RESUMO
The aim of this study was to identify KRAS and BRAF gene mutations in colorectal cancer patients and to assess whether they are linked with clinicopathological features. The results of KRAS and BRAF mutation analysis could be used in the selection of patients for anti-EGFR therapy. All specimens were obtained during routine surgery of patients with colorectal carcinoma. The diagnoses were established by standard procedures and confirmed histopathologically. After DNA extraction, KRAS mutations were analyzed using quantitative real-time PCR and BRAF mutations were analyzed using real-time PCR by fluorescence melting curve analysis. Our results show that KRAS gene mutations were detected in 35.6% samples and the most frequent mutation was Gly12Val. BRAF gene mutation Val600Glu was detected in 8.5% samples. Statistical analysis revealed a significant association between the KRAS mutation and Dukes' stage (p=0.034), with the lowest frequency in Dukes'A, and between the KRAS mutation and histological grade (p=0.044), with no KRAS mutation found in poor differentiated tumors. The first data about KRAS and BRAF mutational status in the sample of Croatian population with colorectal cancer shows that the incidence of KRAS and BRAF mutations is within generally valid limits. Prospective studies are to be continued in order to determine whether these mutations contribute to progression of colorectal cancer.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Croácia , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas p21(ras) , Reação em Cadeia da Polimerase em Tempo Real , Adulto JovemRESUMO
AIM: The aim of this study was to evaluate the moderating effect of peroxisome proliferator activated receptor-γ (PPAR-γ) gene variants on the association of serum C-reactive protein level (CRP) and ischemic stroke (IS). MATERIAL AND METHODS: A total of 114 patients with IS and 135 healthy controls were included. RESULTS: After adjustment for age, sex, total cholesterol, LDL and HDL cholesterol, triglycerides, hypertension, smoking, body mass index and previous therapy with antihypertensive and/or statins, PPAR-γ had statistically significant moderating effect on association of serum CRP level and IS in patients younger than 60. In participants with PPAR CG or GG genotype level of CRP and IS were not statistically significantly associated (ORâ¯=â¯1.00; 95% CI 0.90-1.10; pâ¯=â¯0.933), but in participants with PPAR CC genotype, the association of serum CRP level and IS was significant (ORâ¯=â¯1.67; 95% CI 1.21-2.31; pâ¯=â¯0.002). CONCLUSION: In patients with PPAR CC genotype the association of serum CRP level and IS was significant.
Assuntos
Proteína C-Reativa/análise , AVC Isquêmico/genética , PPAR gama/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , AVC Isquêmico/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
The objective of this study was to determine the association of 5-HT2C (serotonin 2C receptor) and MDR1 (multidrug resistant protein) genetic polymorphisms and antipsychotic-induced metabolic abnormalities among female patients with DSM IV schizophrenia spectrum disorders. We have previously reported the associations of -759CT 5-HT2C and G2677T and C3435T MDR1 genetic polymorphisms and olanzapine/risperidone-induced weight gain in a similar sample of patients. Here, we included a total of 101 previously non-medicated female patients treated with olanzapine/risperidone over a 3-month period. The variables analyzed included fasting glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglyceride levels in blood, blood pressure and waist circumferences. We observed significant association of -759T 5-HT2C genetic variant and greater increase in waist circumference (P=0.03), fasting glucose level (P=0.046) and triglyceride level (P=0.045) in blood after a 3-month period. The 2677T and 3435T MDR1 genetic variants were significantly associated with the greater increase in fasting glucose level in blood when patients were using olanzapine (P<0.001 and P=0.028, respectively). Our data indicate a possible influence of -759CT 5-HT2C and MDR1 G2677T and C3435T MDR1 genetic polymorphisms on the development of metabolic abnormalities among female patients treated with olanzapine/risperidone.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Antipsicóticos/efeitos adversos , Receptor 5-HT2C de Serotonina/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Antipsicóticos/uso terapêutico , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Glicemia/metabolismo , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Olanzapina , Polimorfismo Genético , Receptor 5-HT2C de Serotonina/metabolismo , Risperidona/efeitos adversos , Risperidona/uso terapêutico , Esquizofrenia/metabolismo , Circunferência da Cintura , Adulto JovemRESUMO
