Single Nucleotide Variants (SNVs) of the Mesocorticolimbic System Associated with Cardiovascular Diseases and Type 2 Diabetes: A Systematic Review.

The mesocorticolimbic (MCL) system is crucial in developing risky health behaviors which lead to cardiovascular diseases (CVDs) and type 2 diabetes (T2D). Although there is some knowledge of the MCL system genes linked to CVDs and T2D, a comprehensive list is lacking, underscoring the significance of this review. This systematic review followed PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The PubMed and Web of Science databases were searched intensively for articles related to the MCL system, single nucleotide variants (SNVs, formerly single nucleotide polymorphisms, SNPs), CVDs, T2D, and associated risk factors. Included studies had to involve a genotype with at least one MCL system gene (with an identified SNV) for all participants and the analysis of its link to CVDs, T2D, or associated risk factors. The quality assessment of the included studies was performed using the Q-Genie tool. The VEP and DAVID tools were used to annotate and interpret genetic variants and identify enriched pathways and gene ontology terms associated with the gene list. The review identified 77 articles that met the inclusion criteria. These articles provided information on 174 SNVs related to the MCL system that were linked to CVDs, T2D, or associated risk factors. The COMT gene was found to be significantly related to hypertension, dyslipidemia, insulin resistance, obesity, and drug abuse, with rs4680 being the most commonly reported variant. This systematic review found a strong association between the MCL system and the risk of developing CVDs and T2D, suggesting that identifying genetic variations related to this system could help with disease prevention and treatment strategies.

A Transcriptomic Analysis of Smoking-Induced Gene Expression Alterations in Coronary Artery Disease Patients.

Smoking is a well established risk factor for coronary artery disease (CAD). Despite this, there have been no previous studies investigating the effects of smoking on blood gene expression in CAD patients. This single-centre cross-sectional study was designed with clearly defined inclusion criteria to address this gap. We conducted a high-throughput approach using next generation sequencing analysis with a single-end sequencing protocol and a read length of 75-cycles. Sixty-one patients with a median age of 67 years (range: 28-88 years) were recruited, and only 44 subjects were included for further analyses. Our investigation revealed 120 differentially expressed genes (DEGs) between smokers and nonsmokers, with a fold change (FC) of ≥1.5 and a p-value < 0.05. Among these DEGs, 15 were upregulated and 105 were downregulated. Notably, when applying a more stringent adjusted FC ≥ 2.0, 31 DEGs (5 upregulated, annotated to immune response pathways, and 26 downregulated, involving oxygen and haem binding or activity, with FDR ≤ 0.03) remained statistically significant at an alpha level of <0.05. Our results illuminate the molecular mechanisms underlying CAD, fortifying existing epidemiological evidence. Of particular interest is the unexplored overexpression of RCAN3, TRAV4, and JCHAIN genes, which may hold promising implications for the involvement of these genes in CAD among smokers.

A combination of strongly associated prothrombotic single nucleotide polymorphisms could efficiently predict venous thrombosis risk.

Background: Venous thrombosis (VT) is multifactorial trait that contributes to the global burden of cardiovascular diseases. Although abundant single nucleotide polymorphisms (SNPs) provoke the susceptibility of an individual to VT, research has found that the five most strongly associated SNPs, namely, rs6025 (F5 Leiden), rs2066865 (FGG), rs2036914 (F11), rs8176719 (ABO), and rs1799963 (F2), play the greatest role. Association and risk prediction models are rarely established by using merely the five strongly associated SNPs. This study aims to explore the combined VT risk predictability of the five SNPs and well-known non-genetic VT risk factors such as aging and obesity in the Hungarian population. Methods: SNPs were genotyped in the VT group (n = 298) and control group (n = 400). Associations were established using standard genetic models. Genetic risk scores (GRS) [unweighted GRS (unGRS), weighted GRS (wGRS)] were also computed. Correspondingly, the areas under the receiver operating characteristic curves (AUCs) for genetic and non-genetic risk factors were estimated to explore their VT risk predictability in the study population. Results: rs6025 was the most prevalent VT risk allele in the Hungarian population. Its risk allele frequency was 3.52-fold higher in the VT group than that in the control group [adjusted odds ratio (AOR) = 3.52, 95% CI: 2.50-4.95]. Using all genetic models, we found that rs6025 and rs2036914 remained significantly associated with VT risk after multiple correction testing was performed. However, rs8176719 remained statistically significant only in the multiplicative (AOR = 1.33, 95% CI: 1.07-1.64) and genotypic models (AOR = 1.77, 95% CI: 1.14-2.73). In addition, rs2066865 lost its significant association with VT risk after multiple correction testing was performed. Conversely, the prothrombin mutation (rs1799963) did not show any significant association. The AUC of Leiden mutation (rs6025) showed better discriminative accuracy than that of other SNPs (AUC = 0.62, 95% CI: 0.57-0.66). The wGRS was a better predictor for VT than the unGRS (AUC = 0.67 vs. 0.65). Furthermore, combining genetic and non-genetic VT risk factors significantly increased the AUC to 0.89 with statistically significant differences (Z = 3.924, p < 0.0001). Conclusions: Our study revealed that the five strongly associated SNPs combined with non-genetic factors could efficiently predict individual VT risk susceptibility. The combined model was the best predictor of VT risk, so stratifying high-risk individuals based on their genetic profiling and well-known non-modifiable VT risk factors was important for the effective and efficient utilization of VT risk preventive and control measures. Furthermore, we urged further study that compares the VT risk predictability in the Hungarian population using the formerly discovered VT SNPs with the novel strongly associated VT SNPs.

