Díky svému umístění chrání hydrofobní lipidová doména paraoxonázy-1 (PON-1) lipoproteiny o vysoké hustotě (high-density lipoprotein, HDL), lipoproteiny o nízké hustotě (low-density lipoprotein, LDL) a buněčné membrány na vnější straně před oxidací. Nezastavuje se tím tvorba konjugovaných dienů, ale mění se tak produkty lipoperoxidace na neškodné karboxylové kyseliny místo aldehydů, které by se mohly navazovat na apolipoprotein B. Paraoxonáza-1 v séru negativně ovlivňuje nové příhody u diabetu a aterosklerotického kardiovaskulárního onemocnění (ASKVO). Diabetes, dyslipidemie a zánět snižují aktivitu PON-1. Ablace lidského genu pro PON-1 nebo nadměrná exprese tohoto genu u zvířat posiluje nebo tlumí vnímavost k rozvoji aterosklerózy. Na rozdíl od apolipoproteinu AII zvyšují sérová koncentrace amyloidu A a myeloperoxidáza, apolipoprotein AI a poměr lecitin : cholesterol acyl transferáza antioxidační účinek PON-1. Strava a již užívané léky měnící hodnoty lipidů mohou účinnost PON snížit, je však třeba provádět specifickou léčbu zvyšující hodnoty PON-1.

Due to where paraoxonase-1 (PON-1)'s hydrophobic lipid domain is located, high-density lipoprotein (HDL) protects low-density lipoprotein (LDL) and the cell membranes on the outside from oxidation. It doesn't stop the formation of conjugated dienes, but it changes the products of lipid peroxidation into harmless carboxylic acids instead of aldehydes that could link to apolipoprotein B. Serum PON-1 inversely affects new events in diabetes and atherosclerotic cardiovascular disease (ASCVD). Diabetes, dyslipidemia, and inflammation decrease PON-1 activity. Human PON-1 gene ablation or overexpression in animals enhances or reduces atherosclerosis susceptibility. Unlike AII, serum amyloid A, and myeloperoxidase, apolipoprotein AI and lecithin : cholesterol acyl transferase boost PON-1 antioxidant activity. Diet and pre-existing lipid-modifying drugs may impact PON-1 activity, but specific PON-1-raising therapy is required.

• MeSH
• Aryldialkylphosphatase * physiology   genetics   blood   adverse effects   MeSH
• Atherosclerosis * genetics   blood   MeSH
• Cardiovascular Diseases diagnosis   therapy   MeSH
• Clinical Studies as Topic MeSH
• Humans MeSH
• Lipoproteins, HDL physiology   MeSH
• Lipoproteins MeSH
• Lipid Peroxidation physiology   MeSH
• Polymorphism, Genetic physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

BACKGROUND: The highest mortality and morbidity worldwide is associated with atherosclerotic cardiovascular disease (ASCVD), which has in background both environmental and genetic risk factors. Apolipoprotein L1 (APOL1) variability influences the risk of ASCVD in Africans, but little is known about the APOL1 and ASCVD in other ethnic groups. METHODS: To investigate the role of APOL1 and ASCVD, we have genotyped four (rs13056427, rs136147, rs10854688 and rs9610473) APOL1 polymorphisms in a group of 1541 male patients with acute coronary syndrome (ACS) and 1338 male controls. RESULTS: Individual APOL1 polymorphisms were not associated with traditional CVD risk factors such as smoking, hypertension or diabetes prevalence, with BMI values or plasma lipid levels. Neither individual polymorphisms nor haplotypes were associated with an increased risk of ACS nor did they predict total or cardiovascular mortality over the 10.2 ± 3.9 years of follow-up. CONCLUSIONS: We conclude that APOL1 genetic variability has no major effect on risk of ACS in Caucasians.

