RESUMO
Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.
Assuntos
Doença Celíaca/genética , Doença Celíaca/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Adulto , Estudos de Casos e Controles , Criança , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Finlândia , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , SuéciaRESUMO
Homozygosity for a nonsense mutation in the fucosyltransferase 2 (FUT2) gene (rs601338G>A) leads to the absence of ABH blood groups (FUT2 non-secretor status) in body fluids. As the secretor status has been shown to be a major determinant for the gut microbial spectrum, assumed to be important in the gut immune homeostasis, we studied the association of rs601338-FUT2 with celiac disease (CelD) and inflammatory bowel disease (IBD) in the Finnish population. Rs601338 was genotyped in CelD (n = 909), dermatitis herpetiformis (DH) (n = 116), ulcerative colitis (UC) (n = 496) and Crohn's disease (CD) (n = 280) patients and healthy controls (n = 2738). CelD showed significant genotypic [P = 0.0074, odds ratio (OR): 1.28] and recessive (P = 0.015, OR: 1.28) association with the rs601338-AA genotype. This was also found in the combined CelD+DH dataset (genotype association: P = 0.0060, OR: 1.28; recessive association: P < 0.011, OR: 1.28). The A allele of rs601338 showed nominal association with dominant protection from UC (P = 0.044, OR: 0.82) and UC+CD (P = 0.035, OR: 0.84). The frequency of non-secretors (rs601338-GG) in controls, CelD, DH, UC and CD datasets was 14.7%, 18%, 18.1%, 14.3% and 16.1%, respectively. No association was evident in the DH or CD datasets alone. In conclusion, FUT2 non-secretor status is associated with CelD susceptibility and FUT2 secretor status may also play a role in IBD in the Finnish population.
Assuntos
Doença Celíaca/enzimologia , Doença Celíaca/genética , Fucosiltransferases/genética , Doenças Inflamatórias Intestinais/enzimologia , Doenças Inflamatórias Intestinais/genética , Alelos , Sequência de Bases , Estudos de Casos e Controles , Colite Ulcerativa/enzimologia , Colite Ulcerativa/genética , Doença de Crohn/enzimologia , Doença de Crohn/genética , Primers do DNA/genética , Dermatite Herpetiforme/enzimologia , Dermatite Herpetiforme/genética , Finlândia , Genes Recessivos , Estudos de Associação Genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
OBJECTIVES: QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30-40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample. METHODS: We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. RESULTS: The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT(Nc) interval (P=3.6 x 10(-11)) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QT(Nc) interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P=4.7 x 10(-5)], KCNH2 K897T [-2.6 ms (SE 0.5) or -0.14 SD, P=2.1 x 10(-7)] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P=3.2 x 10(-24)] under additive models. CONCLUSIONS: We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Variação Genética/genética , Síndrome do QT Longo/genética , Polimorfismo de Nucleotídeo Único , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go/genética , Feminino , Finlândia/epidemiologia , Genótipo , Humanos , Síndrome do QT Longo/epidemiologia , Síndrome do QT Longo/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
The risk and outcome of bloodstream infections (BSIs) were evaluated following surgery. BSIs were identified in Helsinki University Hospital during 2009-2014 as part of the national surveillance. Of 711 BSIs identified, 51% were secondary and 49% primary. The rate was highest after cardiovascular surgery (8.7 per 1000 procedures) and lowest after gynaecologic (1.0 per 1000). Surgical site infection was the most frequent source of secondary BSIs (34%) and 45% of primary BSIs were central-line-associated. The 28-day case fatality ranged from zero in gynaecology/obstetrics to 21% in cardiovascular surgery. Besides BSIs related to surgical site infections, half of BSIs were primary, providing additional foci for prevention.