Comparison of Genetic Susceptibility to Coronary Heart Disease in the Hungarian Populations: Risk Prediction Models for Coronary Heart Disease.

Background and Aim: It was evaluated whether the integration of genetic risk scores (GRS-unweighted, wGRS-weighted) into conventional risk factor (CRF) models for coronary heart disease or acute myocardial infarction (CHD/AMI) could improve the predictive ability of the models. Methods: Subjects and data collected in a previous survey were used to perform regression and ROC curve analyses as well as to examine the role of genetic components. Thirty SNPs were selected, and genotype and phenotype data were available for 558 participants (general: N = 279 and Roma: N = 279). Results: The mean GRS (27.27 ± 3.43 vs. 26.68 ± 3.51, p = 0.046) and wGRS (3.52 ± 0.68 vs. 3.33 ± 0.62, p = 0.001) were significantly higher in the general population. The addition of the wGRS to the CRF model yielded the strongest improvement in discrimination among Roma (from 0.8616 to 0.8674), while the addition of GRS to the CRF model yielded the strongest improvement in discrimination in the general population (from 0.8149 to 0.8160). In addition to that, the Roma individuals were likely to develop CHD/AMI at a younger age than subjects in the general population. Conclusions: The combination of the CRFs and genetic components improved the model's performance and predicted AMI/CHD better than CRFs alone.

Prognostic Modelling Studies of Coronary Heart Disease-A Systematic Review of Conventional and Genetic Risk Factor Studies.

This study aims to provide an overview of multivariable prognostic modelling studies developed for coronary heart disease (CHD) in the general population and to explore the optimal prognostic model by comparing the models' performance. A systematic review was performed using Embase, PubMed, Cochrane, Web of Science, and Scopus databases until 30 November 2019. In this work, only prognostic studies describing conventional risk factors alone or a combination of conventional and genomic risk factors, being developmental and/or validation prognostic studies of a multivariable model, were included. A total of 4021 records were screened by titles and abstracts, and 72 articles were eligible. All the relevant studies were checked by comparing the discrimination, reclassification, and calibration measures. Most of the models were developed in the United States and Canada and targeted the general population. The models included a set of similar predictors, such as age, sex, smoking, cholesterol level, blood pressure, BMI, and diabetes mellitus. In this study, many articles were identified and screened for consistency and reliability using CHARM and GRIPS statements. However, the usefulness of most prognostic models was not demonstrated; only a limited number of these models supported clinical evidence. Unfortunately, substantial heterogeneity was recognized in the definition and outcome of CHD events. The inclusion of genetic risk scores in addition to conventional risk factors might help in predicting the incidence of CHDs; however, the generalizability of the existing prognostic models remains open. Validation studies for the existing developmental models are needed to ensure generalizability, improve the research quality, and increase the transparency of the study.

The Higher Prevalence of Venous Thromboembolism in the Hungarian Roma Population Could Be Due to Elevated Genetic Risk and Stronger Gene-Environmental Interactions.