• MeSH
• Acute Coronary Syndrome * genetics   MeSH
• Apolipoprotein L1 * genetics   MeSH
• Apolipoproteins genetics   MeSH
• White People genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Haplotypes MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipoproteins, HDL genetics   MeSH
• Risk Factors MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

BACKGROUND: The associations of risk factors with vascular impairment in type 1 diabetes patients seem more complex than that in type 2 diabetes patients. Therefore, we analyzed the associations between traditional and novel cardiovascular risk factors and vascular parameters in individuals with T1D and modifications of these associations according to sex and genetic factors. METHODS: In a cross-sectional study, we analyzed the association of risk factors in T1D individuals younger than 65 years using vascular parameters, such as ankle brachial index (ABI) and toe brachial index (TBI), duplex ultrasound, measuring the presence of plaques in carotid and femoral arteries (Belcaro score) and intima media thickness of carotid arteries (CIMT). We also used photoplethysmography, which measured the interbranch index expressed as the Oliva-Roztocil index (ORI), and analyzed renal parameters, such as urine albumin/creatinine ratio (uACR) and glomerular filtration rate (GFR). We evaluated these associations using multivariate regression analysis, including interactions with sex and the gene for connexin 37 (Cx37) polymorphism (rs1764391). RESULTS: In 235 men and 227 women (mean age 43.6 ± 13.6 years; mean duration of diabetes 22.1 ± 11.3 years), pulse pressure was strongly associated with unfavorable values of most of the vascular parameters under study (ABI, TBI, Belcaro scores, uACR and ORI), whereas plasma lipids, represented by remnant cholesterol (cholesterol - LDL-HDL cholesterol), the atherogenic index of plasma (log (triglycerides/HDL cholesterol) and Lp(a), were associated primarily with renal impairment (uACR, GFR and lipoprotein (a)). Plasma non-HDL cholesterol was not associated with any vascular parameter under study. In contrast to pulse pressure, the associations of lipid factors with kidney and vascular parameters were modified by sex and the Cx37 gene. CONCLUSION: In addition to known information, easily obtainable risk factor, such as pulse pressure, should be considered in individuals with T1D irrespective of sex and genetic background. The associations of plasma lipids with kidney function are complex and associated with sex and genetic factors. The decision of whether pulse pressure, remnant lipoproteins, Lp(a) and other determinants of vascular damage should become treatment targets in T1D should be based on the results of future clinical trials.

• MeSH
• Diabetes Mellitus, Type 1 * genetics   physiopathology   MeSH
• Diabetic Angiopathies genetics   physiopathology   MeSH
• Adult MeSH
• Phenotype MeSH
• Photoplethysmography MeSH
• Genetic Predisposition to Disease MeSH
• Glomerular Filtration Rate MeSH
• Carotid Intima-Media Thickness MeSH
• Middle Aged MeSH
• Humans MeSH
• Polymorphism, Genetic MeSH
• Gap Junction alpha-4 Protein * genetics   MeSH
• Cross-Sectional Studies MeSH
• Heart Disease Risk Factors MeSH
• Sex Factors MeSH
• Ankle Brachial Index MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The genetic basis of variability in drug response is at the core of pharmacogenomics (PGx) studies, aiming at reducing adverse drug reaction (ADR), which have interethnic variability. This study used the Kardiovize Brno 2030 random urban Czech sample population to analyze polymorphisms in a wide spectrum of genes coding for liver enzymes involved in drug metabolism. We aimed at correlating real life drug consumption with pharmacogenomic profile, and at comparing these data with the SUPER-Finland Finnish PGx database. A total of 250 individuals representative of the Kardiovize Brno 2030 cohort were included in an observational study. Blood DNA was extracted and 59 single nucleotide polymorphisms within 13 genes (BCHE, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5, F2, F5, IFNL3, SLCO1B1, TPMT, UGT1A1, VKORC1), associated to different drug metabolizing rates, were characterized by genotyping using a genome wide commercial array. Widely used drugs such as anti-coagulant warfarin and lipid lowering agent atorvastatin were associated to an alarmingly high percentage of users with intermediate/poor metabolism for them. Significant differences in the frequency of normal/intermediate/poor/ultrarapid/rapid metabolizers were observed for CYPD26 (p<0.001), CYP2C19 (p<0.001) and UGT1A1 (p<0.001) between the Czech and the Finnish study populations. Our study demonstrated that administration of some popular drugs to a Czech random sample population is associated with different drug metabolizing rates and therefore exposing to risk for ADRs. We also highlight interethnic differentiation of some common pharmacogenetics variants between Central (Czech) and North European (Finnish) population studies, suggesting the utility of PGx-informed prescription based on variant genotyping.

