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The association between genetic polymorphisms and early cardiac allograft vasculopathy (CAV) development is relatively unexplored. Identification of genes involved in the CAV process may offer new insights into pathophysiology and lead to a wider range of therapeutic options.This prospective study of 109 patients investigated 44 single nucleotide polymorphisms (SNPs) within the susceptibility loci potentially related to coronary artery disease, carotid artery intima-media thickness (cIMT), and in nitric oxide synthase gene. Genotyping was done by the Fluidigm SNP Type assays and Fluidigm 48.48 Dynamic Array IFC. The intima thickness progression (IT) was evaluated by coronary optical coherence tomography performed 1 month and 12 months after heart transplantation (HTx).During the first post-HTx year, the mean intima thickness (IT) increased by 24.0 ± 34.2 µm (p0.001) and lumen area decreased by ‒0.9 ± 1.8 mm2 (p0.001). The rs1570360 (A/G) SNP of the vascular endothelial growth factor A (VEGFA) gene showed the strongest association with intima thickness progression, even in the presence of the traditional CAV risk factors. SNPs previously related to carotid artery intima-media thickness rs11785239 (PRAG1), rs6584389 (PAX2), rs13225723 (LINC02577) and rs17477177 (CCDC71L), were among the five most significantly associated with IT progression but lost their significance once traditional CAV risk factors had been added.Results of this study suggest that genetic variability may play an important role in CAV development. The vascular endothelial growth factor A gene SNP rs1570360 showed the strongest association with intima thickness (IT) progression measured by OCT, even in the presence of the traditional CAV risk factors (Tab. 3, Fig. 3, Ref. 36). Text in PDF www.elis.sk Keywords: cardiac allograft vasculopathy, optical coherence tomography, vascular endothelial growth factor A, intimal thickening, genetic polymorphism.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread from China in 2019/2020 to all continents. Significant geographical and ethnic differences were described, and host genetic background seems to be important for the resistance to and mortality of COVID-19. Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism (rs4646994) is one of the candidates with the potential to affect infection symptoms and mortality. Methods In our study, we successfully genotyped 408 SARS-CoV-2-positive COVID-19 survivors (163 asymptomatic and 245 symptomatic) and compared them with a population-based DNA bank of 2,559 subjects. Results The frequency of ACE I/I homozygotes was significantly increased in COVID-19 patients compared with that in controls (26.2% vs. 21.2%; P = 0.02; OR [95% CI] = 1.55 [1.17–2.05]. Importantly, however, the difference was driven just by the symptomatic subjects (29.0% vs. 21.2% of the I/I homozygotes; P = 0.002; OR [95% CI] = 1.78 [1.22–2.60]). The genotype distribution of the ACE genotypes was almost identical in population controls and asymptomatic SARS-CoV-2-positive patients (P = 0.76). Conclusions We conclude that ACE I/D polymorphism could have the potential to predict the severity of COVID-19, with I/I homozygotes being at increased risk of symptomatic COVID-19.

Common polymorphisms within the apolipoprotein E (APOE) gene are suggested to be associated with the development of type 2 diabetes mellitus (T2DM), but the potential association with T2DM complications (nephropathy, neuropathy and retinopathy) remains unclear. We perform the case–control study to analyse the association between the APOE polymorphism and risk of T2DM and to analysed the potential relationship between the APOE and T2DM complications. APOE variants (rs429358 and rs7412) were genotyped by TaqMan assay in T2DM patients (N = 1274; N = 829 with complications including retinopathy, neuropathy and nephropathy status) and with PCR–RFLP in healthy nondiabetic controls (N = 2055). The comparison of subjects with genotypes associated with low plasma cholesterol (APOE2/E2 and APOE2/E3 carriers vs. others) did not show an association with T2DM (OR [95% CI] = 0.88 [0.71–1.08). The differences remained insignificant after adjusting for diabetes duration, sex and BMI. Carriers of at least one APOE4 allele (rs429358) are protected against T2DM related retinopathy (OR [95% CI] = 0.65 [0.42–0.99]. Protection against retinopathy is driven mostly by females (OR [95% CI] = 0.50 [0.25–0.99]); and remains significant (P = 0.044) after adjustment for diabetes duration and BMI. Common APOE polymorphism was not associated with T2DM in the Czech population. Yet, APOE4 allele revealed an association with retinopathy. In particular, female T2DM patients with at least one APOE4 allele exhibit lower prevalence of retinopathy in our study subjects.

Tuky z mořských ryb a v nich obsažene omega3 polynenasycene dlouhořetězcove mastne kyseliny (EPA a DHA) maji zasadni vliv nejen na riziko srdecně cevnich onemocněni, ale take na kognitivni funkce. Testovali jsme ucinek do stravy přidaných 800 mg EPA a 1 200 mg DHA na den, obsažených v rybim oleji, na kognitivni funkce (memorovani, koordinace a soustředěni) intenzivně sportujicich chlapců (N = 169, věk 10-15 let). Intervenovana skupina konzumovala po dobu 6 měsiců 2 cajove lžicky oleje denně. Vsichni chlapci denně zapisovali jidelnicek a pravidelně podstupovali antropometricke analýzy pro vylouceni zasadnich změn ve stravovacich a pohybových zvyklostech. Studii dokoncilo celkem 121 chlapců (82 v intervenovane a 39 v kontrolni skupině). Přidani definovaneho množstvi EPA a DHA do stravy bylo verifikovano stanovenim omega3 indexu z kapilarni krve. Změny v omega3 indexu korelovaly s výsledky psychologickeho Bourdonova testu. Výsledky testu potvrdily statisticky významnou souvislost mezi hodnotou omega3 indexu s urovni kognitivnich funkci mladých sportovců (zlepseni o 63 % v intervenovane vs. o 43 % u kontrolni skupiny P = 0,0001; P = 0,007 po adjustaci na věk).

