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1.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638908

RESUMO

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.

2.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360600

RESUMO

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.


Assuntos
Metilação de DNA , Epigênese Genética , Regulação da Expressão Gênica/efeitos dos fármacos , Nanopartículas/efeitos adversos , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Adulto , Estudos de Casos e Controles , Ilhas de CpG , República Tcheca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/genética
3.
Mol Biol Rep ; 48(8): 5873-5879, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34328600

RESUMO

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

4.
Int J Cardiol ; 339: 138-143, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34197842

RESUMO

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: Increasing quantities of miR-126 (P < 0.03) and miR-146a (P < 0.02) was observed at each follow-up visit after LVAD implantation. A positive association between miR-155 and Belcaro score (P < 0.04) and an inverse correlation between miR-126 and endothelial function, measured as the reactive hyperemia index (P < 0.05), was observed. CONCLUSIONS: 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.

5.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299034

RESUMO

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 < 0.05) shared between samples before and after LVAD support was 277. The whole miRNome profile revealed 69 differentially expressed miRNAs (Pcorr < 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.


Assuntos
Valvopatia Aórtica/patologia , Regulação da Expressão Gênica , Insuficiência Cardíaca/cirurgia , Transplante de Coração/efeitos adversos , Coração Auxiliar/efeitos adversos , MicroRNAs/genética , RNA Mensageiro/metabolismo , Adolescente , Adulto , Idoso , Valvopatia Aórtica/etiologia , Valvopatia Aórtica/metabolismo , Feminino , Perfilação da Expressão Gênica , Insuficiência Cardíaca/patologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Adulto Jovem
6.
Artigo em Inglês | MEDLINE | ID: mdl-34012148

RESUMO

BACKGROUND: Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare genetic disorder. Dysfunctional transient receptor potential melastatin 6 causes impaired intestinal absorption of magnesium, leading to low serum levels accompanied by hypocalcemia. Typical signs at initial manifestation are generalized seizures, tetany, and/or muscle spasms. CASE REPORT: We present a 5 w/o female manifesting tonic-clonic seizures. Laboratory tests detected severe hypomagnesemia and hypocalcemia. The molecular genetic analysis revealed two novel mutations within the TRPM6 gene c.3308dupC (p.Pro1104Thrfs*28) (p.P1104Tfs*28) and c.3958C>T (p.Gln1302*) (p.Q1302*) and the patient was successfully treated with Mg supplementation. CONCLUSION: Ion disbalance should be taken into account in the differential diagnosis of infantile seizures. Accurate diagnosis of HSH together with appropriate treatment are crucial to prevent irreversible neurological outcomes.

7.
Clin Chim Acta ; 519: 206-209, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33957095

RESUMO

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.


Assuntos
COVID-19 , SARS-CoV-2 , China , República Tcheca , Humanos , Peptidil Dipeptidase A/genética , Sobreviventes
8.
J Clin Lipidol ; 15(3): 435-440, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33975813

RESUMO

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.

9.
Int J Mol Sci ; 22(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920733

RESUMO

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.


Assuntos
Doenças Cardiovasculares/genética , Testes Genéticos/métodos , Nutrigenômica/métodos , Medicina de Precisão/métodos , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos
10.
Artigo em Inglês | MEDLINE | ID: mdl-31796940

RESUMO

AIM: Plasma values of nicotine and its metabolites are highly variable, and this variability has a strong genetic influence. In our study, we analysed the impact of common polymorphisms associated with smoking on the plasma values of nicotine, nicotine metabolites and their ratios and investigated the potential effect of these polymorphisms and nicotine metabolite ratios on the successful treatment of tobacco dependence. METHODS: Five variants (rs16969968, rs6474412, rs578776, rs4105144 and rs3733829) were genotyped in a group of highly dependent adult smokers (n=103). All smokers underwent intensive treatment for tobacco dependence; 33 smokers were still abstinent at the 12-month follow-up. RESULTS: The rs4105144 (CYP2A6, P<0.005) and rs3733829 (EGLN2, P<0.05) variants were significantly associated with plasma concentrations of 3OH-cotinine and with 3OH-cotinine: cotinine ratios. Similarly, the unweighted gene score was a significant (P<0.05) predictor of both cotinine:nicotine and 3OH-cotinine:cotinine ratios. No associations between the analysed polymorphisms or nicotine metabolite ratios and nicotine abstinence rate were observed. CONCLUSION: Although CYP2A6 and EGLN2 polymorphisms were associated with nicotine metabolism ratios, neither these polymorphisms nor the ratios were associated with abstinence rates.

