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Background: Among many genes which have been analyzed to understand obesity and related metabolic traits among children and adolescents, not many studies are conducted on LGALS3 gene, especially in population of children. A positive correlation of circulating galectin 3 serum levels with impaired blood glucose, high blood pressure and higher values of serum lipids and was found in general population. The aim was to investigate possible association of rs4644 with body mass index, glycaemia, and lipid profile in Serbian adolescents. Methods: The study included 72 boys and 79 girls, 14-15 years of age. Among boys 51 (67.1%) had normal values of BMI, 11 (14.5%) were overweight, and 14 (18.4%) were obese. Among girls, 53 (63.9%) had normal BMI, 16 (19.3%) were overweight, and 14 (16.9%) were obese. Diabetes type 1 or 2, genetic syndromes, generalized inflammation, cardiovascular and malignant diseases were criteria for exclusion. Genotyping was performed by Real time PCR.
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OBJECTIVES: Inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6 can cause brain injury, slow recovery, and adverse effects (ADEs) in ischemic stroke (IS) patients treated with recombinant tissue plasminogen activator (rtPA). We explored the relationship between selected polymorphisms within TNF-α, IL-1ß and IL-6 genes, and post-IS outcome and ADEs in patients treated with rtPA. METHODS: One hundred and sixty-six patients with IS treated with rtPA were included in this study. The modified Rankin Scale (mRS) was used to assess functional recovery 3 months after IS likewise thrombolytic therapy efficacy. Patients were classified into groups with favorable (0-1) or poor recovery based on their mRS score at the ninetieth day post-IS. During hospitalization, ADEs following rtPA were monitored. TNF-α-308 G/A (rs1800629), IL-1ß-511 G/A (rs16944), and IL-6-174 G/C (rs1800795) polymorphisms were genotyped using Real-Time PCR. SPSS software version 22.0 was used for statistical analyses. RESULTS: Patients with the TNF-α-308 G/A GG genotype had a higher mean NIHSS value at admission (12.75 ± 5.176) than those carrying A-allele (10.56 ± 3.979;p = 0.016). Individuals with the CC genotype of the IL-6-174 G/C polymorphism had significantly lower NIHSS scores (8.79 ± 5.053) than those with G-allele (12.06 ± 6.562) 24 hours after rtPA (p = 0.050). Patients with the GG genotype of the IL-6-174 G/C polymorphism had a significantly poorer outcome (p = 0.024; OR = 2.339; 95%CI 1.121-4.880), while patients who were G-allele carriers of the Il-6-174 G/C polymorphism and had the AA genotype of the IL-1ß-511 G/A polymorphism were statistically significantly more likely to experience hemorrhagic transformation (p = 0.046; OR = 2.7273; 95%CI 1.0414-7.1426). CONCLUSION: GG genotype of the IL-6-174 G/C polymorphism is associated with poor recovery after IS treated with rtPA therapy.
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AVC Isquêmico , Fator de Necrose Tumoral alfa , Humanos , Fator de Necrose Tumoral alfa/genética , Interleucina-6/genética , Interleucina-1beta/genética , Ativador de Plasminogênio Tecidual/genética , Ativador de Plasminogênio Tecidual/uso terapêutico , Predisposição Genética para Doença , Frequência do Gene , Polimorfismo de Nucleotídeo Único , Genótipo , Terapia Trombolítica , Estudos de Casos e ControlesRESUMO
The enzymes of the cytochrome P450 superfamily play a critical role in phase I drug metabolism. Among them, CYP2C9 and CYP2C19 are clinically important, as they can mediate severe toxicity, therapy failure, and increased susceptibility to cancer and other diseases caused by chemicals. The aim of this study was to determine the prevalence of pharmacologically most important allelic variants of the CYP2C9 and CYP2C19 genes in the general population of the Republic of Srpska (Bosnia and Herzegovina) and to compare them with other populations. For this purpose we determined the genotype profile and allele frequency of 216 randomly selected healthy volunteers using real-time polymerase chain reaction (RT-PCR). The prevalence of the CYP2C9 *2 and *3 alleles was 13.6 and 7.4 %, respectively. Based on these frequencies, of the 216 participants four (1.86 %) were predicted to be poor metabolisers, 78 (36.11 %) intermediate, and the remaining 134 (62.03 %) normal metabolisers. Based on the prevalence of CYP2C19 *2 and *17 variants - 16.2 and 20.4 %, respectively - nine (4.17 %) were predicted to be poor, 57 (26.39 %) rapid, and nine (4.17 %) ultra-rapid metabolisers. We found no significant differences in allele frequencies in our population and populations from other European countries. These findings suggest that genetically determined phenotypes of CYP2C9 and CYP2C19 should be taken into consideration to minimise individual risk and improve benefits of drug therapy in the Republic of Srpska.