AIM: Ischemic stroke (IS) is multifactorial disease and therefore different genes and proteins play a role in its development. Haptoglobin (Hp) removes free hemoglobin and protects from iron-induced oxidative damage, inflammatory response, atherosclerosis and cerebrovascular diseases. The aim of this study was to investigate Hp genetic variants in patients with carotid atherosclerotic lesions and IS. MATERIAL AND METHODS: A total of 121 subjects with IS participated in the study, 81 male and 40 female. RESULTS: Among 121 patients with IS, 79 had diffuse atherosclerotic plaques and stenosis. Hp genotype was statistically significantly associated with CDFI neck carotid artery stenosis findings (p = 0.006). Patients with Hp1-2 genotype had statistically significantly larger odds for atherosclerotic changes compared to those with Hp1-1 genotype, as well as those with Hp2-2 genotype. CONCLUSION: This study has shown an association of the Hp2-2 genotype and atherosclerosis in patients with IS, indicating Hp2-2 genotype as a genetic biomarker for precision medicine and personalized healthcare.
Assuntos
Aterosclerose/genética , Isquemia Encefálica/genética , Haptoglobinas/genética , Estenose das Carótidas/genética , Feminino , Genótipo , Haptoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/genética , Polimorfismo Genético/genética , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genéticaRESUMO
BACKGROUND: Angiotensin II type 1 receptor (AT1R) gene 1166A>C polymorphism is strongly associated with the incidence of cardiovascular diseases and predicts the development of metabolic syndrome (MetS). There is little information about the gene-diet interactions associated with MetS. This investigation examined the interaction between dietary patterns and AT1R polymorphism in relation to development risk of MetS. METHODS: A prospective, non-interventional, case-control study included 265 MetS patients and 262 healthy controls in an adult population from Croatia. Collected data included clinical variables, type of diet (Mediterranean, continental and mixed), biochemical tests and AT1R genotyping. AT1R 1166A>C genotyping was performed by PCR restriction fragment length polymorphism methods. To examine gene-diet interactions, a total predictive model was built using a hierarchical backward elimination approach. RESULTS: Participants on Continental-diet were nearly 20 times more likely to have MetS than those on Mediterranean or mixed diet (ORâ¯=â¯19.96; 95% CI 10.44-38.18). In multivariate prediction, control subjects with AT1R 1166AC or CC genotype had a higher risk for high triglycerides compared to the AA genotype carriers. 1166AC or CC genotype carriers more often chose Mediterranean or mixed-diet versus 1166AA genotype carriers whose choice often was continental diet. CONCLUSIONS: Our results are the first to suggest the possibility that the choice of diet can undermine the potential genetic risk of the AT1R polymorphism as polymorphism carriers may spontaneously choose the Mediterranean-diet.
Assuntos
Dieta/efeitos adversos , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Angiotensina/genética , Estudos de Casos e Controles , Croácia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Triglicerídeos/análiseRESUMO
Congenital myasthenic syndromes (CMS) result from mutations in various synapse-associated genes. Mutations in the choline acetyltransferase (CHAT) gene cause a presynaptic CMS associated with episodic apnea (CMS-EA). We present two unrelated Croatian children affected by CMS-EA. Beside other clinical findings characteristic for CMS, both patients manifested intermittent apneas since early infancy. Whereas the course of disease is mild in the female patient (patient 2), the male patient (patient 1) experienced recurrent and severe episodes of apnea despite adequate treatment with AChE-inhibitors and shows a global developmental delay with delayed myelination and signs of hypoxic-ischemic injury in brain imaging. Interestingly, sequencing of the CHAT gene revealed identical, compound heterozygous mutations S694C and T354M in both children. These findings are in line with a remarkable clinical heterogeneity observed in patients with CHAT mutations and emphasize the potential role of apneic crises for the development of secondary hypoxic brain damage and psychomotor retardation.