11.
Front Genet ; 11: 574474, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133164

RESUMO

Familial hypercholesterolemia (FH) is one of the most common monogenic diseases, leading to an increased risk of premature atherosclerosis and its cardiovascular complications due to its effect on plasma cholesterol levels. Variants of three genes (LDL-R, APOB and PCSK9) are the major causes of FH, but in some probands, the FH phenotype is associated with variants of other genes. Alternatively, the typical clinical picture of FH can result from the accumulation of common cholesterol-increasing alleles (polygenic FH). Although the Czech Republic is one of the most successful countries with respect to FH detection, approximately 80% of FH patients remain undiagnosed. The opportunities for international collaboration and experience sharing within international programs (e.g., EAS FHSC, ScreenPro FH, etc.) will improve the detection of FH patients in the future and enable even more accessible and accurate genetic diagnostics.

12.
Front Genet ; 11: 568303, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33110422

RESUMO

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.

13.
Circ J ; 84(10): 1779-1785, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32848115

RESUMO

BACKGROUND: 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; P<0.01). The prevalence of GS was 8.9%, twice as high in males compared with females (11.6 vs. 6.1%; P<0.01). TheUGT1A1(TA)7/7promoter repeats significantly influenced serum bilirubin concentrations in the controls, but not in the MI patients. Serum bilirubin concentrations were significantly lower in MI patients (7.7 vs. 10.7 µmol/L; P<0.01), with almost 5-fold lower prevalence of GS. CONCLUSIONS: 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.

14.
Drug Metab Pers Ther ; 35(2)2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32681777

RESUMO

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%; p<0.0001). For rs3892097 (CYP2D6) 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.

15.
Drug Metab Pers Ther ; 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32609646

RESUMO

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%; p<0.0001). For rs3892097 (CYP2D6) 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.

16.
Mol Genet Genomic Med ; 8(9): e1361, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32578971

RESUMO

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 < .01), IGF2BP2 (22% vs. 10% TT homozygotes, p < .0001), ARAP1 (98% vs. 95% of A allele carriers, p < .005), and CDKN2A/2B (81% vs. 66% of TT homozygotes, p < .001) genes; however, less frequently they are carriers of the TCF7L2 risk allele (34% vs. 48% of the T allele p < .0005). Finally, we found significant accumulation of T2DM-associated alleles between the Roma population in comparison with the majority population (25.4% vs. 15.2% of the carriers of at least 12 risk alleles; p < .0001). CONCLUSION: The increased prevalence of T2DM in the Roma population may have a background in different frequencies of the risk alleles of genes associated with T2DM development.


Assuntos
Diabetes Mellitus Tipo 2/genética , Frequência do Gene , Loci Gênicos , Roma (Grupo Étnico)/genética , Adiposidade , Adulto , Glicemia/análise , Colesterol/sangue , República Tcheca , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
17.
Int J Mol Sci ; 21(7)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244494

RESUMO

The risk of exposure to nanoparticles (NPs) has rapidly increased during the last decade due to the vast use of nanomaterials (NMs) in many areas of human life. Despite this fact, human biomonitoring studies focused on the effect of NP exposure on DNA alterations are still rare. Furthermore, there are virtually no epigenetic data available. In this study, we investigated global and gene-specific DNA methylation profiles in a group of 20 long-term (mean 14.5 years) exposed, nanocomposite, research workers and in 20 controls. Both groups were sampled twice/day (pre-shift and post-shift) in September 2018. We applied Infinium Methylation Assay, using the Infinium MethylationEPIC BeadChips with more than 850,000 CpG loci, for identification of the DNA methylation pattern in the studied groups. Aerosol exposure monitoring, including two nanosized fractions, was also performed as proof of acute NP exposure. The obtained array data showed significant differences in methylation between the exposed and control groups related to long-term exposure, specifically 341 CpG loci were hypomethylated and 364 hypermethylated. The most significant CpG differences were mainly detected in genes involved in lipid metabolism, the immune system, lung functions, signaling pathways, cancer development and xenobiotic detoxification. In contrast, short-term acute NP exposure was not accompanied by DNA methylation changes. In summary, long-term (years) exposure to NP is associated with DNA epigenetic alterations.