Acute coronary syndrome (ACS) including myocardial infarction is one of the leading and preventable causes of death in industrialized countries. Conventional cardiovascular risk factors are responsible for approximately 50% of cases. Attention is therefore focused also on genetic variants that are not strongly associated with conventional risk factors. One of them is the rs9818870 marker within the MRAS gene (muscle RAS oncogen homolog-gene, OMIM 608435, 3q22.3), which was recognized as a risk factor for cardiovascular events in Western populations. We analyzed the relationship between the rs9818870 variant and the risk of ACS in the Czech population. Methods: Rs9818870 (C→T) variant was successfully analyzed by PCR-RFLP at the 1,122 control males, younger than 65 years (post- MONICA study) and 1,190 males, consecutive patients with ACS (younger than 65 years). ANOVA and chisquare were used for statistical analyses. Results: Rs9818870 polymorphism was not associated with conventional risk factors (plasma lipids, blood pressure, obesity, smoking, diabetes mellitus) in the control group. We have not detected any association between the DNA marker and ACS (controls – CC = 70.8%, CT = 26.4%, TT = 2.8% vs. patients – CC = 69.7%, CT= 28.2%, TT= 2.1%; P = 0.34). Conclusion: Rs9818870 variant within the MRAS gene region is not robust risk factor for ACS development in the Czech Slavonic males.Acute coronary syndrome (ACS) including myocardial infarction is one of the leading and preventable causes of death in industrialized countries. Conventional cardiovascular risk factors are responsible for approximately 50% of cases. Attention is therefore focused also on genetic variants that are not strongly associated with conventional risk factors. One of them is the rs9818870 marker within the MRAS gene (muscle RAS oncogen homolog-gene, OMIM 608435, 3q22.3), which was recognized as a risk factor for cardiovascular events in Western populations. We analyzed the relationship between the rs9818870 variant and the risk of ACS in the Czech population. Methods: Rs9818870 (C→T) variant was successfully analyzed by PCR-RFLP at the 1,122 control males, younger than 65 years (post- MONICA study) and 1,190 males, consecutive patients with ACS (younger than 65 years). ANOVA and chisquare were used for statistical analyses. Results: Rs9818870 polymorphism was not associated with conventional risk factors (plasma lipids, blood pressure, obesity, smoking, diabetes mellitus) in the control group. We have not detected any association between the DNA marker and ACS (controls – CC = 70.8%, CT = 26.4%, TT = 2.8% vs. patients – CC = 69.7%, CT= 28.2%, TT= 2.1%; P = 0.34). Conclusion: Rs9818870 variant within the MRAS gene region is not robust risk factor for ACS development in the Czech Slavonic males.

Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart transplant patients. DNA was isolated from paired aortic samples of 383 heart recipients (age 50.7 ± 11.9 years) and corresponding donors (age 38.7 ± 12.0 years). Variants within the TERC (rs12696304), TERF2IP (rs3784929 and rs8053257), and OBCF1 (rs4387287) genes were genotyped, and telomere length was measured using qPCR. We identified similar frequencies of genotypes in heart donors and recipients. Antibody-mediated rejection (AMR) was more common (p < 0.05) in carriers of at least one G allele within the TERF2IP locus (rs3784929). Chronic graft dysfunction (CGD) was associated with the TERC (rs12696304) GG donor genotype (p = 0.05). The genetic risk score did not determine posttransplant complication risk prediction. No associations between the analyzed polymorphisms and telomere length were detected in either donor or recipient DNA. In conclusion, possible associations between donor TERF2IP (rs3784929) and AMR and between TERC (rs12696304) and CGD were found. SNPs within the examined genes were not associated with telomere length in transplanted patients.

BACKGROUND Increased levels of plasma lipoproteins are among some of the modifiable risk factors for cardiovascular disease (CVD). Dietary changes and increased physical activity are the most powerful non-pharmacological interventions for achieving optimal plasma lipid levels. OBJECTIVES To investigate the effect of an intensive short-term lifestyle intervention on plasma lipid trajectories in overweight non-diabetic females. MATERIAL AND METHODS A total of 202 healthy overweight (body mass index (BMI) >27.5 kg/m2) females underwent an intensive short-term (ten-week) intervention (at least 4 units of one-hour exercise activity weekly at optimal energy intake) aimed at lowering body weight. Plasma lipid (total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), and triglycerides (TG)) levels were examined at baseline and every 2 weeks over the course of the ten-week intervention. RESULTS There was a significant decrease in BMI (Δ -4.7%, p < 0.001) and body weight (Δ -4.9%, p < 0.001) after the intervention. Positive changes (decreases) in TC (Δ -8%, p < 0.001), TG (Δ -9%, p < 0.001) and LDL-C (Δ -11%, p < 0.001) were observed immediately after 2 weeks, but levels did not decrease further thereafter. In contrast, HDL-C did not increase as expected: after 2 weeks of intervention, we observed a significant decrease of about 6% (p < 0.001) followed by a slow return to baseline values. But even after 10 weeks of intervention, HDL-C values had not reached the values detected at baseline. CONCLUSIONS In overweight females, HDL-C decreased after short-term intensive lifestyle intervention. To confirm the protective effect of increased physical activity, plasma lipids need to be examined over a longer time period.

Increased plasma cholesterol levels are listed between the major atherosclerosis risk factors. The final plasma cholesterol levels result from the interplay between the genetic and environmental (diet, physical activity) factors. Little is known, how dietary factors influence epigenetics. We have analyzed, if an over-generation feeding of rat with cholesterol influences total liver-DNA methylation, and if total liver-DNA methylation differ between the different rat strains (Prague hereditary hypercholesterolemic rats, Prague hereditary hypertriglyceridemic rats and Wistar Kyoto rats). The animals were feed with high fat (additional 5 % over normal capacity) high cholesterol (2 %) diet for 14 days. DNA methylation in the liver tissue in different generations was analyzed using the liquid chromatography coupled with tandem mass spectrometry. We have not observed any significant changes in total liver-DNA methylation over the 9 generations of animals feed by fat/cholesterol enriched diet. Additionally, there were no differences in DNA methylation between different rat strains. In animal model, the dietary changes (hypercholesterolemic diet) not significantly influence the total DNA methylation status within the liver.

The mitochondrial DNA (mtDNA) copy number was analyzed via quantitative real-time PCR. A random subset of 996 people was studied (437 men with an average age of 67.3 ± 7.2 years and 559 women with an average age of 67.6 ± 7.1 years). They were selected from a population cohort of 9360 people who were initially examined in the international HAPIEE project (2003–2005, initial age of 45–69 years) in Novosibirsk. The participants were reexamined after 12 years in 2015–2017. The average relative mtDNA copy number in women was significantly higher than in men, regardless of age and smoking status, p = 0.001. The relative mtDNA copy number of blood leukocytes negatively correlated with age in men (p = 0.005) and women (p < 0.001). In the age-standardized analysis, the mtDNA copy number was negatively associated with waist and hip size and heart rate in people of both genders. Associations with some other indicators depend on gender. In women, the mtDNA copy number was negatively associated with the atherogenicity level, body mass indices, and blood glucose level and positively associated with HDL cholesterol. In men, the mtDNA copy number is positively related to the level of physical activity. Regardless of age, the average relative mtDNA copy number in peripheral blood leukocytes was higher in nonsmoking men than in smokers (p = 0.003). The mtDNA copy number was lower in women with diabetes mellitus than in women without it (p = 0.005). In both genders, people with an initial history of arterial hypertension had a lower mtDNA copy number in peripheral blood leukocytes after 12 years of observation than normotonics (p = 0.05). These results broadly support the hypothesis that the mtDNA copy number may act as a biomarker of age.

