Publications by authors named "Dana Dlouha"

24 Publications

  • Page 1 of 1

ACE I/D polymorphism in Czech first-wave SARS-CoV-2-positive survivors.

Clin Chim Acta 2021 May 3. Epub 2021 May 3.

Czech Technical University, Faculty of Biomedical Engineering, Sítná 3105, Kladno, Czech Republic; Department of Preventive Cardiology, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague, Czech Republic.

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.
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http://dx.doi.org/10.1016/j.cca.2021.04.024DOI Listing
May 2021

Genetics of Cardiovascular Disease: How Far Are We from Personalized CVD Risk Prediction and Management?

Int J Mol Sci 2021 Apr 17;22(8). Epub 2021 Apr 17.

3rd Department of Internal Medicine, General University Hospital and 1st Faculty of Medicine, Charles University, 11636 Prague, Czech Republic.

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.
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http://dx.doi.org/10.3390/ijms22084182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074003PMC
April 2021

Influence of lipoprotein apheresis on circulating plasma levels of miRNAs in patients with high Lp(a).

Atheroscler Suppl 2019 Dec;40:12-16

Centre for Experimental Medicine - Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Czech Republic; Department of Internal Medicine, 2nd Medical Faculty, Charles University, Prague, Czech Republic.

Background: 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).

Materials And Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.atherosclerosissup.2019.08.036DOI Listing
December 2019

Donor PNPLA3 and TM6SF2 Variant Alleles Confer Additive Risks for Graft Steatosis After Liver Transplantation.

Transplantation 2020 03;104(3):526-534

Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

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.
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http://dx.doi.org/10.1097/TP.0000000000002876DOI Listing
March 2020

The Gene Score for Predicting Hypertriglyceridemia: New Insights from a Czech Case-Control Study.

Mol Diagn Ther 2019 08;23(4):555-562

3rd Department of Internal Medicine, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.

Background: 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.

Objectives: 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.

Methods: 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-naïve controls (normotriglyceridemic [NTG] group) with plasma TG values below 1.8 mmol/L.

Results: 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 < 0.00001). Subjects with a WGS over 9 were significantly more common in the HTG group (44.5%) than in the NTG group, in which such a high score was observed in only 4.7% of subjects (OR 16.3, 95% CI 10.0-36.7; P < 0.0000001).

Conclusions: An increased number of risk genetic variants, calculated both in a weighted or unweighted manner, significantly discriminates between the subjects with HTG and controls. Population-specific sets of SNPs included into the gene score seem to yield better discrimination power.
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http://dx.doi.org/10.1007/s40291-019-00412-2DOI Listing
August 2019

Association between aortic telomere length and cardiac post-transplant allograft function.

Int J Cardiol 2019 09 7;290:129-133. Epub 2019 May 7.

Cardio Centre, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague 14021, Czech Republic.

Background: In patients having undergone orthotopic heart transplantation, a number of complications exist that are known to be connected to both telomerase activity and telomere length. The aim of this study was to determine how telomere length in aortic DNA correlates with the subsequent post-transplantation development of the patients.

Materials And Methods: Between 2005 and 2015, we collected aortic samples from 376 heart recipients (age 50.8 ± 11.8 years) and 383 donors (age 38.6 ± 12.2 years). Relative telomere length in aortic tissue DNA was determined using quantitative PCR.

Results: Shorter telomere length was detected in heart allograft recipients compared to donors (P < 0.0001). Patients suffering acute cellular rejection had significantly shorter telomere length (P < 0.01) than patients without rejection. Shorter telomere length was observed in patients with implanted mechanical circulatory support before heart transplantation (P < 0.03), as well as in subjects with cardiac allograft vasculopathy (P < 0.05). Overall survival time after heart transplantation was associated with shorter donor telomeres (P < 0.004).

Conclusions: Telomere length differed between donors and recipients independent of the sex and age of the patients. Our findings suggest a potential new linkage between the aortic telomere length of recipients and post-heart transplant complications. Further studies focusing on epigenetic modifications and gene regulation involved in telomere maintenance in transplanted patients should verify our results.
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http://dx.doi.org/10.1016/j.ijcard.2019.05.006DOI Listing
September 2019

Leukocyte telomere length is not affected by long-term occupational exposure to nano metal oxides.

Ind Health 2019 Nov 28;57(6):741-744. Epub 2019 Mar 28.