• MeSH
• Cytochrome P-450 CYP2D6 genetics   MeSH
• Cytochrome P-450 CYP2C19 genetics   metabolism   MeSH
• Cytochrome P-450 CYP2C9 genetics   metabolism   MeSH
• Vitamin K Epoxide Reductases genetics   MeSH
• Pharmacogenetics * MeSH
• Genotype MeSH
• Humans MeSH
• Polymorphism, Genetic * MeSH
• Liver-Specific Organic Anion Transporter 1 genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

Acid-β-glucosidase (GCase, EC3.2.1.45), the lysosomal enzyme which hydrolyzes the simple glycosphingolipid, glucosylceramide (GlcCer), is encoded by the GBA1 gene. Biallelic mutations in GBA1 cause the human inherited metabolic disorder, Gaucher disease (GD), in which GlcCer accumulates, while heterozygous GBA1 mutations are the highest genetic risk factor for Parkinson's disease (PD). Recombinant GCase (e.g., Cerezyme® ) is produced for use in enzyme replacement therapy for GD and is largely successful in relieving disease symptoms, except for the neurological symptoms observed in a subset of patients. As a first step toward developing an alternative to the recombinant human enzymes used to treat GD, we applied the PROSS stability-design algorithm to generate GCase variants with enhanced stability. One of the designs, containing 55 mutations compared to wild-type human GCase, exhibits improved secretion and thermal stability. Furthermore, the design has higher enzymatic activity than the clinically used human enzyme when incorporated into an AAV vector, resulting in a larger decrease in the accumulation of lipid substrates in cultured cells. Based on stability-design calculations, we also developed a machine learning-based approach to distinguish benign from deleterious (i.e., disease-causing) GBA1 mutations. This approach gave remarkably accurate predictions of the enzymatic activity of single-nucleotide polymorphisms in the GBA1 gene that are not currently associated with GD or PD. This latter approach could be applied to other diseases to determine risk factors in patients carrying rare mutations.

• MeSH
• Cellulases * genetics   MeSH
• Gaucher Disease * drug therapy   genetics   MeSH
• Heterozygote MeSH
• Humans MeSH
• Mutation MeSH
• Parkinson Disease * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

OBJECTIVE: The aim of the study was to evaluate the variant (rs2910829) of the PDE4D gene in relation to its influence on biochemical, anthropometric and physiological parameters in patients with coronary artery disease and healthy subjects of the Eastern Slovak population. METHODS: The male group consisted of 72 individuals and the female group consisted of 132 individuals. On the basis of clinical screening the subjects were divided into two groups - with ischaemic heart disease and control group. Genomic DNA was isolated from peripheral blood using a commercial NucleoSpin® Blood Machenery-Nagel kit. Molecular genetic analysis of the polymorphism under study was performed using the StepOneTM Real-Time PCR System instrument. The lipid profile markers TC, HDL, LDL, TG were measured by Cobas Integra 400 plus biochemical analyser, and systolic and diastolic blood pressure using a digital blood pressure monitor. Among anthropometric parameters, body height and weight, waist and hip circumference were measured and BMI and WHR indices were calculated. RESULTS: A statistically significant (p = 0.018) possible association between the mutant T allele and ischaemic heart disease was found in men. In women, we found a statistically significant difference in the systolic (p = 0.013) and diastolic blood parameters (p = 0.005) in the CC genotype. In the group of women, we found statistically significant differences in all observed anthropometric parameters and in LDL and TC markers. In the group of men divided on the basis of BMI, statistical significance was found in systolic blood pressure (p = 0.028). In the group of women with ischaemic heart disease, we found a negative correlation between BMI and HDL. CONCLUSION: The study contributes to new findings of the representation of genotypes and alleles of the rs2910829 PDE4D gene polymorphism in the Slovak population. This is a pilot study. Interactions between genotype and observed anthropometric, physiological and biochemical markers were confirmed.