Assuntos
Apneia/genética , Colina O-Acetiltransferase/genética , Mutação de Sentido Incorreto/genética , Síndromes Miastênicas Congênitas/genética , Fenótipo , Apneia/complicações , Croácia , Deficiências do Desenvolvimento/etiologia , Feminino , Humanos , Hipóxia Encefálica/etiologia , Recém-Nascido , Masculino , Síndromes Miastênicas Congênitas/complicações , Insuficiência Respiratória/etiologiaRESUMO
AIM: Etiology of ischemic stroke (IS) is multifactorial and includes interaction of genetic and environmental factors. Different genes, their polymorphisms, host susceptibility, and inflammation processes play a role in IS development. The aim of this study was to evaluate the effect of PPAR-γ and IL-6 gene variants on IS onset. MATERIAL AND METHODS: A total of 301 subjects (144 males, 157 females) participated in the study, 114 patients with IS and 187 healthy controls. RESULTS: Statistically significant predictors of IS were male gender (OR 7.13, 95% CI 2.92-17.39, p<0.001), hypertension (OR 7.82. 95% CI 2.53-24.19, p<0.001), lowered HDL cholesterol (OR 8.20, 95% CI 2.41-27.94, p=0.001), elevated C-reactive protein (OR 5.26, 95% CI 1.92-14.41) and IL-6 -174 GC (OR 2.44 95% CI 1.01-5.91, p=0.0048) genotype. Males, compared to females, had 7 times higher odds for stroke. IL6 -174G/C genotype increased the odds for IS for 2.4 times. PPARγ was not statistically significantly associated with stroke. CONCLUSION: We can point to the IL-6 -174G>C polymorphisms as candidate gene marker and risk factor for the prediction of ischemic stroke.
Assuntos
Isquemia Encefálica/genética , Interleucina-6/genética , PPAR gama/genética , Estudos de Casos e Controles , Croácia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
The frequency of apolipoprotein E (apo E) phenotypes and genotypes due to allelic variation at amino acids 112 and 158 was analysed in 50 children with type I diabetes. Phenotypes were determined by isoelectric focusing and genotypes by the technique of polymerase chain reaction using allele-specific oligonucleotide probes (PCR/ASO) and the amplification refractory mutation system (ARMS). Discrepancies between phenotypes and genotypes as assigned by PCR/ASO were observed in 12 (24%) cases and by ARMS in eight (16%) cases. Results revealed the apo E3/3 genotype, as assigned by ARMS, to be the most frequent one (70%), followed by apo E3/4 in 16%, apo E2/2 in 2%, apo E2/3 in 8%, apo E2/4 in 2% and apo E4/4 in 2% of the cases. Apo E3/4 genotype and phenotype were more frequently present in the children with type I diabetes as compared with the diabetic adults previously reported on.
Assuntos
Apolipoproteínas E/genética , Diabetes Mellitus Tipo 1/genética , Mutação , Adolescente , Alelos , Apolipoproteínas E/metabolismo , Sequência de Bases , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Amplificação de Genes , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Sondas de Oligonucleotídeos , Fenótipo , Reação em Cadeia da PolimeraseRESUMO
The dystrophin gene deletion in 53 Duchenne and 21 Becker muscular dystrophy (DMD/BMD) male patients was analyzed by DNA test using multiplex polymerize chain reaction (M-PCR) in Croatian population. The overall percentage of deletion cases observed was 50%; 61% (53/32) for DMD and 38% (21/8) for BMD. The number of deleted exons was variable, but generally DMD deletions involving single-exon 19, 44, 50, 51 and larger exon deletions 3-6, 4-12, 4-17, 8-13, 12-13, 12-19, 48-50, 50-51, 50-52, 51-52 were more frequent. Eight patients with BMD had deletions exon 45-47, 45-48, and exon 3. The results obtained in the present study showed location of breakpoints in the dystrophin gene, and pointed to variability of deletion patterns in Croatian population among different European populations.
Assuntos
Deleção Cromossômica , Distrofias Musculares/genética , Adolescente , Adulto , Criança , Pré-Escolar , Croácia , Distrofina/genética , Éxons , Genética Populacional , Humanos , Masculino , Reação em Cadeia da Polimerase/métodosRESUMO
Apo E genotypes and plasma metabolic risk factors (total cholesterol, triglycerides, HDL and LDL cholesterol, total/HDL cholesterol ratio, lipoprotein Lp (a), apolipoprotein A-I, A-II, apo B, and apo E) were determined in 134 healthy middle-aged (X +/- SD 49.62 +/- 4.83) women. The aim of this study was to investigate metabolic risk markers according to various apo E genotypes, and to evaluate a possible risk for coronary heart disease. The results revealed that the frequencies of apo E3/3 are the most frequent (46%), followed by E4/4 (2%), E3/4 (14%), E2/3 (14%), and E2/4 (2%) in the middle-aged women. Higher mean triglycerides, LDL-C and apo B levels were found with apo E3/4, and lower mean levels of HDL-C i.e. apo A-I than in other analyzed genotypes. Greater mean of total/HDL ratio and lower levels of apo A-II were seen with E2/4. Serum lipoprotein Lp (a) concentration was higher in women with genotypes E3/3. Apo E concentration was the lowest with genotypes E4/4, i.e. the highest with E2/3. Serum total cholesterol tended to be higher in women with genotypes E4/4. Genotype E3/4 is connected with the highest concentrations of (X +/- SD) triglycerides (1.74 +/- 0.78), LDL (4.28 +/- 1.88), apo B (1.03 +/- 0.32) and with the lowest concentrations of HDL cholesterol (1.11 +/- 0.21) in the relation to the other analyzed genotypes. This group of women could possibly represent high risk women for CHD. Genotype E3/3 is associated with the highest concentration of independent genetic risk marker for CHD, lipoprotein Lp (a) (0.19 +/- 0.27). The genotype E4/4 has the highest concentration of total cholesterol (5.93 +/- 1.01), and has to be taken in account for risk evaluation in women. High level of apo E (0.11 +/- 0.05) and low level of apo A-I (1.80 +/- 0.44) were associated with E2/3 genotypes. The significance of E3/4 with the high total/HDL ratio (5.52 +/- 2.21) and low apo A-II (0.53 +/- 0.09) is important indicator, because total/HDL cholesterol ratio represents independent Established Risk Factor (ERF) for CHD. Apolipoprotein E genotypes as genetic markers and investigation of serum metabolic risk markers appear to be important in view for further evaluation of high risk women for CHD in our population.
Assuntos
Apolipoproteínas E/genética , Doença das Coronárias/etiologia , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangueRESUMO
Two genes, i.e. survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) have been mapped to the SMA region of chromosome 5q13. Both genes are frequently deleted or truncated in SMA patients. We have studied 26 patients with SMA types I-III, 29 first relatives, and 14 subjects with mild adult-onset type IV. DNA deletion genotypes were determined by PCR techniques amplifying exons 7 and 8 of SMN, and exon 5 of NAIP gene which distinguish SMN and NAIP telomeric copy from a non-pathogenic gene homologue as a centromeric copy. Results revealed the homozygous deletions of exon 7 and 8 of the SMN gene and exon 5 of the NAIP gene in 3/3 infants with SMA I and in 1/20 with SMA type II. Exons 7 and 8 of the SMN gene were homozygously deleted in 10/20 and only exon 7 in 6/20 children with SMA type II. The overall percentage of deletion cases observed was 77% in children with SMA types I-III. Adult patients with type IV SMA showed no homozygous deletion of exons 7, 8 and 5 of the SMN and NAIP genes. Also, all relatives had both a telomeric and centromeric SMN and NAIP copy. Deletion analysis of SMN and NAIP genes are a significant diagnostic tool, because there are clinical entities resembling SMA which most likely have another pathogenetic background.