Institute of Chemical Process Fundamentals CAS, Czech Republic.

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.
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http://dx.doi.org/10.2486/indhealth.2018-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885603PMC
November 2019

The fat mass and obesity related gene polymorphism influences the risk of rejection in heart transplant patients.

Clin Transplant 2018 12 22;32(12):e13443. Epub 2018 Nov 22.

Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Heart transplantation is a relatively common treatment for end-stage heart failure. The major complication of heart transplantation is organ rejection. Epigenetic could play a role in the pathogenesis of organ rejection, and the FTO gene is a mediator of DNA methylation. We analyzed a tagging FTO SNP rs17817449 in both donor and recipient DNA obtained through 370 heart transplantations. Recipient FTO genotypes were not associated with either type of rejection or with the general increase in the risk of rejection. When compared with patients without a history of rejection, carriers of transplanted hearts with the FTO TT genotype exhibited a significantly increased risk (P = 0.02) of suffering from both types of rejection in comparison to carriers of hearts with at least one G allele (OR; 95% CI = 2.56; 1.15-5.69). Our results suggest that the donor, but not the recipient, FTO genotype could be a significant predictor of acute rejection in heart transplant patients.
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http://dx.doi.org/10.1111/ctr.13443DOI Listing
December 2018

Donor PNPLA3 rs738409 genotype is a risk factor for graft steatosis. A post-transplant biopsy-based study.

Dig Liver Dis 2018 May 9;50(5):490-495. Epub 2018 Jan 9.

Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

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.
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http://dx.doi.org/10.1016/j.dld.2017.12.030DOI Listing
May 2018

The FTO variant is associated with chronic complications of diabetes mellitus in Czech population.

Gene 2018 Feb 14;642:220-224. Epub 2017 Nov 14.

Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Background: 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.

Methods: 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.

Results: The frequency of the GG genotype was significantly higher in T2DM (25.4% vs. 16.7%, P<0.0005) 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, P<0.01) and T2DM patients (G carriers vs. TT homozygotes, P<0.05). FTO genotype predicted the development of diabetic neuropathy (GG vs. TT comparison; P<0.01) 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.gene.2017.11.040DOI Listing
February 2018

Analysis of circulating miRNAs in patients with familial hypercholesterolaemia treated by LDL/Lp(a) apheresis.

Atheroscler Suppl 2017 Nov 1;30:128-134. Epub 2017 Jun 1.

Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Internal Medicine, 2nd Medical Faculty, Charles University, Prague, Czech Republic.

Background: 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.

Materials And Methods: 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.

Results: 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).

Conclusions: LDL/Lp(a) apheresis has an impact on miRNAs associated with lipid homeostasis and vascular status.
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http://dx.doi.org/10.1016/j.atherosclerosissup.2017.05.037DOI Listing
November 2017

Comparison of relative telomere length measured in aortic tissue and leukocytes in patients with end stage heart failure.

Neuro Endocrinol Lett 2016 ;37(2):124-8

Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Objectives: Telomeres are repetitive non-coding DNA sequences on the ends of eukaryotic chromosomes. Relative leukocyte telomere length (LrTL) is considered to reflect biological ageing and fitness. Therefore, we examined whether LrTL would reflect rTL in aortic tissue (ArTL) and whether it could be used as a marker of biological heart age.

Design: We analysed telomere length in aortic and leukocyte samples from 73 heart recipients (63 males, 10 females; age 52.2±11.7 years). Relative telomere length was measured using a quantitative PCR-based method.

Results: Neither LrTL nor ArTL correlated significantly with the age of heart recipients. Mean ArTL was slightly shorter than LrTL (p=0.06) and there was a slight but significant inverse correlation between LrTL and ArTL (p=0.019).

Conclusions: The age of patients with end stage heart failure was not associated with leukocyte or aortic telomere length. An inverse correlation between LrTL and ArTL suggests that LrTL is unlikely to be an important predictor of biological ageing in these patients.
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October 2018

Genetic variants within telomere-associated genes, leukocyte telomere length and the risk of acute coronary syndrome in Czech women.

Clin Chim Acta 2016 Feb 4;454:62-5. Epub 2016 Jan 4.

Laboratory for Atherosclerosis Research, Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

The association between leukocyte telomere length (LTL) and cardiovascular disease (CVD) has been published in many reports, although almost exclusively in men. In our study we analysed the association between LTL and five selected variants within three candidate genes (TERC rs12696304; TERF2IP rs3784929 and rs8053257; UCP2 rs659366 and rs622064), which are not only involved in telomere-length maintenance but also potentially associated with higher risk of acute coronary syndrome (ACS) in Czech women (505 cases and 642 controls). We detected significantly shorter LTL in women with ACS (P<0.001), but the difference disappeared after multiple adjustments. We did not find any significant associations between analysed variants and LTL, except for rs622064 within the UCP2 gene, in which case AA homozygotes had a higher LTL (P<0.04). Genotype frequencies of the analysed SNPs did not differ between controls and women with ACS. Variants within UCP2 (rs622064; CC vs. A allele carriers OR=1.61; 95% CI: 1.21-2.15, P<0.002) and within TERF2IP (rs8053257; A allele carriers vs. GG, OR=1.78; 95% CI: 1.07-3.18, P<0.03) were associated with increased risk of type 2 diabetes mellitus (T2DM). Analysed polymorphisms were not major determinants of telomere length or ACS risk in Czech females.
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http://dx.doi.org/10.1016/j.cca.2015.12.041DOI Listing
February 2016

FTO gene variant and risk of spontaneous abortion.

Acta Obstet Gynecol Scand 2016 Jan 13;95(1):118. Epub 2015 Oct 13.

Department of Obstetrics and Gynecology, 1st Faculty of Medicine and General Faculty Hospital, Prague, Czech Republic.

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http://dx.doi.org/10.1111/aogs.12777DOI Listing
January 2016

SLCO1B1 polymorphism is not associated with risk of statin-induced myalgia/myopathy in a Czech population.

Med Sci Monit 2015 May 20;21:1454-9. Epub 2015 May 20.

3rd Department of Internal Medicine, 1st Faculty of Medicine, Charles University Prague, Prague, Czech Republic.

Background: Gene SLCO1B1, encoding solute organic anionic transport polypeptide OATP1B1, belongs to the group of candidates potentially influencing statin treatment safety. OATP1B1 regulates (not only) the hepatic uptake of statins. Its genetic variation was described as an important predictor of statin-associated myopathy in a cohort of patients treated with a maximum dose of simvastatin. However, the impact of SLCO1B1 gene polymorphism on this risk in patients treated with other statins or lower doses of simvastatin needs to be assessed. Therefore, we performed the present study.

Material/methods: SLCO1B1 tagging rs4363657 polymorphism was analyzed in 2 groups of patients with dyslipidemia (treated with simvastatin or atorvastatin, 10 or 20 mg per day), subgroup with statin-induced myalgia (N=286), and subgroup (N=707) without myalgia/myopathy, and in 2301 population controls without lipid-lowering treatment.

Results: Frequency of the individual genotypes in patients with myalgia/myopathy (TT=62.3%, CT=34.5%, CC=2.8%) did not significantly differ (both P values over 0.19) from that in patients without muscle symptoms (TT=61.4%, CT=32.9%, CC=5.7%) or from the population controls (TT=63.9%, CT=32.5%, CC=3.6%). Null results were also obtained for the dominant and recessive models of the analysis.

Conclusions: In Czech patients treated with low statin doses, there is no association between SLCO1B1 gene polymorphism and risk of myalgia/myopathy.
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http://dx.doi.org/10.12659/MSM.893007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450600PMC
May 2015

FTO first intron rs1558902 variant and platelets count in white middle-aged women: prague pre- and post-menopausal females (3PMFs) study.

J Investig Med 2013 Feb;61(2):291-3

Institute for Clinical and Experimental Medicine, Videnska, Prague, Czech Republic.

The polymorphisms within the FTO gene play an important role in the genetic determination of body weight and body mass index and have been associated with cardiovascular disease, but the causal mechanism is still a matter of debate. The possible effect on the platelet count as a marker of hemocoagulation status as a possible cardiovascular risk factor was suggested in Japanese population. We have analyzed both rs1558902 FTO polymorphism (T > A) and platelet counts in the Prague Pre and Post Menopausal Females (3PMFs) study, including those of 669 women (mean age, 55.7 ± 2.7 years). The frequencies of the FTO genotypes were similar to other populations (TT, 30.4%; TA, 48.1%; and AA, 21.5%). We have not detected a significant association between the FTO rs1558902 variant and platelet counts in white women (TT, 242 ± 55 × 10; TA, 246 ± 67 × 10; and AA, 247 ± 55 × 10; F[2.642] = 0.30, P = 0.75). At least in white persons, platelet count seems not to be a link between the FTO variation and risk of cardiovascular disease.
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http://dx.doi.org/10.2310/JIM.0b013e31827b9994DOI Listing
February 2013

Possible gene-gender interaction between the SLCO1B1 polymorphism and statin treatment efficacy.