• MeSH
• Anthropometry MeSH
• Cyclic Nucleotide Phosphodiesterases, Type 4 genetics   MeSH
• Body Mass Index MeSH
• Myocardial Ischemia * genetics   MeSH
• Humans MeSH
• Coronary Artery Disease * MeSH
• Pilot Projects MeSH
• Risk Factors MeSH
• Body Height MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: The primary objective was to comprehensively assess the association between single nucleotide polymorphisms (rs562556 and rs2479409) in the PCSK9 gene with biochemical parameters - C-reactive protein (CRP), glucose (GLU), triglyceride (TAG), low-density lipoprotein cholesterol (LDL CHOL), non-high-density lipoprotein cholesterol (non HDL CHOL), high-density lipoprotein cholesterol (HDL CHOL), cholesterol (CHOL), and anthropometric parameters (visceral fat), overweight/obesity and cardiovascular risk. METHODS: A total of 71 women aged 23-64 years were divided into three groups based on body mass index (BMI). BMI ≥ 25/≥ 30 kg/m2 was the criterion for assessment of overweight/obesity. Anthropometric, biochemical and genetic examinations were performed on the probands. Changes in markers in each group and their association with cardiovascular risk were monitored. RESULTS: We can conclude that in our study population we observed differences between the BMI categories for biochemical markers (CRP, LDL CHOL, non HDL CHOL, HDL CHOL, LDL CHOL) and anthropometric marker (visceral fat). Atherogenic index of plasma (AIP), Castelli's Risk Index I (CRI-I) and atherogenic coefficient (AC) confirmed high cardiovascular risk for the obese women category (0.045); (< 0.013); (< 0.010). Genotype and allele frequencies for the PCSK9 gene in the overweight and obese groups showed higher allele frequencies of allele A for both polymorphisms of the gene. CONCLUSIONS: PCSK9 gene expression is associated with biological processes such as lipid metabolism and inflammation. Cholesterol-lowering therapies are the gold standard for reducing the risk of cardiovascular mortality and morbidity. Administration of monoclonal antibodies (mAbs) against PCSK9 is a novel lipid-lowering therapeutic approach in adults to reduce the risk of cardiovascular disease.

• MeSH
• Cholesterol MeSH
• Adult MeSH
• Cardiovascular Diseases * MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Overweight * epidemiology   MeSH
• Obesity genetics   MeSH
• Proprotein Convertase 9 genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: Diabetes mellitus type 2 (T2DM) is a multifactorial and polygenic disorder characterised by chronic hyperglycaemia accompanied by impaired lipid, carbohydrate, and protein metabolism. The disease is associated with several genetic polymorphisms, including the FokI polymorphism in the vitamin D receptor (VDR) gene. METHODS: We conducted a study of 327 probands (191 T2DM patients, 136 controls), with a mean age 65.06 (SD ± 10.88) years of patients with T2DM and 58.89 (SD ± 6.59) years in the healthy probands. We investigated the association between FokI polymorphism and biochemical parameters in T2DM patients in the Slovak population. Anthropometric measurements, biochemical, and genetic analysis were statistically evaluated by Statistica ver.13 software using t-tests. RESULTS: Biochemical analysis confirmed significantly higher mean values of total cholesterol (TC), triglyceride (TG), glucose (GLU), and uric acid (UA) (p < 0.001) in T2DM probands and statistically significantly lower values of high-density lipoprotein (HDL), cholesterol and vitamin D (p < 0.001). Allele frequencies and genotype distributions of the FokI (rs2228570) polymorphism were not significantly different between T2DM patients and controls (p = 0.909). Patients with T2DM and TT genotype had the highest glucose level of 11.39 (SD ± 2.32) uU/ml (p < 0.001). CONCLUSION: Our study did not provide evidence for an association of the investigated FokI polymorphism of the VDR gene with T2DM in the Slovak population. Further research is needed to evaluate the impact of single nucleotide polymorphisms (SNPs) in the VDR gene, focusing on related genetic analyses in a larger T2DM cohort.