Assuntos
Infecções Relacionadas a Cateter/complicações , Sepse/epidemiologia , Infecção da Ferida Cirúrgica/complicações , Centros de Atenção Terciária , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Finlândia/epidemiologia , Hospitais Universitários , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sepse/mortalidade , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
A specific type of gene mutation affecting the LDL receptor has been found in many Finnish patients with familial hypercholesterolemia (FH). The mutant allele is characterized by a 9.5-kb deletion extending from intron 15 to exon 18. Molecular cloning and sequencing of a cDNA segment corresponding to the deleted allele indicated that the mutant receptor differs radically from the normal one because of loss of the domains encoded by exons 16, 17, and 18. The carboxy-terminal portion of the normal receptor, comprising the amino acids 750-839, has been replaced by an unrelated stretch of 55 amino acids. The mutant allele was found to occur in 23 (50%) of 46 unrelated FH patients with an established functional defect in the LDL receptor. In cultured fibroblasts from the FH patients with the 9.5-kb deletion, both receptor-mediated binding and internalization of 125I-LDL were lower than normal, the former, on average, by 25%, and the latter, on average, by 50%. This combined functional defect probably results from both impaired attachment and impaired internalization of the mutated receptor. It remains to be investigated whether this Finnish type of LDL receptor gene mutation, here designated FH-Helsinki, occurs in other ethnic groups.
Assuntos
Deleção Cromossômica , Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Éxons , Feminino , Humanos , Lipídeos/sangue , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fenótipo , RNA Mensageiro/análise , Receptores de LDL/metabolismoRESUMO
A mutation of the LDL receptor gene very common among Finnish patients with heterozygous familial hypercholesterolemia (FH) was identified. This mutation, designated as FH-North Karelia, deletes seven nucleotides from exon 6 of the LDL receptor gene, causes a translational frameshift, and is predicted to result in a truncated receptor protein. Only minute quantities of mRNA corresponding to the deleted gene were detected. Functional studies using cultured fibroblasts from the patients revealed that the FH-North Karelia gene is associated with a receptor-negative (or binding-defective) phenotype of FH. Carriers of the FH-North Karelia gene showed a typical xanthomatous form of FH, with mean serum total and LDL cholesterol levels of 12 and 10 mmol/liter, respectively. This mutation was found in 69 (34%) out of 201 nonrelated Finnish FH patients and was especially abundant (prevalence 79%) in patients from the eastern Finland. These results, combined with our earlier data on another LDL receptor gene deletion (FH-Helsinki), demonstrate that two "Finnish-type" mutant LDL receptor genes make up about two thirds of FH mutations in this country, reflecting a founder gene effect. This background provides good possibilities to examine whether genetic heterogeneity affects the clinical presentation or responsiveness to therapeutic interventions in FH.
Assuntos
Deleção Cromossômica , Éxons , Hiperlipoproteinemia Tipo II/genética , Mutação , Receptores de LDL/genética , Alelos , Sequência de Aminoácidos , Sequência de Bases , Finlândia , Humanos , Hiperlipoproteinemia Tipo II/etiologia , Lipídeos/sangue , Dados de Sequência Molecular , Fenótipo , RNA Mensageiro/análiseRESUMO
We have identified a hitherto unknown genetic polymorphism of apolipoprotein A-IV (apoA-IV). The molecular basis for this polymorphism is an A to G substitution at nucleotide 1687 resulting in an Asn to Ser change of amino acid 127. The frequencies of the two apoA-IV alleles (designated apoA-IV127Asn and apoA-IV127Ser), determined by Hin c II restriction analysis of PCR amplified exon three of the apoA-IV gene, were 0.788 and 0.212, respectively, in a Finnish population sample. Allele frequencies of another polymorphism due to a Thr to Ser substitution at amino acid 347 were determined using Hinf I restriction analysis. The allele frequencies were 0.823 for apoA-IV347Thr and 0.177 for apoA-IV347Ser. None of the apoA-IV polymorphisms (apoA-IV127:Asn----Ser, apoA-IV347:Thr----Ser and apoA-IV360:Gln----His) had any effect on plasma lipid and lipoprotein concentrations in cohorts of dyslipidemic men and in a population sample of normolipidemic controls. There was also no association between the history of previous myocardial infarction and any of the apoA-IV alleles.
Assuntos
Alelos , Apolipoproteínas A/genética , Asparagina , Serina , Sequência de Aminoácidos , Apolipoproteínas A/análise , Sequência de Bases , Colesterol/sangue , Códon , Genótipo , Humanos , Hiperlipidemias/genética , Lipoproteínas/sangue , Masculino , Dados de Sequência Molecular , Infarto do Miocárdio/genética , Polimorfismo Genético , Treonina , Triglicerídeos/sangueRESUMO
Background-Homozygosity for a relatively common Cys282Tyr mutation of the human hemochromatosis-associated (HFE) gene was recently found to account for most cases of hereditary hemochromatosis. Because excess iron has been postulated to enhance risk of vascular disease, we studied whether occurrence of this mutation was associated with increased risk of first acute myocardial infarction in healthy middle-aged men in a prospective cohort study. Methods and Results-Study subjects were the 1150 participants in the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42, 48, 54, or 60 years at baseline, who had no coronary heart disease at baseline and for whom a DNA sample was available. Information about myocardial infarctions was collected prospectively by use of FINMONICA (FINnish MONItoring of trends and determinants in CArdiovascular disease study) and hospital data. Events were classified by MONICA (MONItoring of trends and determinants in CArdiovascular disease study) diagnostic criteria. The HFE Cys282Tyr mutation was assayed by a solid-phase minisequencing technique. One subject was homozygous and 76 individuals were heterozygous for the HFE Cys282Tyr mutation (6.7%). During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. In a Cox proportional hazards model allowing for the other strongest risk factors, the carriers had a 2.3-fold (95% CI 1. 1 to 4.8; P=0.03) risk of acute myocardial infarction compared with noncarriers. Conclusions-Male carriers of the common hemochromatosis gene mutation are at 2-fold risk for first acute myocardial infarction compared with noncarriers.
Assuntos
Antígenos HLA/genética , Hemocromatose/genética , Heterozigoto , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana , Infarto do Miocárdio/genética , Adulto , Estudos de Coortes , Finlândia , Proteína da Hemocromatose , Humanos , Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). METHODS AND RESULTS: In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. CONCLUSIONS: Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.
Assuntos
Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/genética , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Finlândia , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , Mutação , Mutação de Sentido Incorreto , Miocárdio/metabolismo , Linhagem , Polimorfismo Genético , Taquicardia Ventricular/patologiaRESUMO
OBJECTIVES: This study investigated the ability of QT duration, QT dispersion (QTD) and clinical diagnostic criteria to correctly identify genetically documented LQT1 type long QT syndrome (LQTS) patients, and to separate symptomatic and asymptomatic LQT1 patients. BACKGROUND: Ventricular repolarization has played an essential role both in diagnosis and risk assessment of LQTS. Today, molecular genetic techniques permit unequivocal identification of many LQTS patients. METHODS: QT interval and QTD in 12 symptomatic and 18 asymptomatic LQT1 patients and their 43 healthy relatives were evaluated. The sensitivity and specificity of upper normal limits of QT interval, two QT interval adjustment methods (Bazett's and Fridericia's formulas), and the proposed clinical criteria for LQTS were assessed. Occurrence of a mutant (D188N) KVLQT1 gene was considered as the basis of classification into affected and nonaffected individuals. RESULTS: Diagnostic sensitivity and specificity values were 90% and 88% using Bazett's formula, and 80% and 100% using Fridericia's cubic root formula or upper normal limits for QT interval. Suggested diagnostic criteria for LQTS reached 100% specificity, but 47% of the DNA-documented LQT1 patients were classified into the category of low or intermediate probability of LQTS. QT interval and heart rate did not differ between symptomatic (464 +/- 47 ms, 70 +/- 9 min(-1)) and asymptomatic 460 +/- 41 ms, 65 +/- 13 min(-1)) LQT1 patients. QTD was increased in symptomatic LQT1 patients compared to unaffected relatives (66 +/- 48 vs. 37 +/- 15 ms, p = 0.02), but symptomatic patients LQT1 did not differ from asymptomatic (45 +/- 19 ms). CONCLUSIONS: Not all LQT1 patients can be distinguished from healthy relatives by assessment of QT duration or clinical criteria. Presence of LQT1 gene can carry the risk of cardiac events even with no or only marginal prolongation of QT interval.