Assuntos
Atrofia Muscular Espinal/genética , Proteínas do Tecido Nervoso/genética , Atrofias Musculares Espinais da Infância/genética , Adulto , Criança , Pré-Escolar , Croácia , Análise Mutacional de DNA , Éxons , Deleção de Genes , Humanos , LactenteRESUMO
The renin-angiotensin-aldosterone system (RAAS) has been considered one of the probable pathophysiologic mechanisms involved in disease progression. Genetic polymorphism of the RAAS has been associated with the clinical course of renal disease. One of the genetic polymorphisms is a deletion or insertion of a 287 base pair fragment in intron 16 of the angiotensin-converting enzyme (ACE) gene. It is known that ACE gene polymorphism is present in humans and that it is associated with an increased risk of cardiovascular diseases, renal disease progression and sarcoidosis. In this study, the potential significance of ACE gene polymorphism in patients with systemic lupus erythematosus (SLE) was investigated. ACE gene polymorphism was determined in 18 patients with SLE and in 21 healthy volunteers as a control group. The mean age of patients was 38.5 years. All patients had a mean follow-up of 30.7 +/- 20.2 months (range 5-95 months). ACE genotypes were determined by the method of polymerase chain reaction. Proteinuria and creatinine were also followed. The frequency of DD, ID and II genotypes was 50%, 28% and 22% in SLE patients and 25%, 50% and 25% in healthy controls, respectively. DD genotype was more common in SLE patients than in the control group. The patients with II genotype had lower proteinuria and creatinine level than those with DD genotype (p < 0.05). The time to disease remission was shorter in patients with II genotype (p < 0.05). Study results indicated an increased frequency of D allele in SLE patients. The increased ACE activity in these patients pointed to the need of further studies of ACE gene polymorphism in SLE.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Creatinina/sangue , Progressão da Doença , Feminino , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Masculino , Reação em Cadeia da Polimerase , ProteinúriaRESUMO
This study investigated the frequency of angiotensin-converting enzyme (ACE) genotypes, concentrations of total cholesterol (T-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein Lp (a), Established Risk Factor (ERF) ratio (total cholesterol/HDL-C), apolipoproteins A-I, A-II, apoBand apoE in 134 menopausal women aged 49.62 +/- 4.83 on oral hormone replacement therapy (HRT) (2 mg 17 beta estradiol plus 1 mg norethisterone acetate/day), during (mean +/- SD) 15.77 +/- 9.94 months. ACE genotypes of 134 menopausal women showed DD genotype in 48 (36%), ID genotype in 59 (44%), and II genotype in 27 (20%) women, with the mean body mass index (BMI) (kg/m2) of 26.34 +/- 4.02, systolic blood pressure (mm Hg) of 145.71 +/- 23.32, diastolic blood pressure of 95.28 +/- 12.88, pulse rate of 77.76 +/- 13.81, positive family history of myocardial infarction (MI) (23%) and stroke (22%); 26% were smokers and 6% consumed alcohol regularly. The mean levels of TC (mmol/l) were 5.72 +/- 1.25, TG (mmol/L) 1.63 +/- 0.82, HDL-C (mmol/L) 1.15 +/- 0.29, LDL-C (mmol/L) 3.98 +/- 1.31, lipoprotein Lp(a) (g/L) 0.16 +/- 0.24, ERF ratio 5.35 +/- 1.90, apolipoproteins (g/L): A-I 1.83 +/- 0.39, A-II 0.57 +/- 0.12, apoB 0.92 +/- 0.31, and apoE 0.08 +/- 0.04. The highest mean levels of T-C 5.89 +/- 1.40, TG 1.67 +/- 0.96, LDL-C 4.15 +/- 1.60, lipoprotein Lp(a) 0.19 +/- 0.25) apoB 0.95 +/- 0.32 and ERF ratio 5.46 +/- 2.24 were found in ID genotype, while in DD genotype HDL-C 1.11 +/- 0.28 and apo A-I 1.78 +/- 0.34 were lowest. In II genotype, the levels of apo A-II 0.56 +/- 0.11 were lowest and of apoE 0.09 +/- 0.05 highest. According to DD, ID and II genotypes and lipid, lipoprotein Lp(a), ERF ratio and apolipoprotein concentrations, there were no statistically significant differences between groups. ERF ratio in DD genotype showed a positive correlation with TG (r = 0.59) and LDL-C (r = 0.57), a slight positive correlation with apoB (r = 0.40), and a