Type 2 diabetes mellitus (T2DM) is a prototypical complex disease with polygenic architecture playing an important role in determining susceptibility to develop the disease (and its complications) in subjects exposed to modifiable lifestyle factors. A current challenge is to quantify the degree of the individual's genetic risk using genetic risk scores (GRS) capturing the results of genome-wide association studies while incorporating possible ethnicity- or population-specific differences.This study included three groups of T2DM (T2DM-I, N = 1,032; T2DM-II, N = 353; and T2DM-III, N = 399) patients and 2,481 diabetes-free subjects. The status of the microvascular and macrovascular diabetes complications were known for the T2DM-I patients. Overall, 21 single nucleotide polymorphisms (SNPs) were analyzed, and selected subsets were used to determine the GRS (both weighted - wGRS and unweighted - uGRS) for T2DM risk predictions (6 SNPs) and for predicting the risks of complications (7 SNPs).The strongest T2DM markers (P 0.0001) were within the genes for TCF7L2 (transcription factor 7-like 2), FTO (fat mass and obesity associated protein) and ARAP1 (ankyrin repeat and PH domain 1). The T2DM-I subjects with uGRS values greater (Odds Ratio, 95 % Confidence Interval) than six had at least twice (2.00, 1.72-2.32) the risk of T2DM development (P 0.0001), and these results were confirmed in the independent groups (T2DM-II 1.82, 1.45-2.27; T2DM-III 2.63, 2.11-3.27). The wGRS (0.6) further improved (P 0.000001) the risk estimations for all three T2DM groups. The uGRS was also a significant predictor of neuropathy (P 0.0001), nephropathy (P 0.005) and leg ischemia (P 0.0005).If carefully selected and specified, GRS, both weighted and unweighted, could be significant predictors of T2DM development, as well as the diabetes complications development.

Purpose of review Chronic inflammation has been recognized as one of the most important pathophysiological mechanisms' initiation and progression of atherosclerosis. Statins belong to most successful therapeutic agents in the prevention and treatment of atherothrombotic vascular disease. Their non-lipid related effects including suppression of inflammation have been repeatedly proven in both experimental and clinical settings. Recent findings Recently, the importance of inflammation in the process of atherosclerosis has been confirmed by interventions targeting inflammation selectively. Clinical trial with selective inhibitor of a principal inflammatory mediator interleukin 1-beta - canakinumab - confirmed the notion of direct vasculoprotective effects of primarily targeting inflammation. This has increased interest in the non-lipid, pleiotropic and, particularly, anti-inflammatory effects of statins. Anti-inflammatory effects of statins have been proven both experimentally and in clinical settings beyond any doubt. They comprise a direct positive effect on not only many cell types and pathways that are lipid independent but, also, some that are mediated by lipid modification. Undoubtedly, suppression of inflammatory response by statins contributes to their generally positive action in atherosclerosis and represents an important part of the vasculo- and atheroprotective effect of this drug class.

Chronic inflammation has been recognized as one of the most important pathophysiological mechanisms' initiation and progression of atherosclerosis. Statins belong to most successful therapeutic agents in the prevention and treatment of atherothrombotic vascular disease. Their non-lipid related effects including suppression of inflammation have been repeatedly proven in both experimental and clinical settings.Recently, the importance of inflammation in the process of atherosclerosis has been confirmed by interventions targeting inflammation selectively. Clinical trial with selective inhibitor of a principal inflammatory mediator interleukin 1-beta - canakinumab - confirmed the notion of direct vasculoprotective effects of primarily targeting inflammation. This has increased interest in the non-lipid, pleiotropic and, particularly, anti-inflammatory effects of statins. Anti-inflammatory effects of statins have been proven both experimentally and in clinical settings beyond any doubt. They comprise a direct positive effect on not only many cell types and pathways that are lipid independent but, also, some that are mediated by lipid modification. Undoubtedly, suppression of inflammatory response by statins contributes to their generally positive action in atherosclerosis and represents an important part of the vasculo- and atheroprotective effect of this drug class.

Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361–0.7719 and OR 0.1522; 95% CI 0.02941–0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk.

Lipoprotein apheresis (LA) is a well-established therapy for lowering lipid levels in serious cases of dyslipidaemia, including high levels of lipoprotein(a) [Lp(a)]. This method lowers both LDL cholesterol and Lp(a) by more than 60% in most of patients; however, because randomized clinical studies could be extremely difficult, also other markers of the effect of this procedures on vascular health are of importance. Therefore, in addition to changes in plasma lipids and Lp(a) during LA, we also analysed the response of biomarkers associated with vascular integrity: small non-coding microRNAs (miRNAs).We analysed the changes in miRNAs in two women (age 70 and 72 years) with clinically manifest extensive and progressive atherosclerotic disease and high levels of Lp(a) and with different clinical course who were treated by LA. In both women we analysed changes of 175 circulating plasma miRNAs using pre-defined serum/plasma focus panels at the beginning of and one year after the therapy.In addition to reduced levels of plasma lipids and Lp(a), circulating plasma levels of miR-193a-5p; -215-5p; -328-3p; -130a-3p; -362-3p; -92b-3p decreased, and levels of miR-125a-5p; -185-5p; -106a-5p; -320b; -19a increased (all P 0.05) in both women. Moderate differences were found between both women with regard to the different course of atherosclerotic disease.Long-term LA substantially changes circulating plasma miRNAs associated with vascular integrity reflected different clinical course in both women. If confirmed, this approach could improve the assessment of the effectiveness of this therapy on an individual basis.

Plasma triglyceride (TG) values are significant predictors of cardiovascular and total mortality. The plasma levels of TGs have an important genetic background. We analyzed whether 32 single nucleotide polymorphisms (SNPs) identified in genome-wide association studies are discriminators of hypertriglyceridemia (HTG) in the Czech population. The objective of this study was to replicate and test the original findings in an independent study and to re-analyze the gene score leading to HTG. In total, we analyzed 32 SNPs in 209 patients with plasma TG levels over 10 mmol/L (HTG group) and compared them in a case–control design with 524 treatment-naive controls (normotriglyceridemic [NTG] group) with plasma TG values below 1.8 mmol/L. Sixteen SNPs were significantly associated with an increased risk of HTG development, with odds ratios (ORs) (95% confidence interval [CI]) varying from 1.40 (1.01–1.95) to 4.69 (3.29–6.68) (rs964184 within the APOA5 gene). Both unweighted (sum of the risk alleles) and weighted gene scores (WGS) (log of the achieved ORs per individual genotype) were calculated, and both gene scores were significantly different between groups. The mean score of the risk alleles was significantly increased in the HTG group compared to the NTG group (18.5 ± 2.5 vs. 15.7 ± 2.3, respectively; P

The aim of this study was to ascertain whether long-term occupational exposure to nanoparticles would affect relative leukocyte telomere length (LrTL). We analysed occupational exposure to size-resolved aerosol particles, with special emphasis on nanoparticles at two workshops: i/ the production of nanocomposites containing metal oxides; ii/ laboratory to test experimental exposure of nano-CuO to rodents. Thirty five exposed researchers (age 39.5 ± 12.6 yr; exposure duration 6.0 ± 3.7 yr) and 43 controls (40.4 ± 10.5 yr) were examined. LrTL did not significantly (p=0.14) differ between the exposed researchers (0.92 ± 0.13) and controls (0.86 ± 0.15). In addition, no significant correlation (r=-0.22, p=0.22) was detected between the duration of occupational exposure and LrTL. The results remained non-significant after multiple adjustments for age, sex and smoking status. Our pilot results suggest that relative leukocyte telomere length is not affected by occupational exposure to nanoparticles.

Among unique cardiovascular risk factors in women are complications during pregnancy, including miscarriage. Important risk factor is also genetic background. One of powerful candidate genes for cardiovascular disease of atherosclerotic origin (aCVD) is gene for connexin 37 (Cx37) with strong gene-environment interaction including smoking status, that is also strong risk factor for complications in pregnancy including spontaneous abortion (SA). We analyzed association between SA and Cx37 gene polymorphism (1019C>T; Pro319Ser) in 547 fetuses and its potential interaction with smoking status of mothers. Using genetic analyses from women from general population as controls, ORs for T allele, found in our previous studies to be protective against aCVD, were calculated. T allele carriers (fetuses), had OR 0.91 (95 % CI 0.72-1.14) and no interaction with smoking was observed. In conclusion, no significant association between Cx37 polymorphism and SA was observed and no modifying effect of smoking status on this association was detected.

With stage 5 chronic kidney disease (CKD5) more prevalent in the Czech Republic than in most European countries, genetic susceptibility is potentially implicated.In a group of 1489 CKD5 kidney transplantation patients (93% with complete clinical characteristics; mean age 52.0 years, 37% females) and 2559 healthy controls (mean age 49.0 years, 51% females), we examined the prevalence of six APOL1 SNPs (rs73885319, rs71785313, rs13056427, rs136147, rs10854688 and rs9610473) and one newly detected 55-nucleotide insertion/deletion polymorphism.The rs73885319 and rs71785313 variants were monomorphic in the Czech Caucasian population. Genotype frequencies of the three SNPs examined (rs13056427, rs136147 and rs9610473) were almost identical in patients and controls (all P values were between 0.39 and 0.91). Minor homozygotes of rs10854688 were more common between the patients (13.2%) than in controls (10.7%) (OR [95% CI]; 1.32 [1.08-1.64]; P 0.01). Prevalence of the newly detected 55-bp APOL1 deletion was significantly higher in CKD5 patients (3.0% vs. 1.7%; OR [95% CI]; 1.80 [1.16-2.80]; P 0.01) compared to controls. Frequencies of some individual APOL1 haplotypes were borderline different between patients and controls.We found an association between rs10854688 SNP within the APOL1 gene and end-stage renal disease in the Czech Caucasian population. Further independent studies are required before a conclusive association between the newly detected APOL1 insertion/deletion polymorphism and CKD5 can be confirmed.

Implantation of current generation left ventricular assist devices (LVADs) in the treatment of end-stage heart failure (HF), not only improves HF symptoms and end-organ perfusion, but also leads to cellular and molecular responses, presumably in response to the continuous flow generated by these devices. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression in multiple biological processes, including the pathogenesis of HF. In our study, we examined the influence of long-term LVAD support on changes in flow-sensitive miRNAs in plasma.Blood samples from patients with end-stage heart failure (N = 33; age = 55.7 ± 11.6 years) were collected before LVAD implantation and 3, 6, 9, and 12 months after implantation. Plasma levels of the flow-sensitive miRNAs; miR-10a, miR-10b, miR-146a, miR-146b, miR-663a, miR-663b, miR-21, miR-155, and miR-126 were measured using quantitative PCR.Increasing quantities of miR-126 (P0.03) and miR-146a (P0.02) was observed at each follow-up visit after LVAD implantation. A positive association between miR-155 and Belcaro score (P0.04) and an inverse correlation between miR-126 and endothelial function, measured as the reactive hyperemia index (P0.05), was observed.Our observations suggest that after LVAD implantation, low pulsatile flow up-regulates plasma levels of circulating flow-sensitive miRNAs, contributing to endothelial dysfunction and vascular remodeling.

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease (COVID-19), has spread widely around the globe. Significant inter-individual differences have been observed during the course of the infection, which suggests that genetic susceptibility may be a contributing factor. CC chemokine receptor 5 (CCR5), which acts as a co-receptor for the entry of HIV-1 into cells, is promising candidate whose can have an influence on SARS-CoV-2 infection. A genetic mutation known as CCR5Δ32, consisting of a 32-nucleotide deletion, encodes a truncated protein that protects homozygous carriers of the deletion from HIV-1 infection. Similarly, inhibition of CCR5 seems to be protective against COVID-19. In our study, we successfully genotyped 416 first-wave SARS-CoV-2-positive infection survivors (164 asymptomatic and 252 symptomatic) for CCR5Δ32, comparing them with a population based sample of 2,404 subjects. We found the highest number (P=0.03) of CCR5Δ32 carriers in SARS-CoV-2-positive/COVID-19-asympto-matic subjects (23.8 %) and the lowest number in SARS-CoV-2-positive/COVID-19-symptomatic patients (16.7 %), with frequency in the control population in the middle (21.0 %). We conclude that the CCR5Δ32 I/D polymorphism may have the potential to predict the severity of SARS-CoV-2 infection.

Despite the rapid progress in diagnosis and treatment of cardiovascular disease (CVD), this disease remains a major cause of mortality and morbidity. Recent progress over the last two decades in the field of molecular genetics, especially with new tools such as genome-wide association studies, has helped to identify new genes and their variants, which can be used for calculations of risk, prediction of treatment efficacy, or detection of subjects prone to drug side effects. Although the use of genetic risk scores further improves CVD prediction, the significance is not unambiguous, and some subjects at risk remain undetected. Further research directions should focus on the “second level” of genetic information, namely, regulatory molecules (miRNAs) and epigenetic changes, predominantly DNA methylation and gene-environment interactions.

We describe the casuistry of a homozygous familial hypercholesterolemia female patient with a biallelic missense variant (NM_000527.4:c.1775G>A, p.Gly592Glu) in the LDLR gene, severe hypertriglyceridemia and late manifestation of coronary heart disease not earlier than at the age of 45 years. An atypical phenotype led to a delayed diagnosis.