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Hidrocarboneto de Aril Hidroxilases , Alelos , Hidrocarboneto de Aril Hidroxilases/genética , Bósnia e Herzegóvina , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Humanos , Polimorfismo Genético , PrevalênciaRESUMO
Adenosine receptors ADORA2A and ADORA3 are part of the adenosine-mediated antiinflammatory pathway and are overexpressed in patients with Rheumatoid arthritis (RA). Methotrexate (MTX) antiinflammatory effects are partially mediated via increased release of adenosine into extracellular space. Polymorphisms in ADORA2A and ADORA3 genes may have an impact on the efficacy and toxicity of MTX in RA patients. The study included 127 RA patients. Treatment efficacy was estimated using the changes in Disease activity score (DAS28) after 6 months of MTX monotherapy, according to EULAR response criteria. Patients with good and moderate response were classified as "responders", and with a poor response as "nonresponders". Adverse effects were collected during the follow-up period. Genotyping for polymorphisms within ADORA2A gene (rs2298383, rs2236624, rs5751876, rs17004921) and ADORA3 gene (rs2298191, rs1544223, rs3393) was performed using the KASPar assays. Among patients 112 (88.19%) were responders (18.8% good, 81.2% moderate). We observed no association between analyzed genotypes or alleles and MTX response by EULAR criteria but carriers of ADORA2A rs17004921 T allele (CT + TT) had a higher DAS28 decrease after 6 months of treatment than patients with CC genotype (p = 0.013). Adverse effects were reported in 31 patients (24.41%). Bone erosions were present in 82 (64.6%) patients. Haplotype block was observed among all 3 analyzed polymorphisms within ADORA3 gene and TAA haplotype was associated with bone erosions (29% vs 15.6%, p = 0.023) and hepatotoxicity (51.3% vs 21.6%, p = 0.013). According to our study, ADORA3 TAA haplotype may be associated with bone erosions and hepatotoxicity in RA patients treated with MTX.
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Artrite Reumatoide/genética , Genótipo , Haplótipos/genética , Metotrexato/efeitos adversos , Receptor A2A de Adenosina/genética , Receptor A3 de Adenosina/genética , Adulto , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Resultado do TratamentoRESUMO
For many decades, methotrexate (MXT) has remained the drug of choice in the treatment of rheumatoid arthritis (RA). Unfortunately, a considerable number of patients do not achieve an appropriate therapeutic response. Pharmacogenetics studies do not give usable results regarding differences in MTX response among RA patients. The mechanism of MTX action in RA is not completely understood. We present and discuss data regarding the molecular basis of folate and adenosine pathways, the most obvious MTX targets, to explain possible causes of therapy failure. The molecular basis of the disease could also have an impact on therapy outcomes and in this review we explore this. Finally, we make a short review of available pharmacogenetics study results.
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Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Metotrexato/efeitos adversos , Farmacogenética , Adenosina/genética , Antirreumáticos/uso terapêutico , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Feminino , Ácido Fólico/genética , Humanos , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Polimorfismo GenéticoRESUMO
Early-onset neonatal sepsis (EOS) is diagnosed during the first 7 days of neonatal life and is the major cause of morbidity and mortality among preterm infants. Genetic predisposition may have an impact on EOS susceptibility and outcome. The aim of our study was to explore the association between TNF-α -308 G/A or IL-6 -174 G/C gene polymorphism and the susceptibility and outcome of EOS in preterm infants. The study included 471 preterm infants: 282 with EOS (151 with culture proven sepsis and 131 with clinical sepsis) and 189 without infection (control group). TNF-α -308 G/A and IL-6 -174 G/C were genotyped using Real-time RCR method. We observed significantly higher frequency of A allele of TNF-α -308 G/A polymorphism in blood culture proven EOS (p = 0.017) or clinical EOS (p = 0.025) compared with the control group. Logistic regression confirmed significant association between TNF-α -308 GA+AA genotypes and development of culture proven EOS (B = -0.718, p = 0.013) or clinical EOS (B = -0.602, p = 0.027). No significant differences in IL6 -174G/C alleles or genotypes distribution have been observed between culture proven EOS group, clinical EOS group and the control group. An association between TNF-α -308 G/A or IL-6 -174 G/C genotypes and EOS lethal outcome was not observed (p = 0.652 and p = 0.384, respectively). According to our analysis of large cohort of preterm infants with clearly defined EOS groups, the TNF-α -308 A allele may be a risk factor for the EOS occurrence.
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Estudos de Associação Genética , Predisposição Genética para Doença , Recém-Nascido Prematuro/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Sepse/genética , Fator de Necrose Tumoral alfa/genética , Alelos , Feminino , Humanos , Recém-Nascido , MasculinoRESUMO
PURPOSE: Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs). METHODS: The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX. RESULTS: According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed. CONCLUSION: The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients.