antibodies and auto‐antibodies against human heat shock protein, hsp60. Here, we investigated whether there are differences between antih‐sp65 and anti‐hsp60 antibodies in their association with CHD.

Interpopulation effect of ACE I/D polymorphism on serum concentration of ACE in diagnosis of sarcoidosis

518 Vol 350 • August 16, 1997 of sACE activity was linked to the presence of allele D. Increased sACE concentrations in patients with sarcoidosis and the contribution of ACE gene polymorphism to sACE activity in both controls and patients was verified in Japan. All these workers proposed that ACE genotypes should be determined to avoid falsenegative results in the diagnosis of sarcoidosis, selection bias, and the underestimation of sACE concentration in patients with genotype II compared with controls with genotype DD (mean 29·5 vs 27·5 U/mL). The ACE-gene polymorphism does not have an important role as a genetic risk factor for susceptibility for sarcoidosis, however, the detection of abnormal ACE concentrations would be more accurate if new normal reference intervals based on individual genotypes were established.

Chemokine receptor CCR2 and CCR5 polymorphisms in children with insulin- dependent diabetes mellitus

Studies have shown the important roles of several regulatory and proinflammatory cytokines in insulin-dependent diabetes mellitus (IDDM). CC-chemokine receptors CCR2 and CCR5 bind chemokines that are involved in the trafficking of leukocytes in both basal and inflammatory states. A common 32-bp deletion mutation in the CCR5 gene (CCR5Δ32) and a G-to-A nucleotide substitution in the CCR2 at position 190 (CCR2-64I) have recently been described. In the present study, we have determined the frequency of the CCR5Δ32 and CCR2-64I alleles in children with IDDM [n = 115; age 1-14 (9.3 ± 4.3) y] and in nondiabetic subjects [n = 280; age 1-14 (8.5 ± 4.5) y]. The CCR5Δ32 allele frequencies were 0.117 in children with IDDM and 0.111 in nondiabetic subjects, indicating that the deletion allele has no association with IDDM. The CCR2-64I allele frequency in children with IDDM was 0.226, which differed significantly from the allele frequency in controls (0.114, p = 0.001). The role of this mutation in IDDM cannot be explained yet, but, because CCR2 mediates the chemotaxis of CD4+ and CD8+ T cells to areas of inflammation and because these cells play important roles in insulitis, a mutation in the CCR2 gene may contribute to the susceptibility to the disease. Alternatively, the 64I allele could be a marker of a linked mutation through linkage disequilibrium. According to these results, the CCR2 gene may be a new candidate for the susceptibility locus of IDDM. However, because no IDDM locus has been identified near 3p21 until now, further investigations are needed to confirm this statement.

Association of primary biliary cirrhosis with vitamin D receptor BsmI genotype polymorphism in a Hungarian population

We sought to determine the distribution of vitamin D receptor genotypes defined by the BsmI polymorphism and to investigate their association with bone mineral density in patients with primary biliary cirrhosis. Vitamin D receptor genotype and bone mineral density at the lumbar spine was determined in 31 female Hungarian patients with primary biliary cirrhosis and 51 age-matched healthy female controls. The genotype frequency (BB: 45%, Bb: 32%, bb: 22%) of the patients was significantly different from the control group (P = 0.01) due to an overrepresentation of the BB genotype. There was an apparent trend, not reaching statistical significance, for a lower bone mineral density in both the patient and control groups carrying a B allele. In conclusion, we found a strikingly high frequency of the BB genotype in patients with primary biliary cirrhosis, which raises questions about hormonal influences on the development of primary biliary cirrhosis.

Association of polymorphisms and allelic combinations in the tumour necrosis factor-α-complement MHC region with coronary artery disease

It is a complicating factor in the search for disease associated genes in the human population that most diseases are very heterogeneous clinically and that certain genetic factors may not alone cause susceptibility to a disease, but in association with other genetic and environmental factors. It is especially true for coronary artery disease (CAD) and disease susceptibility genes in the human major histocompatibility complex (MHC). Given the conservation of whole haplotypes (polymorphic frozen blocks or extended haplotypes) and the cis acting genes within the MHC, it is highly likely that disease association is the result of a multiplicity of interactive genetic influences rather than a single gene.1 By tradition, a disease is said to be MHC associated if the frequency of one or more alleles is increased or decreased significantly when a patient group is compared with a relevant control group. This approach cannot uncover the possible interactions of different alleles and may result in both false positive and false negative association. In our study on patients with CAD, we make an attempt to investigate not only the impact of single allelic variations within the MHC, but also the impact of a combination of these allelic variations on susceptibility to the disease. The tumour necrosis factor-α ( TNFα ) gene is located on chromosome 6 between the class I and III clusters of the human MHC.2 It has been suggested that TNFα plays a role in cardiovascular pathophysiology as it may affect lipid metabolism3 and predispose to obesity related insulin resistance.4 Several TNFα variants with polymorphisms in their promoter regions have been described.5 Two of them (−308G-A and −238G-A) have been found to be associated with a variety of MHC linked diseases.5–7 Complement factor genes are located just a few hundred kilobases (kb) from the …