Neuro Endocrinol Lett 2012 ;33 Suppl 2:22-5

Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Objectives: A significant inter-individual variability in statin treatment efficacy is likely to have a strong genetic background. A candidate gene with the potential to influence statin treatment efficacy is SLCO1B1. This gene codes for the solute carrier organic anion transporter, which has been shown to regulate the hepatic uptake of statins and some other drugs.

Materials And Methods: The SLCO1B1 rs4149056 (T>C) polymorphism was successfully analysed in a group of 253 patients with dyslipidemia (treated with simvastin or atorvastatin, 10 or 20 mg per day) and 470 healthy normolipidemic controls. The polymorphism was analysed using nested PCR-RFLP. Lipid levels (total, LDL and HDL cholesterol; triglycerides) were analysed before and after 10-13 weeks of treatment.

Results: After treatment, as expected, there was a significant decrease both in the total cholesterol (7.60±1.36 → 5.37±1.12 mmol/L, p<0.001) and LDL cholesterol (5.04±1.34 → 3.17±0.99 mmol/L, p<0.001) levels. The distribution of the individual genotypes in the patients (TT=61.7%, CT=31.6%, CC=6.7%) was similar (p=0.35) to that of the normolipidemic controls (TT=64.4%, CT=31.3%, CC=4.3%). Homozygous CC males exhibited the lowest (Δ -21.2±7.2%) decrease of total cholesterol in contrast to the females, in whom the same genotype was associated with the highest (Δ -33.5±7.6 %) decrease (p=0.04 for gene-gender interaction).

Conclusions: The results of our pilot study suggest possible gender-dependent effects of the rs4149056 variant within the SLCO1B1 gene on statin treatment efficacy.
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April 2013

Variants within HNF1α and ANGPTL4 genes and acute coronary syndrome in Czech population. The GENDEMIP study.

Neuro Endocrinol Lett 2012 ;33 Suppl 2:13-6

Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Background: Atherosclerosis is a complex arterial disease involving interactions between multiple genetic and environmental factors. A large number of genetic polymorphisms associated with atherosclerotic diseases have been identified in recent years. We investigated the possible association between hepatic nuclear factor (HNF1-α) and angiopoietin-like 4 (ANGPTL4) single nucleotide polymorphisms and the risk of acute coronary syndrome (ACS) in the Czech population.

Materials And Methods: A total of 1,182 patients with ACS (835 males and 347 females) and 1,200 healthy controls (827 males and 373 females) were included in the study. All patients were younger than 65 years of age. rs7310409 (A>G within the HNF1-α gene) and rs116843064 (G>A within the ANGPTL4 gene) were genotyped using TaqMan genotyping assays.

Results: The frequencies of the genotypes in patients with ACS did not significantly differ from the control group for the rs7310409 polymorphism (AA=17.1%, AG=46.6%, GG=36.2% vs. AA=14.4%, AG=50.3%, GG=35.3%, respectively; p=0.12) or the rs116843064 polymorphism (AA=0.1%, AG=3.5%, GG=96.4% vs. AA=0.1%, AG=4.2%, GG=95.7%, respectively; p=0.69). There was no interaction with gender. In addition, gene variants were not associated with common cardiovascular risk factors (dyslipidaemia, hypertension, smoking, obesity and diabetes).

Conclusions: No association was observed between polymorphisms within the HNF1-α and ANGPTL4 genes and the risk of ACS in the Czech population.
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April 2013

Lack of an association between three tagging SNPs within the FTO gene and smoking behavior.

Nicotine Tob Res 2012 Aug 9;14(8):998-1002. Epub 2011 Dec 9.

Institute for Clinical and Experimental Medicine, Department of Medicine, Videnska 1958/9, 14021 Prague 4, Czech Republic.