Respiratory distress syndrome caused by a secondary surfactant deficiency is one of the most common diagnoses requiring admission to the Neonatal Intensive Care Unit. We illustrate the case of a term female newborn without prenatal and peripartal risks. There had been significant signs of respiratory distress 4 h after delivery. The condition gradually worsened to the point of needing oscillatory ventilation. The most common infectious and non-infectious causes were excluded. Considering the course of illness, a congenital surfactant deficiency was suspected. There nevertheless was no significant improvement after administration of surfactant. Following a short period of palliative care, the child died at 34 days of age due to respiratory failure. DNA diagnostics revealed compound heterozygosity of ABCA3 functional mutations leading to the p.Pro147Leu and p.Pro246Leu exchanges. The second identified mutation of ABCA3 c.737C>T had not to date been described in connection with primary surfactant deficiency.

The potential antiatherogenic role of bilirubin is generally acknowledged, so the aim of this study was to determine serum bilirubin concentrations and the prevalence of Gilbert syndrome (GS) in the Czech general population with particular reference to its relationship to the risk of myocardial infarction (MI).Methods and Results:Biochemical markers were analyzed in 2 independent Czech post-MONICA studies (in total, n=3,311), and in 741 male MI patients. TheUGT1A1promoter gene variant (rs81753472) was analyzed in these MI patients and in the first control population cohort (n=717). Medians of serum bilirubin concentrations in the 2 Czech general population cohorts were 9.6 and 9.8 μmol/L (10.7 and 11.3 μmol/L in males, and 8.3 and 8.8 μmol/L in females; P0.01). The prevalence of GS was 8.9%, twice as high in males compared with females (11.6 vs. 6.1%; P0.01). TheUGT1A1(TA)Serum bilirubin concentrations and the prevalence of GS were determined in the Czech general population. Significantly lower serum bilirubin concentrations were observed in male MI patients.

Aim: We examined associations of eight SNPs in/near seven candidate genes with glycemic response to 6 month treatment with DPP4 inhibitors. Patients & methods: 206 patients with type 2 diabetes (116 men and 90 women) were treated with sitagliptin or vildagliptin (both 100 mg/day) in combination with metformin or metformin/sulphonylurea over 6 months, and the reduction in glycated hemoglobin (HbA1c) was measured. Results: Rs6923761 in GLP1R was significantly associated with a reduction in HbA1c (adjusted p = 0.006). Homozygotes for the minor A allele had smaller reduction in HbA1c by 0.4% (4 mmol/mol) than the G allele carriers (p = 0.016). Conclusion: The missense variant rs6923761 in the GLP1R gene was associated with a smaller glycemic response to 6 month gliptin therapy in diabetic patients of central European origin.

Background The Czech governmental study suggests up to a 25% higher prevalence of type 2 diabetes mellitus (T2DM) in the Roma population than within the majority population. It is not known whether and to what extent these differences have a genetic background. Methods To analyze whether the frequencies of the alleles/genotypes of the FTO, TCF7L2, CDKN2A/2B, MAEA, TLE4, IGF2BP2, ARAP1, and KCNJ11 genes differ between the two major ethnic groups in the Czech Republic, we examined them in DNA samples from 302 Roma individuals and 298 Czech individuals. Results Compared to the majority population, Roma are more likely to carry risk alleles in the FTO (26% vs. 16% GG homozygotes, p, The frequency of most T2DM‐associated genotypes differed significantly between the Czech majority population and Roma. Roma subjects have in mean increased numbers of risky alleles. Likely, genes are in background of the increased T2DM incidence in this ethnic group.

Objectives Cytochromes P450 play a role in human drugs metabolic pathways and their genes are among the most variable in humans. The aim of this study was to analyze genotype frequencies of five common polymorphisms of cytochromes P450 in Roma/Gypsy and Czech (non-Roma) population samples with Czech origin. Methods Roma/Gypsy (n=302) and Czech subjects (n=298) were genotyped for CYP1A2 (rs762551), CYP2A6 (rs4105144), CYP2B6 (rs3745274) and CYP2D6 (rs3892097; rs1065852) polymorphisms using PCR-RFLP or Taqman assay. Results We found significant allelic/genotype differences between ethnics in three genes. For rs3745274 polymorphism, there was increased frequency of T allele carriers in Roma in comparison with Czech population (53.1 vs. 43.7%; p=0.02). For rs4105144 (CYP2A6) there was higher frequency of T allele carriers in Roma in comparison with Czech population (68.7 vs. 49.8%; pCYP2D6) there was more carriers of the A allele between Roma in comparison with Czech population (39.2 vs. 38.2%; p=0.048). Genotype/allelic frequencies of CYP2D6 (rs1065852) and CYP1A2 (rs762551) variants did not significantly differ between the ethnics. Conclusions There were significant differences in allelic/genotype frequencies of some, but not all cytochromes P450 polymorphisms between the Czech Roma/Gypsies and Czech non-Roma subjects.

We investigated the relationship between ‘epigenetic age’ (EA) derived from DNA methylation (DNAm) and myocardial infarction (MI)/acute coronary syndrome (ACS). A random population sample was examined in 2003/2005 (n = 9360, 45–69, the HAPIEE project) and followed up for 15 years. From this cohort, incident MI/ACS (cases, n = 129) and age- and sex-stratified controls (n = 177) were selected for a nested case-control study. Baseline EA (Horvath’s, Hannum’s, PhenoAge, Skin and Blood) and the differences between EA and chronological age (CA) were calculated (ΔAHr, ΔAHn, ΔAPh, ΔASB). EAs by Horvath’s, Hannum’s and Skin and Blood were close to CA (median absolute difference, MAD, of 1.08, –1.91 and –2.03 years); PhenoAge had MAD of −9.29 years vs. CA. The adjusted odds ratios (ORs) of MI/ACS per 1–year increments of ΔAHr, ΔAHn, ΔASB and ΔAPh were 1.01 (95% CI 0.95–1.07), 1.01 (95% CI 0.95–1.08), 1.02 (95% CI 0.97–1.06) and 1.01 (0.93–1.09), respectively. When classified into tertiles, only the highest tertile of ΔAPh showed a suggestion of increased risk of MI/ACS with OR 2.09 (1.11–3.94) independent of age and 1.84 (0.99–3.52) in the age- and sex-adjusted model. Metabolic modulation may be the likely mechanism of this association. In conclusion, this case-control study nested in a prospective population-based cohort did not find strong associations between accelerated epigenetic age markers and risk of MI/ACS. Larger cohort studies are needed to re-examine this important research question.