Background: Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures. Objective: To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations. Methods: The study was based on data extracted from a database consisting of results previously obtained from a complex health survey with three pillars (questionnaire-based, physical, and laboratory examinations) involving 406 general Hungarian and 395 Roma subjects. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. After allele frequency comparisons, the odds ratio (OR) was calculated for individual SNPs. Furthermore, genetic risk scores (weighted GRS, unweighted GRS) were computed to estimate the joint effect of the genetic factors. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk after interaction terms were created between genetic and VTE risk factors [diabetes mellitus (DM), cancer, chronic kidney diseases (CKD), coronary artery diseases (CAD), migraine, depression, obesity, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein (HDL-C), triglyceride (TG), and smoking]. Results: Interestingly, the rs121909567 (SERPINC1, ATBp3 mutation) SNP was not present in the general population at all. However, the risk allele frequency was 1% among the Roma population, which might suggest a founder effect in this minority. This polymorphism multiplicatively interacted with CAD, CKD, cancer, DM, depression, migraine, and obesity. Even though interactions were not statistically significant, the trend of interaction showed the probability of an incremental VTE risk among the Roma population. The risk of VTE was 4.7 times higher (p > 0.05) for Roma subjects who had ≥3 wGRS (median value) compared with individuals having lower wGRS values but lower for the general subjects (OR = 3.1 × 10-8). Additionally, the risk of VTE was 6.6 times higher in the Roma population that had ≥3 risk alleles (median value) than in individuals with the 0-1 risk allele, and the overall risk was much higher for the Roma population (OR = 6.6; p > 0.05) than for the general Hungarian population (OR = 1.5; p > 0.05). Five positive and significant GxE interactions were identified in the Roma population. The risk of VTE was higher among depressive Roma subjects who carried the risk variant rs2036914 (ß = 0.819, p = 0.02); however, this interaction was not significant for the general subjects. The joint presence of high levels of LDL-C and rs2066865 (FGG) increased the VTE risk only among Roma individuals (ß = 0.389, p = 0.002). The possibility of VTE risk increment, as a result of a multiplicative interaction between rs8176719 (ABO) and cancer, was identified, which was higher for the Roma population (ß = 0.370, p < 0.001) than for the general population (ß = -0.042, p = 0.6). The VTE risk increased in the Roma population (ß = 0.280, p = 0.001), but was higher in the general population (ß = 0.423, p = 0.001) as a result of the multiplicative interaction between CAD and rs2036914 (F11). The presence of a multiplicative interaction between rs2066865 (FGG) and CAD increased the VTE risk for the Roma population (ß = 0.143, p = 0.046) but not for the general population (ß = -0.329, p < 0.001). Conclusions: rs121909567 (SERPINC1, ATBp3) was confirmed as a founder mutation in the Roma population. Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE, although the finding is highly subjected to the selection and observational biases due to the very small number of VTE cases and the observational nature of the study design, respectively. As a result of higher genetic load and GxE interactions, this minority Roma population is at higher risk of VTE than the general Hungarian population. Thus, our results suggest the need for an intensive search for the rs121909567 (SERPINC1; ATBp3) founder mutation, which might be an important factor for the assessment of thrombotic disease susceptibility among the Roma population. In addition, we strongly recommend further studies among a large number of VTE cases to explore the more precise impact of genetic and environmental risk factors on VTE in the study populations.

Leptin Receptor (rs1137101) and Brain-Derived Neurotrophic Factor (rs925946) Gene Variants Are Associated with Obesity in the Early- but Not in the Late-Onset Population of Hungarian Psoriatic Patients.

BACKGROUND: Psoriatic patients have considerably higher odds of being obese compared with the general population; however, the exact pathophysiological link between psoriasis and obesity needs to be elucidated. METHODS: To investigate the association of psoriasis with established obesity-related gene variants, we conducted a population-based case-control study including 3541 subjects (574 psoriasis cases and 2967 controls from the general Hungarian population). Genotyping of 20 SNPs at ADIPOQ, BDNF, FTO, GNPDA2, LEPR, MC4R, NEGR1, NPY, PPARG, TMEM18, and UCP2 were determined, and differences in genotype and allele distributions were investigated. Multiple logistic regression analyses were implemented. RESULTS: Analysis revealed an association between the G allele of the rs1137101 polymorphism (LEPR gene) and obesity risk (OR: 3.30 (1.45; 7.50), p = 0.004) in the early-onset group of psoriatic patients. Furthermore, the T allele of rs925946 polymorphism (BDNF gene) was also associated with increased risk of obesity in early-onset psoriasis (OR: 2.26 (1.24; 4.14), p = 0.008). CONCLUSIONS: Our results suggest that in psoriatic patients, there are prominent differences in the causes of obesity that should be accounted for, including not only environmental factors but also patient characteristics, such as the time of disease onset as well as genetic factors.

Roma Socioeconomic Status Has a Higher Impact on Smoking Behaviour than Genetic Susceptibility.