Receptor polymorphisms and diseases

The aim of our review is to summarize common genetic variations of some receptors associated with clinical consequences, which were not outlined in the previous special issue of this journal. Because of the multiple pathomechanisms of diseases, a set of genetic variation can play a role in the development of pathological conditions. From the data available three articles would merit a greater interest. In systemic lupus erythematosus the associations related to some polymorphisms of Fc-, tumor necrosis factor (TNF) alpha- and interferon receptor may explore new autoimmunological and inflammatorical pathomechanisms. In the endocrinology, the androgen receptor repeat polymorphism will exert significant aspects in the development of prostate cancer. The pleoitropic responsibility of vitamin D3 receptor polymorphism in the pathogenesis of immunological disorders (primary biliary cirrhosis, inflammatory bowel disease, type 1 diabetes mellitus) and of malignancies (malignant melanoma, breast cancer) shed light on the importance of common nuclear receptors. Nevertheless, in the future studies a more consistent approach minimizing requirement bias in the selection of patients will approve our understanding the role of genetic influence on the pathogenesis of diseases.

Increased apolipoprotein E4 allele frequency is associated with vascular dementia in the Hungarian population

Introduction – The regulatory role of apolipoprotein E in lipid transport and metabolism was utilized to investigate the allelic association between the apolipoprotein E4 (apoE4) allele and vascular dementia (VD) in a selected sample of Hungarian patients with multiple deep subcortical infarcts and leukoaraiosis. Material and methods – Thirty‐four Caucasian VD cases and 79 healthy control probands were involved in this study according to the criteria of ICD‐10 and NINDS–AIREN International Workshop Diagnostic Criteria. The genomic DNA was isolated from whole blood and the apoE alleles were determined by polymerase chain reaction. Results – The E2, E3 and E4 allele frequencies in the VD group were 5%, 76%, and 19%, respectively; and significant (P<0.03) differences were found in comparison with the data on the healthy controls (E2, 6%; E3, 87%; E4, 8%). The apoE4 allele frequency was intermediate between HC and Alzheimers dementia group (28%). Conclusion – These results indicate that the apoE4 allele could be a risk factor not only for certain primary degenerative, but also for vascular dementias.

Angiotensin II type 1 receptor gene polymorphism and mitral valve prolapse syndrome

BACKGROUND Mitral valve prolapse syndrome (MVPS), a term applied to patients who have a variety of symptoms, has been associated with autonomic or neuroendocrine dysfunction. Recent evidence suggests that effects of angiotensin II mediated by the angiotensin II type 1 (AT(1)) receptor are involved in modulation of cardiovascular autonomic control in human beings. Association of a genetic polymorphism (A-C(1166)) of the AT(1) gene with abnormal vasomotion and low blood pressure related to autonomic control has been reported recently. Because the role of this genetic variant in MVPS has not been studied, we performed a case-control study of the A-C(1166) variant in a group of 76 white subjects with MVPS. METHODS AND RESULTS All patients were genotyped by use of a mismatch polymerase chain reaction/Afl II restriction fragment length polymorphism analysis. Frequency of the C(1166) allele was 0.4 in patients with MVPS and 0.26 in control patients. The difference in genotype (chi square = 6.5; P <.05) and allele (chi square = 5.9; P =.02) frequencies between the groups was significant. The odds ratio in favor of carrying the C allele was 4 times greater for patients with MVP than for control patients (95% confidence interval 1.4 to 12.1). CONCLUSIONS The current results indicate that the A-C(1166) polymorphism of the angiotensin II type 1 receptor gene is associated with MVPS in the white population.

Prevalence of metabolic syndrome estimated by International Diabetes Federation criteria in a Hungarian population

Aims. In recent years, metabolic syndrome (MS) became a distinct pathological entity. MS is positively associated with cardiovascular mortality. The prevalence of MS is high and a continuing increase is expected. For this reason, all attempts to prevent or manage MS by interventions are extremely important. The new set of definition by International Diabetes Federation (IDF) standardizes criteria for the diagnosis of MS and facilitates its recognition. In a large sample (n = 13 383) of outpatients visiting their general practitioners, we determined the prevalence of risk factors of MS according to the earlier Adult Treatment Panel (ATP) III and the new IDF criteria. Methods and results. The age‐standardized prevalence of MS was 14.9% in males and 8.6% in females (11.5% for all). The most prevalent factors were obesity (ATP III: 38.8% and IDF: 60%) and hypertriglyceridemia (34.1%). Hypertension dominated in men (28.7%), whereas in women obesity was the most prevalent factor (ATP III: 47.4% and IDF: 64%). Conclusion. The prevalence of MS depends on applied definition. The new IDF criteria offer the possibility of focusing on the importance of different components. The real comparison of prevalence among special populations has to be based on age‐standardized data and the use of the same components. In our study, the dominance of obesity, hypertension and hypertriglyceridemia appears to be the major detrimental factors. The 11.5% general prevalence of MS in Hungarians, which means a 25–30% value in the middle‐aged population, needs an urgent preventive approach with lifestyle changes.