Réka Tóth

Characterization of candidate gene copy number alterations in the 11q13 region along with BRAF and NRAS mutations in human melanoma

Amplification of the 11q13 chromosomal region is a common event in primary melanomas. Several candidate genes are localized at this sequence; however, their role in melanoma has not been clearly defined. The aim of this study was to develop an accurate method for determining the amplification pattern of six candidate genes that map to this amplicon core and to elucidate the possible relationship between BRAF, NRAS mutations and CCND1 copy number alterations, all of which are key components of the MAP kinase pathway. Characterization of gene copy numbers was performed by quantitative PCR and, as an alternative method, fluorescence in situ hybridization was used to define the CCND1 amplification pattern at the single cell level. Samples with amplified CCND1 (32%) were further analyzed for copy number alterations for the TAOS1, FGF3, FGF19, FGF4 and EMS1 genes. Coamplification of the CCND1 and TAOS1 was present in 15% of tumors and was more frequent in ulcerated lesions (P=0.017). Furthermore, 56% of primary melanomas had either BRAF or NRAS mutations, but these two mutations were not present in any of the lesions analyzed. Of these cases, 34% also had CCND1 amplification. There was a significant relationship between NRAS activating mutations and UV exposure (P=0.005). We did not find correlations between CCND1 gene amplification status and any of the patients’ clinicopathological parameters. However, CCND1 amplification simultaneously with either BRAF or NRAS activation mutations was observed mainly in primary tumors with ulcerated surfaces (P=0.028). We assume that coamplification of these candidate genes in the 11q13 region or CCND1 gene alterations along with either BRAF or NRAS mutations might be more important for prognosis than the presence of these alterations alone.

Insertion/deletion polymorphism of angiotensin-1 converting enzyme is associated with metabolic syndrome in Hungarian adults

The aim of our study was to evaluate whether any association exists between metabolic syndrome (MS) and ACE I/D and AGT M235T gene polymorphisms in Hungarians as an example of European Caucasian population. Study subjects of our cross-sectional study were recruited from the Hungarian General Practitioners’ Morbidity Sentinel Stations Program. The study population (n = 1762) approximates very well the age and sex distribution of the general Hungarian population. MS was defined according to the latest diagnostic criteria proposed by the International Diabetes Federation. The frequency of DD genotype (31.36% vs. 25.42%, p = 0.006) and the frequency of D allele (0.56 vs. 0.51, p = 0.006) were significantly higher in the metabolic group than in the non-metabolic group. The distribution of the AGT M235T polymorphism was similar in each group investigated. Association was shown in the case of patients in whom central obesity was combined with elevated TG and low HDL cholesterol level (p = 0.024 and p = 0.022). It suggests that ACE I/D polymorphism is likely to be involved in lipid metabolism.

Combined effect of ADH1B rs1229984, rs2066702 and ADH1C rs1693482/rs698 alleles on alcoholism and chronic liver diseases

The aim of this study was to analyze the combined effect of the most frequent alcohol dehydrogenase polymorphisms (Arg48His and Arg370Cys in ADH1B, Arg272Gln and Ile350Val in ADH1C) on the alcohol use habits, alcohol dependence and chronic liver diseases in Hungary. The study included men, aged 45–64 years. Altogether, 241 cases with chronic liver disease (CLD) and 666 randomly selected controls without CLD were analysed for all four polymorphisms. Associations between the polymorphisms, individually, and in combination, and excessive and problem drinking and CLD, were assessed using logistic regression. In this study we have identified a novel mutation, called ADH1B Arg370His. The ADH1C Arg272Gln and Ile350Val showed almost complete linkage. The 272Gln/350Val allele increased the risk of excessive and problem drinking in homozygous form (OR = 1.582, p = 0.035, CI = 1.034–2.421, OR = 1.780, p = 0.016, CI = 1.113–2.848, respectively). The joint analysis showed that when combined with the wild type ADH1C Arg272/Ile350 allele, the ADH1B 48His is protective against CLD (OR = 0.368, p = 0.019, CI = 0.159–0.851). The results obtained in the study help not only to clarify the effects of different ADH SNPs but to better understand how these polymorphisms modify each other’s effects in the development of alcoholism and related diseases.

ADH1B*2 allele is protective against alcoholism but not chronic liver disease in the Hungarian population.

BACKGROUND Standardized death rates from chronic liver diseases (CLDs) in Hungary are much higher than the European Union average. Carrying the alcohol dehydrogenase 1B 48His allele (rs1229984 or ADH1B*2) could decrease the risk of alcoholism, but with persistent drinking may confer a greater risk of CLDs. The aim of this study was to assess the prevalence of this polymorphism in the Hungarian population and its association with alcohol consumption and with CLDs. METHODS AND RESULTS A total of 278 cases with diagnosed CLDs and 752 controls without any alterations in liver function, all males aged 45-64, were screened for ADH1B Arg48His polymorphism. ADH1B*2 allele frequencies in controls and cases were 8.31% and 4.50%, respectively (chi(2) = 9.2; P = 0.01). Carrying the ADH1B*2 allele was associated with significantly lower odds ratio (OR) for drinking frequency (OR = 0.63; P = 0.003), the number of positive answers on CAGE (Cut-down, Annoyed, Guilt, Eye-opener) assessment (OR = 0.58; P = 0.005) and a positive CAGE status (OR = 0.55; P = 0.007). There was a significant association between ADH1B*2 and CLDs (OR = 0.50; P = 0.003), but it disappeared after adjusting for CAGE status and scores (OR = 0.67 P = 0.134; OR = 0.67 P = 0.148, respectively) and weakened after adjusting for drinking frequency (OR = 0.61; P = 0.045). Among heavy drinkers the presence of ADH1B*2 did not increase the risk of cirrhosis but there was a significant interaction between genotype and CAGE status (P = 0.003, P = 0.042), with ADH1B*2 conferring reduced risk of CLDs in CAGE negatives. CONCLUSION In Hungarians, the ADH1B 48His allele reduces the risk of alcoholism, but not the risk of chronic liver disease among heavy drinkers.