It is a matter of speculation whether the high prevalence of smoking among Hungarian Roma (HR) is related to genetic, gene-environmental interactions or cultural factors. Our aim is to compare the genetic susceptibility and possible effects of determinants associated with smoking behaviours in the Hungarian general (HG) and Roma populations. A complex health survey including three pillars (questionnaire, physical and laboratory examinations) was carried out (NHG = 412 and NHR = 402). Risk allele frequencies of ten single-nucleotide polymorphisms (SNPs) were compared, and their combined effect was estimated by computing unweighted and weighted genetic risk scores (GRS, wGRS). The effects of genetic and environmental factors were investigated in regression analyses after confounders were introduced. Socio-economic status (SES) was calculated based on the Kuppuswamy scale 2019. Risk allele frequencies of only four SNPs were found to be different between populations (p < 0.01). Median values of GRS did not differ, while the wGRS median was slightly higher among Roma individuals (5.2 vs. 4.9; p = 0.02). Roma individuals were more likely to be heavy smokers (ORmales = 2.05, 95% CI [1.47-2.86]; ORfemales = 1.89, 95% CI [1.58-2.25]. Smokers have lower SES compared to never smokers (SES ßHR = -0.039, p = 0.023; ßHG = -0.010, p = 0.049). An inverse relationship was found between SES and smoking behaviours (p < 0.0001) and was found to be a better predictor of smoking behaviours than genetic susceptibility. Our study findings suggest that the high prevalence of smoking behaviours and nicotine-dependence were not revealed to have a genetic susceptibility among HR individuals; therefore, the highest efforts should be focused on targeting SES-related factors in the Roma population. Strengths of the study: This is the first study carried out to investigate and detect the most relevant factors and the possible genetic background of the extremely high prevalence of smoking based in the Roma population. Limitations of the study: No standard instrument has been used to assess the intensity of addiction to nicotine. Because of some participants' unwillingness to define themselves as Roma, the overall HR population was not represented by the sample of this study.

Impact of Genetic Factors on the Age of Onset for Type 2 Diabetes Mellitus in Addition to the Conventional Risk Factors.

It is generally accepted that the early detection of type 2 diabetes mellitus (T2DM) is important to prevent the development of complications and comorbidities, as well as premature death. The onset of type 2 diabetes mellitus results from a complex interplay between genetic, environmental, and lifestyle risk factors. Our study aims to evaluate the joint effect of T2DM associated single nucleotide polymorphisms (SNPs) on the age of onset for T2DM in combination with conventional risk factors (such as sex, body mass index (BMI), and TG/HDL-C ratio) in the Hungarian population. This study includes 881 T2DM patients (Case population) and 1415 samples from the Hungarian general population (HG). Twenty-three SNPs were tested on how they are associated with the age of onset for T2DM in the Case population and 12 of them with a certified effect on the age of T2DM onset were chosen for an optimized genetic risk score (GRS) analysis. Testing the validity of the GRS model developed was carried out on the HG population. The GRS showed a significant association with the age of onset for T2DM (ß = -0.454, p = 0.001) in the Case population, as well as among T2DM patients in the HG one (ß = -0.999, p = 0.003) in the replication study. The higher the GRS, the earlier was the T2DM onset. Individuals with more than eight risk alleles will presumably be diabetic six and a half years earlier than those with less than four risk alleles. Our results suggest that there is a considerable genetic predisposition for the early onset of T2DM; therefore, in addition to conventional risk factors, GRS can be used as a tool for estimating the risk of the earlier onset of T2DM and stratifying populations at risk in order to define preventive interventions.

Prevalence of Insulin Resistance in the Hungarian General and Roma Populations as Defined by Using Data Generated in a Complex Health (Interview and Examination) Survey.

Data mainly from one-off surveys clearly show that the health of Roma, the largest ethnic minority of Europe, is much worse than that of the general population. However, results from comprehensive exploratory studies are missing. The aim of our study was to create a complex database for comparative and association studies to better understand the background of the very unfavourable health of Roma, especially the high burden of cardiometabolic diseases. A three-pillar (questionnaire-based, physical and laboratory examinations) health survey was carried out on randomly selected samples of the Hungarian general (HG, n = 417) and Roma (HR, n = 415) populations, and a database consisting of more than half a million datapoints was created. Using selected data, the prevalence rates of metabolic syndrome (MetS) and of its components were determined, and to estimate the risk of insulin resistance (IR), surrogate measures (the homeostasis model assessment of insulin resistance index, quantitative insulin sensitivity check index, McAuley and TyG indices and the TG/HDL-C ratio) were calculated. Receiver operating characteristic curve analysis and Youden's method were used to define the optimal cut-off values of each IR index. The prevalence of MetS was very high in both study populations (HG: 39.8%, HR: 44.0%) with no statistically significant difference between the two groups in females or males. The prevalence of MetS showed a very marked increase in the HR 35-49 years age group. Among surrogate measures, the TyG index showed the greatest power for predicting IR/MetS at a cut-off value of 4.69 (77% sensitivity, 84% specificity) and indicated a 42.3% (HG) and 40.5% (HR) prevalence of IR. The prevalence of MetS and IR is almost equally very unfavourable in both groups; thus, the factors underlying the high premature mortality burden of Roma should be further clarified by investigating the full spectrum of risk factors available in the database, with a special focus on the access of Roma people to preventive and curative health services.