strong negative correlation with HDL-C (r = -0.73). ERF in ID genotype showed a strong negative correlation with HDL-C (r = -0.73), strong positive correlation with TG (r = 0.70), and T-C (r = 0.58), and slight positive correlation with LDL-C (r = 0.36) and alcohol abuse (r = 0.34). In II genotype, ERF ratio showed a strong positive correlation with LDL-C (r = 0.73), T-C (r = 0.70) and apoE (r = 0.58), slight positive correlation with apoB (r = 0.46) and TG (r = 0.36), and negative correlation with HDL-C (r = -0.54). Matrix correlation of DD genotypes showed the highest positive correlation between T-C and LDL-C (r = 0.91) and apoE (r = 0.45), and negative correlation between HDL-C and ERF ratio (r = 77), and LDL-C and ERF ratio (r = 0.55). In ID genotype, T-C showed a strong positive correlation between LDL-C (r = 0.75) and ERF ratio (r = 0.63), TG and ERF ratio (r = 0.73), and negative with HDL-C (r = 0.53). In genotype II, T-C showed a strong positive correlation between LDL-C (r = 0.96), ERF ratio (r = 0.71), apoB (r = 0.66) and apoE (r = 0.46). LDL-C correlated positively with ERF ratio (r = 0.72), apoB (r = 0.61) and apoE (r = 0.48). These findings indicated the frequency of ACE genotypes to differ within the group of menopausal women. Analysis of ACE genotypes showed ID genotype to be most common among menopausal women. This result indicated their intermediate risk of coronary heart disease (CHD) and myocardial infarction (MI). It has been well established that an increased risk of MI is associated with high frequency of DD genotype, and a low risk with high frequencies of II genotype. In addition to ACE polymorphism analysis, assessment of lipid, apolipoprotein, and lipoprotein Lp(a) concentrations, and of ERF ratio provides further important parameters for better understanding of the risk factors for CDH in women. In the present study, assessment of the genetic, metabolic and environmental markers pointed to an intermediate risk of CHD in menopausal women on HRT, although the mechanism underlying the disease is not clear and well understood yet.
Assuntos
Apolipoproteínas/sangue , Terapia de Reposição de Estrogênios , Lipídeos/sangue , Menopausa , Peptidil Dipeptidase A/genética , Doença das Coronárias/etiologia , Feminino , Genótipo , Humanos , Menopausa/sangue , Menopausa/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Polimorfismo Genético , Fatores de RiscoRESUMO
Weight gain and metabolic disturbances represent serious side-effects in antipsychotic (AP) treatment, particularly with clozapine and olanzapine. The methylenetetrahydrofolate reductase (MTHFR) gene is a key determinant in the folate metabolism and previous studies reported a significant effect on AP-induced weight gain and related metabolic abnormalities. Thus, we investigated MTHFR gene variants and changes in several important metabolic parameters in AP-treated patients. In this study, two functional MTHFR polymorphisms, rs1801133 (C677T) and rs1801131 (A1298C), were investigated for changes in weight and metabolic parameters. Genotypic associations were evaluated in a large population (n = 347 including 66 first episode psychosis, FEP patients) treated mostly with clozapine and olanzapine. We did not detect any genotypic association with weight changes (p > 0.05) in our total sample and in the sample refined for ancestry and medication. In our allelic analyses, we observed a trend for the 677-C allele to be associated with weight gain in the total sample (p = 0.03). This effect appeared to be driven by the FEP patients where those carrying the C-allele gained, on average, twice as much weight. Exploratory analyses revealed a significant association between the C677T and the A1298C polymorphism with HDL cholesterol serum levels in patients (p = 0.031). Overall we did not detect a major effect of two functional MTHFR gene variants and AP-induced weight gain. However, our findings suggest an effect of the C677T polymorphism in FEP patients and changes in weight and cholesterol levels. Further investigations in a larger sample are required.