• MeSH
• Cholesterol MeSH
• Diabetes Mellitus, Type 2 * complications   MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• Glucose MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Receptors, Calcitriol * genetics   metabolism   MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH

Nealkoholová tuková choroba jater (NAFLD) se stala jedním z nejdiskutovanějších hepatologických témat posledních let díky své vysoké a nadále stoupající celosvětové prevalenci kopírující vysoký výskyt obezity a metabolického syndromu. Za poslední dvě dekády se významně rozšířily naše znalosti o patofyziologii NAFLD, které jsou klíčové pro pochopení této jednotky a pro identifikování účinné léčby a tím zmírnění socioekonomických důsledků spojených s morbiditou a mortalitou pacientů s NAFLD. Genetické rizikové faktory hrají v patofyziologii NAFLD významnou roli, dědičnost onemocnění je odhadována kolem 40 %. Celogenomovými asociačními studiemi byly identifikovány polymorfismy genů, které u svých nositelů významně zvyšují riziko vzniku NAFLD (například PNPLA3, TM6SF2, GCKR). Zlatým standardem diagnostiky je i nadále necílená biopsie jater. Jedná se o invazivní metodu, proto je snaha identifikovat spolehlivé a široce dostupné neinvazivní diagnostické metody. Řada slibných testů úzce souvisí právě s objasněním patofyziologie NAFLD (například specifické miRNA, sérový cytokeratin 18). V tomto přehledu shrnujeme aktuální pohled na patofyziologii NAFLD, včetně hlavních genetických rizikových faktorů, aktuálních diagnostických metod a stručně i léčebných možností onemocnění.

Nonalcoholic fatty liver disease (NAFLD) is nowadays one of the most discussed issues in hepatology due to its high and still raising prevalence reflecting the increasing prevalence of obesity and metabolic syndrome. In last two decades our knowledge of NAFLD pathophysiology expanded substantially. Understanding the pathophysiology is essential for identification of effective treatment, that is currently lacking, which could then reduce morbidity and mortality and eventually also mitigate the socioeconomical consequences of NAFLD. Genetic risk factors are crucial part of pathophysiology in NAFLD. Heritability of NAFLD is estimated to be around 40% and genome-wide association studies (GWAS) identified several single-nucleotide polymorphisms linked to the risk of NAFLD (e.g. PNPLA3, TM6SF2, GCKR). A gold standard for diagnosing NAFLD is a liver biopsy. Since liver biopsy is an invasive method a lot of effort is focused on finding reliable and accessible noninvasive diagnostic methods. Some of the promising methods are targeted to researched pathophysiological mechanisms (e.g. detecting the specific microRNA, serum cytokeratin-18). In this review we attempted to summarize the current knowledge about NAFLD pathophysiology, including the genetic risk factors, discuss the available diagnostic methods and also briefly cover the treatment options.

• MeSH
• Genetic Predisposition to Disease MeSH
• Insulin Resistance MeSH
• Humans MeSH
• Lipid Metabolism MeSH
• Non-alcoholic Fatty Liver Disease * diagnosis   etiology   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Long-chain polyunsaturated fatty acids (LC-PUFAs) play important roles in human health, from controlling inflammation to lipid and glucose homeostasis. In our previous study, which employed a cluster analysis of a plasma fatty acid (FA) pattern, we identified two clusters of metabolic syndrome (MetS) independent of clinical and biochemical parameters within the whole study group (controls together with metabolic syndrome (MetS) patients). FA desaturase (FADS) genes are the key regulators of LC-PUFA metabolism. The aim of this study was to analyze associations between FADS polymorphisms and clusters of MetS. The study group consisted of 188 controls and 166 patients with MetS. The first cluster contained 71 controls (CON1) and 109 MetS patients (MetS1). The second cluster consisted of 117 controls (CON2) and 57 MetS patients (MetS2). In comparison with MetS2, cluster MetS1 displayed a more adverse risk profile. Cluster CON1 had, in comparison with CON2, higher body weight and increased triacylglycerol levels (p < 0.05). We found that the FADS rs174537 (p < 0.001), rs174570 (p < 0.01), and rs174602 (p < 0.05) polymorphisms along with two inferred haplotypes had statistically significant genotype associations with the splitting of MetS into MetS1 and MetS2. Conversely, we observed no significant differences in the distribution of FADS polymorphisms between MetS and CON subjects, or between CON1 and CON2. These associations between FADS polymorphisms and two clusters of MetS (differing in waist circumference, HOMA-IR, lipolysis, and oxidative stress) implicate the important influence of genetic factors on the phenotypic manifestation of MetS.

• Publication type
• Journal Article MeSH