The genetic risk for hypertension is lower among the Hungarian Roma population compared to the general population.

Estimating the prevalence of cardiovascular diseases (CVDs) and risk factors among the Roma population, the largest minority in Europe, and investigating the role of genetic or environmental/behavioral risk factors in CVD development are important issues in countries where they are significant minority. This study was designed to estimate the genetic susceptibility of the Hungarian Roma (HR) population to essential hypertension (EH) and compare it to that of the general (HG) population. Twenty EH associated SNPs (in AGT, FMO3, MTHFR-NPPB, NPPA, NPPA-AS1, AGTR1, ADD1, NPR3-C5orf23, NOS3, CACNB2, PLCE1, ATP2B1, GNB3, CYP1A1-ULK3, UMOD and GNAS-EDN3) were genotyped using DNA samples obtained from HR (N = 1176) and HG population (N = 1178) subjects assembled by cross-sectional studies. Allele frequencies and genetic risk scores (unweighted and weighted genetic risk scores (GRS and wGRS, respectively) were calculated for the study groups and compared to examine the joint effects of the SNPs. The susceptibility alleles were more frequent in the HG population, and both GRS and wGRS were found to be higher in the HG population than in the HR population (GRS: 18.98 ± 3.05 vs. 18.25 ± 2.97, p<0.001; wGRS: 1.4 [IQR: 0.93-1.89] vs. 1.52 [IQR: 0.99-2.00], p<0.01). Twenty-seven percent of subjects in the HR population were in the bottom fifth (GRS ≤ 16) of the risk allele count compared with 21% of those in the HG population. Thirteen percent of people in the HR group were in the top fifth (GRS ≥ 22) of the GRS compared with 21% of those in the HG population (p<0.001), i.e., the distribution of GRS was found to be left-shifted in the HR population compared to the HG population. The Roma population seems to be genetically less susceptible to EH than the general one. These results support preventive efforts to lower the risk of developing hypertension by encouraging a healthy lifestyle.

Applicability of Obesity-Related SNPs and their Effect Size Measures Defined on Populations with European Ancestry for Genetic Risk Estimation among Roma.

Investigations on the impact of genetic factors on the development of obesity have been limited regarding the Roma population-the largest and most vulnerable ethnic minority in Europe of Asian origin. Genetic variants identified from genetic association studies are primarily from European populations. With that in mind, we investigated the applicability of data on selected obesity-related single nucleotide polymorphisms (SNPs), obtained from the Hungarian general (HG) population of European origin, on the Hungarian Roma (HR) population. Twenty preselected SNPs in susceptible alleles, known to be significantly associated with obesity-related phenotypes, were used to estimate the effect of these SNPs on body mass index (BMI) and waist circumference (WC) in HG (N = 1783) and HR (N = 1225) populations. Single SNP associations were tested using linear and logistic regression models, adjusted for known covariates. Out of 20 SNPs, four located in FTO (rs1121980, rs1558902, rs9939609, and rs9941349) showed strong association with BMI and WC as continuous variables in both samples. Computations based on Adult Treatment Panel III (ATPIII) and the International Diabetes Federation's (IDF) European and Asian criteria showed rs9941349 in FTO to be associated only with WC among both populations, and two SNPs (rs2867125, rs6548238) in TMEM18 associated with WC only in HG population. A substantial difference (both in direction and effect size) was observed only in the case of rs1801282 in PPARγ on WC as a continuous outcome. Findings suggest that genetic risk scores based on counting SNPs with relatively high effect sizes, defined based on populations with European ancestry, can sufficiently allow estimation of genetic susceptibility for Roma. Further studies are needed to clarify the role of SNP(s) with protective effect(s).

The Effect of Haplotypes in the CETP and LIPC Genes on the Triglycerides to HDL-C Ratio and Its Components in the Roma and Hungarian General Populations.