Assuntos
Metilação de DNA/efeitos dos fármacos , Nanopartículas/efeitos adversos , Exposição Ocupacional , Adulto , Idoso , Epigênese Genética , Feminino , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Nanocompostos/efeitos adversos , Adulto Jovem
18.
Pharmacogenomics ; 21(5): 317-323, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32308134

RESUMO

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.

19.
Transplantation ; 104(3): 526-534, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31356578

RESUMO

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.


Assuntos
Lipase/genética , Transplante de Fígado/efeitos adversos , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/genética , Complicações Pós-Operatórias/genética , Adulto , Alelos , Aloenxertos/patologia , Biópsia , Feminino , Seguimentos , Técnicas de Genotipagem/estatística & dados numéricos , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/patologia , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , Doadores de Tecidos/estatística & dados numéricos , Transplantados/estatística & dados numéricos , Adulto Jovem
20.
Clin Toxicol (Phila) ; 58(4): 241-253, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31298045

RESUMO

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 of co-morbidities, complications, and methanol-induced brain lesions on hospital, follow-up, and total mortality.Methods: All patients hospitalized with methanol poisoning during a mass poisoning outbreak were followed in a prospective cohort study until death or final follow-up after 6 years. The age-adjusted Charlson co-morbidity index (ACCI) score was calculated for each patient. A multivariate Cox regression model was used to calculate the adjusted hazards ratio (HR) for death. The survival was modeled using the Kaplan-Meier method.Results: Of 108 patients (mean age with SD 50.9 ± 2.6 years), 24 (54.4 ± 5.9 years) died during hospitalization (mean survival with SD 8 ± 4 days) and 84 (49.9 ± 3.0 years; p = .159) were discharged, including 27 with methanol-induced brain lesions. Of the discharged patients, 15 (56.3 ± 6.8 years) died during the follow-up (mean survival 37 ± 11 months) and 69 (48.5 ± 3.3 years; p = .044) survived. The hospital mortality was 22%, the follow-up mortality was 18%; the total mortality was 36%. Cardiac/respiratory arrest, acute respiratory failure, multiorgan failure syndrome, and arterial hypotension increased the HR for hospital and total (but not follow-up) mortality after adjustment for age, sex, and arterial pH (all p < .05). All patients who died in the hospital had at least one complication. A higher ACCI score was associated with greater total mortality (HR 1.22; 1.00-1.48 95% CI; p = .046). Of those who died, 35 (90%) had a moderate-to-high ACCI. The Kaplan-Meier curve demonstrated that patients with a high ACCI had greater follow-up mortality compared to ones with low (p = .027) or moderate (p = .020) scores. For the patients who died during follow-up, cancers of different localizations were responsible for 7/15 (47%) of the deaths.Conclusions: The character and number of complications affected hospital but not follow-up mortality, while the burden of co-morbidities affected follow-up mortality. Methanol-induced brain lesions did not affect follow-up mortality. Relatively high cancer mortality rate may be associated with acute exposure to metabolic formaldehyde produced by methanol oxidation.


Assuntos
Formaldeído/envenenamento , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Metanol/envenenamento , Envenenamento/mortalidade , Adolescente , Adulto , Estudos de Coortes , Surtos de Doenças/estatística & dados numéricos , Feminino , Seguimentos , Formaldeído/metabolismo , Humanos , Estudos Longitudinais , Masculino , Metanol/farmacocinética , Pessoa de Meia-Idade , Envenenamento/epidemiologia , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
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