Assuntos
Antipsicóticos/efeitos adversos , Doenças Metabólicas/induzido quimicamente , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Aumento de Peso/efeitos dos fármacos , Adolescente , Adulto , Análise de Variância , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Aumento de Peso/genética , Adulto JovemRESUMO
Congenic mouse strains are widely used in mapping traits to specific loci or short chromosomal regions. The precision of the mapping depends on the information available about the length of the differential segment--the segment introduced from the donor into the background strain. Until recently, very few markers flanking the differential locus were known and consequently the length of the foreign segment could only be determined imprecisely. Now, in an attempt to construct a map of the mouse chromosome 17, we have produced a set of DNA markers distributed along the chromosome. These markers provide a new opportunity to measure the length of the differential segment of the congenic strains and thus increase their usefulness for gene mapping. Here we examined the DNA of 96 H-2 congenic strains using 30 DNA markers; of these, the most proximal is located roughly 1.5 centiMorgans (cM) from the centromere and the most distal is about 20 cM telomeric from the H-2 complex (the complex itself being some 20 cM from the centromere). The mapping depends on polymorphism among the input strains and can therefore establish only the minimal length of the differential segment. This point is emphasized by the fact that the average observed length of the differential segment is only about one half of the expected values.
Assuntos
Antígenos H-2/genética , Camundongos Endogâmicos/genética , Alelos , Animais , Mapeamento Cromossômico , Marcadores Genéticos , CamundongosRESUMO
Today, approximately 15% of couples have reduced fertility. In most cases the reason is male infertility, usually of genetic origin. Thus, in the context of research in genes involved in reproduction and sex determination, genetic defects in gametogenesis are being extensively studied. The most frequent pathogenic causes of male infertility are Y chromosomal microdeletions and obstructive azoospermia due to congenital absence of the vas deferens (CAVD) in the presence of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We have investigated the most common CFTR gene alterations in Croatian men with CAVD, using Roche research prototype assays. Results revealed that the 5T variant was present in 27% of the subjects. The F508 deletion was found in 21% of the subjects. It was the most frequent mutation, although its incidence was much lower than among patients with cystic fibrosis. The prevalence of microdeletions in the azoospermia factor region (AZF) of the Y chromosome in Croatia was 4.5%. This is the first report of Y microdeletions in the Croatian population. Genetic counseling of all couples with the diagnosis of male infertility is recommended before intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection, and should also include AZF and CFTR genotyping. Couples requesting assisted reproductive treatment should be offered molecular analysis of the CFTR gene, if male infertility due to obstructive azoospermia is the underlying cause. Also, men with severe oligozoospermia or non-obstructive azoospermia seeking assisted reproductive treatment should be screened for deletions in the Y chromosome.