BACKGROUND: The triglycerides (TG) to high-density lipoprotein (HDL)-cholesterol (HDL-C) ratio (TG/HDL-C) is a well-known predictor for cardiovascular diseases (CVDs) with great heritability background. The cholesteryl ester transfer protein (CETP) and hepatic lipase (LIPC) gene affect TG/HDL-C ratio. This study aims to explore the association between haplotypes (H) in CETP (based on 5 single nucleotide polymorphisms (SNPs)) and LIPC (based on 6 SNPs) genes and the TG/HDL-C ratio and its components, among Roma and Hungarian general populations. METHODS: The prevalence of haplotypes and their effect on HDL-C, TG and TG/HDL-C ratio were calculated in both populations and compared. RESULTS: Ten haplotypes in CETP and 6 in LIPC gene were identified. Three haplotypes in CETP and 3 in LIPC have significant effect on HDL-C level, whereas two in CETP and 3 in LIPC on TG level. The H6 in CETP (ß = 0.52, p = 0.015; odds ratio (OR) = 1.87, p = 0.009) and H5 in LIPC (ß = 0.56, p < 0.001; OR = 1.51, p = 0.002) have a significant increasing effect on TG/HDL-C ratio and have shown higher prevalence among the Roma, as compared to Hungarian general population. The H2 in the CETP gene has a decreasing effect on the TG/HDL-C ratio (OR = 0.58, p = 0.019) and is significantly less frequent among the Roma. CONCLUSIONS: Accumulation of harmful haplotypes in CETP and LIPC genes might have a role in the elevated TG/HDL-C ratio in the Roma population, which contributes to a higher risk in the development of cardiovascular diseases.

Age and Origin of the Founder Antithrombin Budapest 3 (p.Leu131Phe) Mutation; Its High Prevalence in the Roma Population and Its Association With Cardiovascular Diseases.

Background: Antithrombin (AT) is one of the most important regulator of hemostasis. AT Budapest 3 (ATBp3) is a prevalent type II heparin-binding site (IIHBS) deficiency due to founder effect. Thrombosis is a complex disease including arterial (ATE) and venous thrombotic events (VTE) and the Roma population, the largest ethnic minority in Europe has increased susceptibility to these diseases partly due to their unfavorable genetic load. We aimed to calculate the age and origin of ATBp3 and to explore whether the frequency of it is higher in the Roma population as compared with the general population from the corresponding geographical area. We investigated the association of ATBp3 with thrombotic events in well-defined patients' populations in order to refine the recommendation when testing for ATBp3 is useful. Methods and Results: Prevalence of ATBp3, investigated in large samples (n = 1,000 and 1,185 for general Hungarian and Roma populations, respectively) was considerably high, almost 3%, among Roma and the founder effect was confirmed in their samples, while it was absent in the Hungarian general population. Age of ATBp3-as calculated by analysis of 8 short tandem repeat sequences surrounding SERPINC1-was dated back to XVII Century, when Roma migration in Central and Eastern Europe occurred. In our IIHBS cohort (n = 230), VTE was registered in almost all ATBp3 homozygotes (93%) and in 44% of heterozygotes. ATE occurred with lower frequency in ATBp3 (around 6%); it was rather associated with AT Basel (44%). All patients with ATE were young at the time of diagnosis. Upon investigating consecutive young (<40 years) patients with ATE (n = 92) and VTE (n = 110), the presence of ATBp3 was remarkable. Conclusions: ATBp3, a 400-year-old founder mutation is prevalent in Roma population and its Roma origin can reasonably be assumed. By the demonstration of the presence of ATBp3 in ATE patients, we draw the attention to consider type IIHBS AT deficiency in the background of not only VTE but also ATE, especially in selected populations as young patients without advanced atherosclerosis. We recommend including the investigation of ATBp3 as part of thrombosis risk assessment and stratification in Roma individuals.

SNP-Based Genetic Risk Score Modeling Suggests No Increased Genetic Susceptibility of the Roma Population to Type 2 Diabetes Mellitus.