Methyl alcohol intoxication is a global problem with high mortality and long-term visual sequelae and severe brain damage in survivors. The role of neuroinflammation in the mechanisms of methyl alcohol-induced toxic brain damage has not been well studied. We measured the acute concentrations and dynamics of lipoxins LxA4 and LxB4 and the interleukins IL-4, IL-5, IL-9, IL-10, and IL-13 in the serum of patients treated with methyl alcohol poisoning and the follow-up concentrations in survivors two years after discharge from the hospital. A series of acute measurements was performed in 28 hospitalized patients (mean age 54.2 ± 5.2 years, mean observation time 88 ± 20 h) and the follow-up measurements were performed in 36 subjects who survived poisoning (including 12/28 survivors from the acute group). Visual evoked potentials (VEP) and magnetic resonance imaging of the brain (MRI) were performed to detect long-term visual and brain sequelae of intoxication. The acute concentrations of inflammatory mediators were higher than the follow-up concentrations: LxA4, 62.0 ± 6.0 vs. 30.0 ± 5.0 pg/mL; LxB4, 64.0 ± 7.0 vs. 34.0 ± 4.0 pg/mL; IL-4, 29.0 ± 4.0 vs. 15.0 ± 1.0 pg/mL; IL-5, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-9, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-10, 38.0 ± 5.0 vs. 16.0 ± 1.0 pg/mL; IL-13, 35.0 ± 4.0 vs. 14.0 ± 1.0 pg/mL (all p 0.001). The patients with higher follow-up IL-5 concentration had prolonged latency P1 (r = 0.413; p = 0.033) and lower amplitude N1P1 (r = -0.498; p = 0.010) of VEP. The higher follow-up IL-10 concentration was associated with MRI signs of brain necrotic damage (r = 0.533; p = 0.001) and brain hemorrhage (r = 0.396; p = 0.020). Our findings suggest that neuroinflammation plays an important role in the mechanisms of toxic brain damage in acute methyl alcohol intoxication.

Bilirubin is the major catabolic product of heme degradation. It has long been regarded as an unimportant waste product. However, within the last twenty-five years, it has been demonstrated to play a very important role in maintaining the bodys redox equilibrium. Disturbances of this equilibrium - increased oxidative stress - are currently considered one of the major risk factors for the development of non-communicable diseases. Although the exact mechanism is not known, a number of human studies have proved a reduced incidence of a number of (especially cardiovascular but also cancer) diseases in individuals with mildly elevated bilirubin concentrations. Key words: bilirubin - cardiovascular disease - morbidity - mortality.

Background & aims The rs738409 c.444C > G (p.I148M) polymorphism in PNPLA3 is a major factor predisposing to non-alcoholic fatty liver disease. The aim of the study was to clarify the impact of liver and extrahepatic expression of the PNPLA3 p.148M variant on liver graft steatosis after liver transplantation. Methods Fat content was assessed in liver biopsies from 176 transplant recipients. During a period of 4 ± 1 years after transplantation, 17 patients developed grade 3 steatosis, 14 patients grade 2 steatosis, 56 patients grade 1 steatosis, and 89 patients grade 0 steatosis. The influence of the recipient and donor rs738409 genotype and clinical and laboratory data on liver fat content were analyzed using ordinal logistic regression. Results The PNPLA3 rs738409 CC/CG/GG genotype frequencies, respectively, were 0.494/0.449/0.057 in the graft donors and 0.545/0.330/0.125 in the graft recipients. In the multivariate analysis, the presence of the PNPLA3 c.444G allele in donor (OR 1.62; 95%CI 1.12–2.33), post-transplant BMI (OR 1.14; 95%CI 1.07–1.22), diabetes mellitus (OR 1.99; 95%CI 1.22–3.22), and serum triglycerides (OR 1.40; 95%CI 1.11–1.76) were independent risk factors for increased liver graft fat content. Conclusions These data indicate that the liver expression of the PNPLA3 p.148M variant confers a genetic predisposition to liver graft steatosis along with nutritional status and diabetes.

Nowadays atrial fibrillation (AF) retains its leading position among arrhythmias in the world. Despite significant progress in treatment, this rhythm disturbance remains one of the leading causes of stroke (Str) and heart failure. Obviously, more action is needed on the ascertainment and the quality control of treatment of AF. Aim. To assess the frequency and main groups of drug therapy in patients with AF in the Russian population sample of middle, elderly and senile age in cross-sectional study, 2015-2016. Material and methods. The random urban population sample of men and women of 58-82 y.o. (n=2339) was examined in 2015-2016 in Novosibirsk. The entire subsample with AF included 76 people (3,2%). The presence of AF was defined by ECG with Minnesota coding. Cardiovascular diseases and their risk factors were assessed by standard epidemiological methods. We took into account the regular intake of drugs during the last two weeks, followed by coding with Anatomical therapeutic chemical classification system. ANOVA and nonparametric statistical methods were used. Results. In studied entire subsample of subjects with AF aged 58-82 y.o., the average CHA2DS2VASc estimate of Str risk was of 4,7 in women and of 3,2 in men. Those with AF received beta-blockers (BB) in 43,4% of, angiotensin-converting-enzyme inhibitors (ACEi) — in 38,2%, cardiac glycosides — in 25,0%, anti-atherosclerotic drugs — about 33% and antidiabetic — 14,5%. Anticoagulants and antiplatelet were received in 42,1%, the aspirin was most frequent (25%), direct inhibitors of thrombin (NOAC) were received in 4% of subjects with AF. About 16% were in a drug-free state. Overall, the frequency of the medication taking of the drug treatment groups analyzed in the population sample was higher in women than in men. Conclusion. In 2015-2016, the general spectrum of drug treatment in subjects with AF in Russian population sample aged 58-82 was in line with the recommended standards for AF treatment, but the coverage of treatment with main drug classes is insufficient (about 40%). The most common were BB, ACEi, lipid-lowering drugs, aspirin and digoxin. Every 4th subject with AF took an aspirin for the prevention of thromboembolism, and only 4% received NOAC.

Genome-wide association studies have resulted in the identification of the FTO gene as an important genetic determinant of diabetes mellitus. The aim of this study was to confirm the role of this gene in the development of DM in the Czech-Slavonic population and to analyse whether this gene is associated with common DM complications.Two groups of patients (814 with T1DM and 848 with T2DM) and a group of healthy controls (2339 individuals) - both of Czech origin - were genotyped for the FTO rs17817449 SNP. ANOVA and logistic regression were used for the statistical evaluations.The frequency of the GG genotype was significantly higher in T2DM (25.4% vs. 16.7%, P0.0005) but not in T1DM patients (19.3% vs. 16.7%, P=0.20) than in controls. The increased risk of development of diabetic nephropathy was observed both for T1DM patients (GG vs. TT homozygotes, P0.01) and T2DM patients (G carriers vs. TT homozygotes, P0.05). FTO genotype predicted the development of diabetic neuropathy (GG vs. TT comparison; P0.01) in the T2DM patients only. No association between FTO genotype and development of retinopathy was detected. All presented values are after adjustment for age, sex, BMI and duration of diabetes.We confirm the association between the FTO rs17817449 SNP and susceptibility to T2DM in the Czech-Slavonic population. The same variant is associated with a spectrum of chronic complications in both types of diabetes.