Introduction: Using genome-wide screening, a polymorphism within the second intron of the FTO gene (rs2302673) was found to be associated with smoking habits in females. In a population-based, cross-sectional study, we analyzed three tagging FTO single-nucleotide polymorphisms (SNPs) for their association with smoking behavior.

Methods: Subjects from the Czech post-MONICA study, including 1,191 adult males (32.1% smokers) and 1,368 adult females (22.5% smokers) were included in this study. Smoking habits were obtained through questionnaire data analysis, and three FTO tagging SNPs were genotyped (rs17817449: intron 1, rs2302673: intron 2, and rs17818902: intron 3).

Results: We detected slightly lower frequencies (p = .043) of the GG genotype of the rs17818902 SNP in males who quit smoking compared with others. However, the significance disappeared after adjusting for multiple testing. Within the entire population, or in either males or females alone, we failed to detect a significant difference between other FTO genotypes and smoking status. Also, the number of cigarettes smoked per day was independent of individual FTO genotypes in both genders.

Conclusions: We did not find an association between the FTO gene tagging variants and smoking status. FTO is unlikely to be a major genetic determinant of smoking status.
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http://dx.doi.org/10.1093/ntr/ntr255DOI Listing
August 2012

The FTO gene polymorphism is associated with end-stage renal disease: two large independent case-control studies in a general population.

Nephrol Dial Transplant 2012 Mar 25;27(3):1030-5. Epub 2011 Jul 25.

Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Background: Genome-wide association studies identified the FTO (fat mass and obesity gene) gene as an important determinant of body weight. More recently, the FTO gene was reported to be associated with other outcomes, including major risk factors for chronic kidney disease (CKD). We investigated the role of this gene in the risk of end-stage renal disease (ESRD) caused by CKD.

Methods: We conducted two large population-based case-control studies of ESRD. Study 1 compared 984 haemodialysed patients with ESRD with 2501 participants in the Czech post-MONICA study; Study 2 compared 1188 patients included in a kidney transplantation programme for ESRD with 6681 participants in the Czech HAPIEE study. The frequencies of the FTO rs17817449 single nucleotide polymorphism genotype were compared between cases and controls.

Results: The FTO rs17817449 genotype was significantly associated with CKD in both studies (P-values 0.00004 and 0.006, respectively). In the pooled data, the odds ratios of CKD for GG and GT, versus TT genotype, were 1.37 (95% confidence interval 1.20-1.56) and 1.17 (1.05-1.31), respectively (P for trend <0.0001). Among haemodialysed and kidney transplant patients, the onset of ESRD in GG homozygotes was 3.3 (P = 0.012) and 2.5 (P = 0.032) years, respectively, earlier than in TT homozygotes.

Conclusions: These two large independent case-control studies in the general population found robust associations between the FTO rs17817449 polymorphism and the ESRD. The results suggest that the morbidities associated with the FTO gene include CKD.
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http://dx.doi.org/10.1093/ndt/gfr418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289895PMC
March 2012

A FTO variant and risk of acute coronary syndrome.

Clin Chim Acta 2010 Aug 1;411(15-16):1069-72. Epub 2010 Apr 1.

Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Background: The FTO gene plays an important role in the determination of body weight and BMI and it has been suspected of being associated with all-case mortality.

Methods: We have analyzed the FTO rs17817449 variant in consecutive 1092 male patients with acute coronary syndrome (ACS) and in 1191 randomly selected Caucasian individuals (population controls).

Results: The FTO variant was significantly associated with BMI both in controls (P<0.02) and ACS patients (P<0.01). In both groups, BMI was highest in GG homozygotes and lowest in TT homozygotes. There was a significant difference between the ACS patients and controls in the frequency of the FTO genotype GG (21.4% vs. 15.9%, P<0.005). FTO GG homozygotes had a significantly increased risk of ACS, compared with TT homozygotes which was independent of age and BMI (odds ratio 1.49, 95% confidence interval 1.16-1.93). The odds ratio of ACS patients for the GG genotype remained significant even after the exclusion of diabetics (100 controls and 339 ACS patients), with OR 1.32 (95% CI 1.01-1.72).

Conclusions: This study provides an evidence of an association between the FTO variant and risk of ACS in Caucasian males.
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http://dx.doi.org/10.1016/j.cca.2010.03.037DOI Listing
August 2010