BACKGROUND: In a previous survey, an elevated fasting glucose level (FG) and/or known type 2 diabetes mellitus (T2DM) were significantly more frequent in the Roma population than in the Hungarian general population. We assessed whether the distribution of 16 single nucleotide polymorphisms (SNPs) with unequivocal effects on the development of T2DM contributes to this higher prevalence. METHODS: Genetic risk scores, unweighted (GRS) and weighted (wGRS), were computed and compared between the study populations. Associations between GRSs and FG levels and T2DM status were investigated in separate and combined study populations. RESULTS: The Hungarian general population carried a greater genetic risk for the development of T2DM (GRSGeneral = 15.38 ± 2.70 vs. GRSRoma = 14.80 ± 2.68, p < 0.001; wGRSGeneral = 1.41 ± 0.32 vs. wGRSRoma = 1.36 ± 0.31, p < 0.001). In the combined population models, GRSs and wGRSs showed significant associations with elevated FG (p < 0.001) and T2DM (p < 0.001) after adjusting for ethnicity, age, sex, body mass index (BMI), high-density Lipoprotein Cholesterol (HDL-C), and triglyceride (TG). In these models, the effect of ethnicity was relatively strong on both outcomes (FG levels: ßethnicity = 0.918, p < 0.001; T2DM status: ORethnicity = 2.484, p < 0.001). CONCLUSIONS: The higher prevalence of elevated FG and/or T2DM among Roma does not seem to be directly linked to their increased genetic load but rather to their environmental/cultural attributes. Interventions targeting T2DM prevention among Roma should focus on harmful environmental exposures related to their unhealthy lifestyle.

Genetic profiling revealed an increased risk of venous thrombosis in the Hungarian Roma population.

BACKGROUND: Besides modifiable risk factors, genetic susceptibility may also explain the high cardiovascular disease burden of the Roma population. OBJECTIVES: Aim of this study was to define the genetic susceptibility of Hungarian Roma to venous thrombosis (VT) and comparing it to that of the general population. METHODS: Fifty-two SNPs associated with VT (in F2, F5, F9, F11, F15, FGA, FGB, FGG, CYP4V2, KLKB1 and vWF) were selected and analyzed in the group of Roma (N = 962) and general (N = 1492) subjects collected by cross-sectional studies. Allele frequencies and genetic risk scores (GRS, unweighted and weighted) were computed for the study groups and compared to estimate the joint effects of SNPs. RESULTS: The majority of the susceptible alleles were more prevalent in the Roma population, and both GRS and wGRS were found to be significantly higher in Roma than in the general population (GRS: 41.83 ±â€¯5.78 vs. 41.04 ±â€¯6.04; wGRS: 7.78 ±â€¯1.28 vs. 7.46 ±â€¯1.33, p = .001). Only 2.39% of subjects in the Roma population were in the bottom fifth of the wGRS (wGRS≤0.19) compared with 3.62% of those in the general population (p = .080); 2.88% of the general subjects were in the top fifth of the wGRS (wGRS≥10.02), while 4.26% of the Roma population were (p = .066). CONCLUSION: In conclusion, the Roma population seems to have increased genetic susceptibility to VT. This might have important implications in the future in identifying possible new opportunities for targeted prevention and treatment for those subgroups in the populations who are at greater risk for VT development.

The prevalence of ADH1B and OPRM1 alleles predisposing for alcohol consumption are increased in the Hungarian psoriasis population.

Alcohol intake affects in great the symptoms and life of  psoriasis patients, although the association of SNPs related to increased alcohol consumption with psoriasis has not been elucidated. Therefore, to investigate the association of psoriasis with established alcohol consumption and dependence-related gene variants we conducted a population-based case-control study including 3743 subjects (776 psoriasis cases and 2967 controls from the general Hungarian population). Genotyping of 23 SNPs at ADH1B, ADH1C, ALDH1A1, ALDH2, SLC6A3, DDC, GABRA2, GABRG1, HTR1B, MAOA, TPH2, CHRM2, GRIN2A, POMC, OPRM1, OPRK1 and BDNF were determined and differences in genotype and allele distributions were investigated. Multiple logistic regression analyses were implemented. Analysis revealed association between C allele of the rs1229984 polymorphism (ADH1B gene) and psoriasis risk (ORadditive = 1.58, 95% CI 1.23-2.03, p < 0.001, ORrecessive = 1.58, 95% CI 1.22-2.04, p = 0.001). Furthermore, the G allele of rs1799971 polymorphism (OPRM1 gene) increased the risk of familial aggregation (ORadditive = 1.99, 95% CI 1.36-2.91, p < 0.001 ORdominant = 2.01, 95% CI 1.35-3.01, p < 0.001). In subgroups of psoriatic patients with history of early onset and familial aggregation effect allele 'C' of rs1229984 showed association in the additive and recessive models (ORadditive = 2.41, 95% CI 1.26-4.61, p < 0.01, ORrecessive = 2.42, 95% CI 1.26-4.68, p < 0.01). While effect allele 'G' of rs1799971 (OPRM1) also associated with increased risk of early onset and familial aggregation of psoriasis in the additive and dominant models (ORadditive = 1.75, 95% CI 1.27-2.43, p = 0.001, ORdominant = 1.82, 95% CI 1.26-2.63, p = 0.001). Our results suggest that genetically defined high-risk individuals for alcohol consumption are more common in the psoriasis population.