Assuntos
Eletrocardiografia , Síndrome do QT Longo/genética , Adolescente , Adulto , Idoso , Criança , DNA/genética , Feminino , Genótipo , Frequência Cardíaca/fisiologia , Humanos , Síndrome do QT Longo/classificação , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/fisiopatologia , Pessoa de Meia-Idade , Biologia Molecular , Mutação/genética , Probabilidade , Medição de Risco , Sensibilidade e Especificidade , Fatores de Tempo , Função Ventricular/fisiologiaRESUMO
OBJECTIVES: This study was performed to evaluate the QT interval and heart rate responses to exercise and recovery in gene and mutation type-specific subgroups of long QT syndrome (LQTS) patients. BACKGROUND: Reduced heart rate and repolarization abnormalities are encountered among long QT syndrome (LQTS) patients. The most common types of LQTS are LQT1 and LQT2. METHODS: An exercise stress test was performed in 23 patients with a pore region mutation and in 22 patients with a C-terminal end mutation of the cardiac potassium channel gene causing LQT1 type of long QT syndrome (KVLQT1 gene), as well as in 20 patients with mutations of the cardiac potassium channel gene causing LQT2 type of long QT syndrome (HERG gene) and in 33 healthy relatives. The QT intervals were measured on electrocardiograms at rest and during and after exercise. QT intervals were compared at similar heart rates, and rate adaptation of QT was studied as QT/heart rate slopes. RESULTS: In contrast to the LQT2 patients, achieved maximum heart rate was decreased in both LQT1 patient groups, being only 76 +/- 5% of predicted in patients with pore region mutation of KvLQT1. The QT/heart rate slopes were significantly steeper in LQT2 patients than in controls during exercise. During recovery, the QT/heart rate slopes were steeper in all LQTS groups than in controls, signifying that QT intervals lengthened excessively when heart rate decreased. At heart rates of 110 or 100 beats/min during recovery, all LQT1 patients and 89% of LQT2 patients had QT intervals longer than any of the controls. CONCLUSIONS: LQT1 is associated with diminished chronotropic response and exaggerated prolongation of QT interval after exercise. LQT2 patients differ from LQT1 patients by having marked QT interval shortening and normal heart rate response to exercise. Observing QT duration during recovery enhances the clinical diagnosis of these LQTS types.
Assuntos
Proteínas de Transporte de Cátions , Proteínas de Ligação a DNA , Exercício Físico/fisiologia , Síndrome do QT Longo/fisiopatologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/fisiologia , Nó Sinoatrial/fisiopatologia , Transativadores , Adolescente , Adulto , Idoso , Criança , Canal de Potássio ERG1 , Eletrocardiografia/métodos , Eletrocardiografia/estatística & dados numéricos , Canais de Potássio Éter-A-Go-Go , Teste de Esforço/métodos , Teste de Esforço/estatística & dados numéricos , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Canais de Potássio KCNQ , Canal de Potássio KCNQ1 , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Mutação/fisiologia , Canais de Potássio/genética , Estatísticas não Paramétricas , Regulador Transcricional ERGRESUMO
OBJECTIVES: We took advantage of the genetic isolate of Finns to characterize a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LQTS. BACKGROUND: The LQTS is caused by mutations in different ion channel genes, which vary in their molecular nature from family to family. METHODS: The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands and their available family members. The functional properties of the mutation were studied using a whole-cell patch-damp technique. RESULTS: We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the KCNQ1 subunit. The voltage threshold of activation for the KCNQ1-Fin channel was markedly increased compared to the wild-type channel. This mutation was present in homozygous form in two siblings with JLNS, and in heterozygous form in 34 of 114 probands with Romano-Ward syndrome (RWS) and 282 family members. The mean (+/- SD) rate-corrected QT intervals of the heterozygous subjects (n = 316) and noncarriers (n = 423) were 460 +/- 40 ms and 410 +/- 20 ms (p < 0.001), respectively. CONCLUSIONS: A single missense mutation of the KCNQ1 gene accounts for 30% of Finnish cases with LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome. The relative enrichment of this mutation most likely represents a founder gene effect. These circumstances provide an excellent opportunity to examine how genetic and nongenetic factors modify the LQTS phenotype.