Assuntos
Deleção Cromossômica , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Infertilidade Masculina/genética , Cromossomo Y/genética , Aconselhamento Genético , Humanos , Infertilidade Masculina/terapia , Masculino , Mutação , Oligospermia/genética , Injeções de Esperma IntracitoplásmicasRESUMO
In humans, methylmalonyl acidemia is caused by a deficiency of L-methylmalonyl-CoA mutase (MUT) controlled by a gene that has been mapped to chromosome 6. The mouse homolog of this gene has now been mapped to mouse chromosome 17. Recombinant inbred and congenic strains place the mouse Mut locus 1.06 cM distal to H-2, between Pgk-2 and Ce-2. The relative order of syntenic probes flanking H-2 on mouse chromosome 17 and HLA on human chromosome 6 is shown to be different.
Assuntos
Isomerases/genética , Metilmalonil-CoA Mutase/genética , Camundongos/genética , Animais , Mapeamento Cromossômico , Cricetinae , Cricetulus , Genes , Células Híbridas/análise , Mesocricetus , Camundongos Endogâmicos/genética , Recombinação GenéticaRESUMO
AIM: Presentation of a prenatally diagnosed case of Werdnig-Hoffmann disease, the most severe type of spinal muscular atrophy. METHODS: DNA obtained from cultivated amniocytes was analyzed for deletions in the survival motor neuron gene and neuronal apoptosis inhibitory protein gene. RESULTS: The fetus was diagnosed as an affected homozygote for deletions in exon 7 and exon 8 of the survival motor neuron gene. No deletions of exon 5 in the neuronal apoptosis inhibitory protein gene were found. CONCLUSION: Direct DNA deletion analysis of the survival motor neuron gene and neuronal apoptosis inhibitory protein gene in affected families represents a highly reliable and fast method for prenatal diagnosis of Werdnig-Hoffmann disease.
Assuntos
Amniocentese , DNA/genética , Deleção de Genes , Atrofias Musculares Espinais da Infância/diagnóstico , Adulto , Âmnio/citologia , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , DNA/análise , Éxons/genética , Feminino , Homozigoto , Humanos , Proteínas do Tecido Nervoso/genética , Proteína Inibidora de Apoptose Neuronal , Gravidez , Proteínas de Ligação a RNA , Reprodutibilidade dos Testes , Proteínas do Complexo SMNRESUMO
AIM: To assess lipid profile and the genotype distribution of lipoprotein lipase gene polymorphism at Pvu II polymorphic site within the intron between exons 6 and 7 in patients with hypertriglyceridemia. METHODS: Pvu II polymorphism was determined in 116 hypertriglyceridemic patients and 50 normolipidemic controls from Zagreb, Croatia. DNA was extracted from peripheral blood mononuclear cells. Polymerase chain reaction was used for amplification of 6th intron, which was then restricted with Pvu II-restriction endonuclease. Serum lipid and lipoprotein fractions were determined by standard enzymatic methods. Cholesterol concentrations in HDL subfractions, HDL2 and HDL3, were determined after precipitation with polyethyleneglycol. Apolipoproteins (apo) A-I and B were determined by immunonephelometry. RESULTS: Triglycerides showed a positive correlation with total cholesterol (r=0.222, 95% CI=0.041-0.389, p=0.017) and inverse correlation with HDL-cholesterol (r= -0.278, 95% CI= -0.449 to -0.088, p=0.005), especially with HDL3-cholesterol (r= -0.333, 95% CI= -0.497 to -0.147, p=0.001). The respective frequencies for genotypes /, +/, and +/+ were 22, 58, and 36 in the patient group, and 17, 17, and 16 in the control group. Serum triglycerides in the patient group, expressed as median in mmol/L, were 3.30 (range, 2.60-10.90), 3.60 (range, 2.50-21.50), and 3.99 (range, 2.50-15.56), respectively. Serum concentration of triglycerides differed significantly between the +/+ and / genotype (p=0.043). CONCLUSION: There is an association between genetic variation at the locus for lipoprotein lipase and high serum triglyceride levels. This might prove useful in the detection of individuals susceptible to the development of hypertriglyceridemia, as well as a marker in the analysis of this genetic defect in patient families.