Generalizability and applicability of results obtained from populations of European descent regarding the effect direction and size of HDL-C level-associated genetic variants to the Hungarian general and Roma populations.

OBJECTIVES: Large-scale association studies that mainly involve European populations identified many genetic loci related to high-density lipoprotein cholesterol (HDL-C) levels, one of the most important indicators of the risk for cardiovascular diseases. The question with intense speculation of whether the effect estimates obtained from European populations for different HDL-C level-related SNPs are applicable to the Roma ethnicity, the largest minority group in Europe with a South Asian origin, was addressed in the present study. DESIGN: The associations between 21 SNPs (in the genes LIPC(G), CETP, GALNT2, HMGCP, ABCA1, KCTD10 and WWOX) and HDL-C levels were examined separately in adults of the Hungarian general (N = 1542) and Roma (N = 646) populations by linear regression. Individual effects (direction and size) of single SNPs on HDL-C levels were computed and compared between the study groups and with data published in the literature. RESULTS: Significant associations between SNPs and HDL-C levels were more frequently found in general subjects than in Roma subjects (11 SNPs in general vs. 4 SNPs in Roma). The CETP gene variants rs1532624, rs708272 and rs7499892 consistently showed significant associations with HDL-C levels across the study groups (p ˂ 0.05), indicating a possible causal variant(s) in this region. Although nominally significant differences in effect size were found for three SNPs (rs693 in gene APOB, rs9989419 in gene CETP, and rs2548861 in gene WWOX) by comparing the general and Roma populations, most of these SNPs did not have a significant effect on HDL-C levels. The ß coefficients for SNPs in the Roma population were found to be identical both in direction and magnitude to the effect obtained previously in large-scale studies on European populations. CONCLUSIONS: The effect of the vast majority of the SNPs on HDL-C levels could be replicated in the Hungarian general and Roma populations, which indicates that the effect size measurements obtained from the literature can be used for risk estimation for both populations.

Distinct Penetrance of Obesity-Associated Susceptibility Alleles in the Hungarian General and Roma Populations.

AIMS: The aim of our study was to explore differences in genetic predisposition to obesity between the Hungarian general and Roma populations. METHODS: A total of 1,152 samples from the Hungarian Roma population and 1,743 samples from the Hungarian general population were genotyped for 20 single nucleotide polymorphisms (SNPs) associated with the risk of obesity. Two types of multilocus genetic risk scores were constructed to estimate the combined effect of selected SNPs. RESULTS: Risk allele frequencies differed significantly between the two populations for 11 SNPs, with no enrichment in any of the two study groups. Variants (rs1558902, rs1121980, rs9939609, and rs9941349) in the fat mass and obesity-associated (FTO) gene exhibited strong but ethnicity-independent association with obesity. Genetic risk scores showed stronger associations with obesity in the Roma population compared with the Hungarian general population; however, without significant gene-population interaction. CONCLUSION: Differences in obesity prevalence between the Hungarian general and Hungarian Roma populations could not be explained by their distinct genetic susceptibility, rather by ethnicity-related environmental and behavioral factors. Nonetheless, particular gene-environment interactions might contribute to the distinct penetrance of the obesity-associated genetic factors in populations of different ethnic backgrounds.

Data to genetic risk assessment on high-density cholesterol level associated polymorphisms in Hungarian general and Roma populations.

Data obtained by genotyping single nucleotide polymorphisms (SNPs) related to high-density lipoprotein cholesterol (HDL-C) levels were utilized in Genetic Risk Score [unweighted (GRS) and weighted (wGRS)] computation on Hungarian general and Roma populations. The selection process of the SNPs as well as the results obtained are published in our research article (Piko et al., 2017) [1]. Linkage analyses were performed by study groups. Study populations were stratified by quintiles of weighted Genetic Risk Score. Multivariate linear regression analyses were performed using Genetic Risk Scores and HDL-C levels as dependent variables; and ethnicity, sex and age as independent variables. The study subjects were categorized into quintiles according their wGRS values. Associations of Genetic Risk Scores with plasma HDL-C levels (as a continuous variable) were observed in both populations. Finally, the two populations were merged and analyzed together by multivariate logistic regression where reduced plasma HDL-C level was the dependent variable; while ethnicity, age and sex were the independent ones.