This study investigated 12-year blood lipid trajectories and whether these trajectories are modified by smoking and lipid lowering treatment in older Russians. To do so, we analysed data on 9,218 Russian West-Siberian Caucasians aged 45–69 years at baseline participating in the international HAPIEE cohort study. Mixed-effect multilevel models were used to estimate individual level lipid trajectories across the baseline and two follow-up examinations (16,445 separate measurements over 12 years). In all age groups, we observed a reduction in serum total cholesterol (TC), LDL-C and non-HDL-C over time even after adjusting for sex, statin treatment, hypertension, diabetes, social factors and mortality (P 60 years at baseline). In smokers, TC, LDL-C, non-HDL-C and TG decreased less markedly than in non-smokers, while HDL-C decreased more rapidly while the LDL-C/HDL-C ratio increased. In subjects treated with lipid-lowering drugs, TC, LDL-C and non-HDL-C decreased more markedly and HDL-C less markedly than in untreated subjects while TG and LDL-C/HDL-C remained stable or increased in treatment naïve subjects. We conclude, that in this ageing population we observed marked changes in blood lipids over a 12 year follow up, with decreasing trajectories of TC, LDL-C and non-HDL-C and mixed trajectories of TG. The findings suggest that monitoring of age-related trajectories in blood lipids may improve prediction of CVD risk beyond single measurements.

A DNA methylation pattern represents an original plan of the function settings of individual cells and tissues. The basic strategies of its development and changes during the human lifetime are known, but the details related to its modification over the years on an individual basis have not yet been studied. Moreover, current evidence shows that environmental exposure could generate changes in DNA methylation settings and, subsequently, the function of genes. In this study, we analyzed the effect of chronic exposure to nanoparticles (NP) in occupationally exposed workers repeatedly sampled in four consecutive years (2016–2019). A detailed methylation pattern analysis of 14 persons (10 exposed and 4 controls) was performed on an individual basis. A microarray-based approach using chips, allowing the assessment of more than 850 K CpG loci, was used. Individual DNA methylation patterns were compared by principal component analysis (PCA). The results show the shift in DNA methylation patterns in individual years in all the exposed and control subjects. The overall range of differences varied between the years in individual persons. The differences between the first and last year of examination (a three-year time period) seem to be consistently greater in the NP-exposed subjects in comparison with the controls. The selected 14 most differently methylated cg loci were relatively stable in the chronically exposed subjects. In summary, the specific type of long-term exposure can contribute to the fixing of relevant epigenetic changes related to a specific environment as, e.g., NP inhalation.

Studying the long-term impact of continuous-flow left ventricular assist device (CF-LVAD) offers an opportunity for a complex understanding of the pathophysiology of vascular changes in aortic tissue in response to a nonphysiological blood flow pattern. Our study aimed to analyze aortic mRNA/miRNA expression changes in response to long-term LVAD support. Paired aortic samples obtained at the time of LVAD implantation and at the time of heart transplantation were examined for mRNA/miRNA profiling. The number of differentially expressed genes (Pcorr &lt, 0.05) shared between samples before and after LVAD support was 277. The whole miRNome profile revealed 69 differentially expressed miRNAs (Pcorr &lt, 0.05). Gene ontology (GO) analysis identified that LVAD predominantly influenced genes involved in the extracellular matrix and collagen fibril organization. Integrated mRNA/miRNA analysis revealed that potential targets of miRNAs dysregulated in explanted samples are mainly involved in GO biological process terms related to dendritic spine organization, neuron projection organization, and cell junction assembly and organization. We found differentially expressed genes participating in vascular tissue engineering as a consequence of LVAD duration. Changes in aortic miRNA levels demonstrated an effect on molecular processes involved in angiogenesis.

BACKGROUND Genome-wide association studies (GWAs) focused on cardiovascular diseases reveal variants within genes which have not been analyzed through the pre-GWAs era, and whose function is often unknown. One of them is variant rs9818870 at the MRAS gene locus. OBJECTIVES To analyze if MRAS polymorphism is associated with acute coronary syndrome (ACS) risk in a Czech population and with mortality in male patients after myocardial infarction. MATERIAL AND METHODS 1,779 male patients with ACS (aged 55.3 ±7.9 years) and 673 female patients with ACS (aged 64.0 ±8.1 years) were genotyped for rs9818870 polymorphism using the PCR-RFLP method. In a subset of 1,221 patients, detailed diagnoses (901 subjects with STEMI, 280 subjects with NSTEMI, 40 cases with unstable angina pectoris) were recorded. In 1,614 males, records about total and cardiovascular mortality were available. RESULTS Whether the entire populations or males and females have been analyzed separately or not, we have not confirmed the described association between DNA marker rs9818870 and ACS in Czechs (30.4% vs 29.4% carriers of the minor T allele [recessive model], p = 0.54; OR 1.05; 95% CI 0.89-1.24 for males and 32.1% vs 29.7% carriers of the minor T allele, p = 0.28; OR 1.12; 95% CI 0.91-1.37 for females). Types of the ACS (STEMI and NSTEMI) or mortality (in males only) were not associated with the analyzed polymorphism (all p > 0.34). CONCLUSIONS The rs9818870 variant is not associated with ACS or mortality in ACS patients in the Czech Slavonic population.

LDL/Lp(a) apheresis therapy is a well-established method of aggressively lowering LDL and Lp(a). Recently, miRNAs have been discussed as markers of vascular status including atherosclerosis. MiRNAs inhibit post-transcriptional processes through RNA duplex formation resulting in gene silencing or regulation of gene expression.We measured a profile of 175 plasma-circulating miRNAs using pre-defined Serum/Plasma Focus Human microRNA PCR Panels in pooled samples of 11 subjects with familial hypercholesterolaemia under long-term apheresis treatment. Subsequently we analysed expressions of ten pre-selected miRNAs potentially involved in lipid homeostasis in the same group of subjects. We compared plasma-circulating miRNA levels isolated from peripheral blood collected immediately before and after apheresis.The greatest differences in plasma levels were found in miR-451a, miR-16, miR-19a/b, miR-223 and miR-185. In subsequent individual miRNA assay we detected a significant increase in miR-33b levels after apheresis (P 0.05). Additionally, correlations between plasma lipids and miR-33a (P 0.04) and miR-122 (P 0.01) have been determined. Moreover, miR-122 levels in LDLR homozygotes were higher compared to heterozygotes after, but not before, apheresis treatment (P 0.04).LDL/Lp(a) apheresis has an impact on miRNAs associated with lipid homeostasis and vascular status.

MicroRNAs (miRNAs) are a class of short non-coding regulatory RNA molecules which play an important role in intracellular communication and cell signaling and which influence cellular processes such as proliferation, differentiation, and cellular death. Over the past two decades, the crucial role of microRNAs in controlling tissue homeostasis and disease in cardiovascular systems has become widely recognized. By controlling the expression levels of their targets, several miRNAs have been shown to modulate the function of endothelial cells (miR-221/222 and -126), vascular smooth muscle cells (miR-143/145) and macrophages (miR-33, -758, and -26), thereby regulating the development and progression of atherosclerosis. The stability of miRNAs within the blood suggests that circulating miRNAs may function as important biomarkers of disease development and progression. Numerous circulating miRNAs have been found to be dysregulated in a wide variety of different disease states, including diabetes, cancer, and cardiovascular disease.

Since 2007, the year of their first widespread use, genome-wide association studies (GWAS) have become the “gold standard” for the detection of causal genes and polymorphisms in all fields of human medicine. Cardiovascular disease (CVD), one of the major causes of morbidity and mortality, is no exception. The first GWAS focused on hypercholesterolemia and dyslipidemia as the major CVD determinants. GWAS confirm the importance of most of the previously identified genes (e.g. APOE, APOB, LDL-R) and recognize the importance of new genetic determinants (e.g. within the CILP2 or SORT1 gene clusters). Nevertheless, the results of GWAS still require confirmation by independent studies, as interethnic and interpopulation variability of SNP effects have been reported. We analyzed an association between eight variants within seven through GWAs detected loci and plasma lipid values in the Czech post-MONICA population sample (N=2,559). We confirmed an association (all P

Methanol poisoning leads to lesions in the basal ganglia and subcortical white matter, as well as to demyelination and atrophy of the optic nerve. However, information regarding cognitive deficits in a large methanol sample is lacking. The principal aim of the present study was to identify the cognitive sequelae of methanol poisoning and their morphological correlates. A sample of 50 patients (METH; age 48 ± 13 years), 3–8 months after methanol poisoning, and 57 control subjects (CS; age 49 ± 13 years) were administered a neuropsychological battery. Forty-six patients were followed in 2 years' perspective. Patients additionally underwent 1.5T magnetic resonance imaging (MRI). Three biochemical and toxicological metabolic markers and a questionnaire regarding alcohol abuse facilitated the classification of 24 patients with methanol poisoning without alcohol abuse (METHna) and 22 patients with methanol poisoning and alcohol abuse (METHa). All groups were compared to a control group of similar size, and matched for age, education, premorbid intelligence level, global cognitive performance, and level of depressive symptoms. Using hierarchical multiple regression we found significant differences between METH and CS, especially in executive and memory domains. METHa showed a similar pattern of cognitive impairment with generally more severe executive dysfunction. Moreover, all METH patients with extensive involvement on brain MRI (lesions in ≥2 anatomical regions) had a more severe cognitive impairment. From a longitudinal perspective, we did not find any changes in their cognitive functioning after 2 years' follow-up. Our findings suggest that methanol poisoning is associated with executive dysfunction and explicit memory impairment, supposedly due to basal ganglia dysfunction and disruption of frontostriatal circuitry proportional to the number of brain lesions, and that these changes are persistent after 2 years' follow-up.

BACKGROUND The rs58542926 polymorphism in transmembrane 6 superfamily member 2 (TM6SF2) is a genetic factor predisposing to nonalcoholic fatty liver disease. We aimed to explore the effect of recipient and donor TM6SF2 rs58542926 genotypes on liver graft fat content after liver transplantation. METHODS Steatosis was evaluated in liver biopsies from 268 adult recipients. The influence of recipient and donor TM6SF2 genotypes, patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 genotypes, and nongenetic factors on the steatosis grade assessed 6-30 months after transplantation was analyzed by ordinal logistic regression. RESULTS The presence of the TM6SF2 c.499A allele in the donor (P = 0.014), PNPLA3 c.444G allele in the donor (P < 0.001), posttransplant body mass index (P < 0.001), and serum triglycerides (P = 0.047) independently predicted increased liver fat content on multivariable analysis, whereas noncirrhotic liver disease, as an indication for liver transplantation, was associated with lower risk of steatosis (P = 0.003). The effects of the donor TM6SF2 A and PNPLA3 G alleles were additive, with an odds ratio of 4.90 (95% confidence interval, 2.01-13.00; P < 0.001), when both minor alleles were present compared with an odds ratio of 2.22 (95% confidence interval, 1.42-3.61; P = 0.002) when only one of these alleles was present. CONCLUSIONS The donor TM6SF2 c.499A allele is an independent risk factor of liver graft steatosis after liver transplantation that is additive to the effects of donor PNPLA3 c.444G allele.

Context: The influence of co-morbid conditions on the outcome of acute methanol poisoning in mass poisoning outbreaks is not known.Objective: The objective of this is to study the impact of burden ...

Introduction Abdominal obesity is a strong cardiometabolic risk factor that often occurs as early as in childhood. The negative effect of abdominal obesity on the metabolism is partially mediated by changes to the production of the major adipocyte hormones leptin and adiponectin. Leptin/adiponectin imbalance is associated with increased risk of developing obesity and type 2 diabetes mellitus. Aim To determine whether leptin, adiponectin and the leptin/adiponectin ratio are significant predictors of body weight loss in intensively treated children/adolescents. Methods 183 paediatric overweight or obese patients (71 boys and 112 girls), aged 7–16 years, were enrolled in a one-month intensive lifestyle intervention programme. Participants reduced their energy intake and engaged in a supervised exercise programme consisting of 5 physical activity units per day. The subjects were examined both before and after the intervention. Results The mean BMI decrease achieved was−2.38±0.07 kg/m² (P Conclusion The leptin/adiponectin ratio at baseline may be a useful predictor of results from interventions focused on decreasing BMIs in children/adolescents.

Objective: Apolipoprotein A5 (lipoprotein lipase activator) and cholesterol 7α-hydroxylase (microsomal cytochrome P450) are almost exclusively expressed in liver tissue. Variants within the...

Apolipoprotein A5 (APOA5) is a small protein, expressed predominantly in the liver. In plasma, it is located on triglyceride rich lipoprotein particles (chylomicrones and VLDL) and on HDL. Plasma concentration of apolipoprotein A5 is very low, suggesting rather regulatory (activation of lipoprotein lipase, …) than structural function. APOA5 is an important determinant of plasma triglyceride concentration; this effect has been confirmed both on animal models, as well as on human studies. Minor alleles of three commonly analysed variants within this gene (rs662799, rs3135506, rs2075291) are associated with higher plasma TG values and increased risk of myocardial infarction, with some important interethnic differences observed. Further roles of APOA5; determination of BMI, diabetes and last but not least nutri- and pharmaco-genetic interactions are suggested, but without the definitive conclusions.

Aim: Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1 rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants. Methods: We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis. Results: In the novel candidate gene CLCN1, we identified a heterozygote truncating mutation p.R894* in four patients. In addition, we detected predictably pathogenic case-specific variants in MYOT, CYP3A5, SH3TC2, FBXO32 and RBM20. Conclusion: These findings support the role of rare variants and nominate loci for follow-up studies.