Cell death in HIV pathogenesis and its modulation by retinoids.

Abstract: Patients infected with the human immunodeficiency virus exhibit a progressive decline in the CD4 T‐cell number, resulting in immunodeficiency and increased susceptibility to opportunistic infections and malignancies. Although CD4 T cell production is impaired in patients infected with HIV, there is now increasing evidence that the primary basis of T cell depletion is accelerated apoptosis of CD4 and CD8 T cells. The rate of lymphocyte apoptosis in HIV infection correlates inversely with the progression of the disease: it is low in long‐term progressors and in patients undergoing highly active antiretroviral therapy. Interestingly, only a minor fraction of apoptotic lymphocytes are infected by HIV, indicating that the enhanced apoptosis does not necessarily always serve to remove the HIV+ cells and results from mechanisms other than direct infection. Thus, understanding and influencing the mechanisms of HIV‐associated lymphocyte apoptosis may lead to new therapies for HIV disease. In this paper the potential effects of retinoids on CD4 T cell apoptosis is discussed.

High Prevalence of Smoking in the Roma Population Seems to Have No Genetic Background

INTRODUCTION The prevalence of smoking in Romani of both genders is significantly higher than in the general population. Our aim was to determine whether a genetic susceptibility contributes to the high prevalence of smoking among Roma in a study based on data collected from cross-sectional surveys. METHODS Twenty single nucleotide polymorphisms known to be closely related to smoking behavior were investigated in DNA samples of Hungarian Roma (N = 1273) and general (N = 2388) populations. Differences in genotype and allele distribution were investigated. Genetic risk scores (GRSs) were generated to estimate the joint effect of single nucleotide polymorphisms in genes COMT, CHRNA3/4/5, CYP2A6, CTNNA3, DRD2, MAOA, KCNJ6, AGPHD1, ANKK1, TRPC7, GABRA4, and NRXN1. The distribution of scores in study populations was compared. Age, gender, and body mass index were considered as confounding factors. RESULTS Difference in allele frequencies between the study populations remained significant for 16 polymorphisms after multiple test correction (p < .003). Unexpectedly, the susceptible alleles were more common in the general population, although the protective alleles were more prevalent among Roma. The distribution of unweighted GRS in Roma population was left shifted compared to general population (p < .001). Furthermore, the median weighted GRS was lower among the subjects of Roma population compared to the subjects of general population (p < .001) even after adjustment for confounding factors. CONCLUSIONS The harmful smoking behavior of the Roma population could not be accounted for by genetic susceptibility; therefore, interventions aimed at smoking prevention and cessation should focus on cultural and environmental factors. IMPLICATIONS This is the first study designed to determine whether genetic background exists behind the harmful behavior of the smoking of the Roma population. Although the frequencies of susceptible and protective alleles strongly differ between the Hungarian Roma and general populations, it is shown that calculated GRSs being significantly higher in the general population, which do not support the hypothesis on the genetic susceptibility of the Roma population. Interventions aimed at smoking cessation in the Roma population should preferentially target cultural and environmental factors.

Distribution Characteristics and Combined Effect of Polymorphisms Affecting Alcohol Consumption Behaviour in the Hungarian General and Roma Populations

Aims Harmful alcohol drinking habits, even among Roma children and adolescents, are more common than in the majority population. The aim of the study was to evaluate the genetic susceptibility of Roma to hazardous alcohol consumption compared to the Hungarian general population. Methods A total of 1273 samples from the population of segregated Hungarian Roma colonies and 2967 samples from the Hungarian general population were genotyped for 25 polymorphisms. Differences in genotype and allele distributions were investigated. Genetic risk scores (GRS) were generated to estimate the joint effect of individual single-nucleotide polymorphisms (SNPs). After unweighted and weighted GRS were calculated the distribution of scores in study populations was compared. Results The allele frequencies differed significantly between the study populations for 17 SNPs (P < 0.002), but the genetic alterations that predispose to or protect against harmful alcohol consumption were not overrepresented in the Roma population. The distribution of unweighted GRS in Roma population was left shifted compared to general population (P = 0.0013). The median weighted genetic risk score was lower among the subjects of Roma population compared to the subjects of general population (0.53 vs 0.65, P = 3.33 × 10−27) even after adjustment for confounding factors. Conclusions Differences in alcohol consumption habits between the Hungarian Roma and Hungarian general populations do not appear to be linked to genetic constitution, this behaviour may occur as a result of different cultural values and environmental exposures. Population-based measures to tackle the fundamental drivers of consumption, which take account of cultural acceptability, are needed to reduce harmful alcohol consumption in the Roma population.