Assuntos
Efeito Fundador , Síndrome do QT Longo/genética , Mutação de Sentido Incorreto/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Surdez/genética , Feminino , Finlândia , Frequência do Gene/genética , Genética Populacional , Genótipo , Humanos , Canais de Potássio KCNQ , Canal de Potássio KCNQ1 , Síndrome do QT Longo/diagnóstico , Masculino , Pessoa de Meia-Idade , Técnicas de Patch-Clamp , Linhagem , Fenótipo , SíndromeRESUMO
OBJECTIVES: We studied whether left ventricular mass in athletes associates with polymorphisms in genes encoding components of the renin-angiotensin system. BACKGROUND: Adaptive left ventricular hypertrophy is a feature of the athlete's heart. However, similarly training athletes develop left ventricular mass to a different extent, suggesting that genetic factors may modulate heart size. METHODS: We measured left ventricular mass by echocardiography in 50 male and 30 female elite endurance athletes aged 25 +/- 4 (mean +/- SD) years. Deoxyribonucleic acid samples were prepared for genotyping of angiotensinogen (AGT) gene M235T polymorphism, angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and angiotensin II type 1 receptor (AT1) gene A1166C polymorphism. RESULTS: The AGT gene M235T genotypes were significantly associated with left ventricular mass independently of blood pressure in both genders (p = 0.0036 for pooled data). TT homozygotes had greater mass compared with MM homozygotes in both men (147 +/- 12 g/m vs. 132 +/- 15 g/m, p = 0.032) and women (121 +/- 12 g/m vs. 101 +/- 13 g/m, p = 0.019). There was a gender difference in the relation between myocardial mass and AGT genotype, MT heterozygotes resembling MM homozygotes among women and TT homozygotes among men. The other studied gene polymorphisms were not associated with left ventricular mass. CONCLUSIONS: Angiotensinogen gene M235T polymorphism is associated with the variability in left ventricular hypertrophy induced by endurance training, with athletes homozygous for the T allele having the largest hearts. We found no association between ACE gene I/D or AT1 gene A1166C polymorphisms and left ventricular mass.
Assuntos
Adaptação Fisiológica/genética , Angiotensinogênio/genética , Predisposição Genética para Doença , Hipertrofia Ventricular Esquerda/genética , Polimorfismo Genético , Esportes , Adulto , Ecocardiografia , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Masculino , Peptidil Dipeptidase A/genética , Resistência Física , Receptores de Angiotensina/genética , Fatores SexuaisRESUMO
OBJECTIVES: We studied the clinical characteristics and molecular background underlying a severe phenotype of long QT syndrome (LQTS). BACKGROUND: Mutations of cardiac ion channel genes cause LQTS, manifesting as increased risk of ventricular tachycardia and sudden death. METHODS: We studied two siblings showing prolonged QT intervals corrected for heart rate (QTc), their asymptomatic parents with only marginally prolonged QTc intervals and their family members. The potassium channel gene HERG was screened for mutations by deoxyribonucleic acid sequencing, and the electrophysiologic consequences of the mutation were studied in vitro using the whole-cell patch-clamp technique. RESULTS: A novel missense mutation (L552S) in the HERG channel, present in the homozygous state in the affected siblings and in the heterozygous state in their parents, as well as in 38 additional subjects from six LQTS families, was identified. One of the homozygous siblings had 2:1 atrioventricular block immediately after birth, and died at the age of four years after experiencing unexplained hypoglycemia. The other sibling had an episode of torsade de pointes at the age of two years. The mean QTc interval differed significantly (p < 0.001) between heterozygous symptomatic mutation carriers (500 +/- 59 ms), asymptomatic mutation carriers (452 +/- 34 ms) and noncarriers (412 +/- 23 ms). When expressed in vitro, the HERG-L552S formed functional channels with increased activation and deactivation rates. CONCLUSIONS: Our data demonstrate that homozygosity for a HERG mutation can cause a severe cardiac repolarization disorder without other phenotypic abnormalities. Absence of functional HERG channels appears to be one cause for intrauterine and neonatal bradycardia and 2:1 atrioventricular block.
Assuntos
Proteínas de Transporte de Cátions , Proteínas de Ligação a DNA , Síndrome do QT Longo/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Transativadores , Adulto , Criança , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Feminino , Finlândia , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Índice de Gravidade de Doença , Regulador Transcricional ERGRESUMO
OBJECTIVES: The purpose of this study was to provide clinical and anatomical characteristics as well as genetic background of a malignant arrhythmogenic disorder. BACKGROUND: An inherited autosomally dominant cardiac syndrome causing stress-induced polymorphic ventricular tachycardia and syncope in the absence of structural myocardial changes was detected in two families. METHODS: Two unrelated families with six victims of sudden death and 51 living members were evaluated. Resting and exercise electrocardiograms (ECG), echocardiography, magnetic resonance imaging (MRI), cineangiography, microscopic examination of endomyocardial biopsies and a drug testing with a class IC antiarrhythmic agent flecainide were performed. A genetic linkage analysis was carried out to map the gene locus. RESULTS: Of the 24 affected individuals, 10 had succumbed with six cases of sudden death, and 14 survivors showed evidence of disease. Exercise stress test induced ventricular bigeminy or polymorphic ventricular tachycardia in affected individuals. Three children initially examined before 10 years of age developed arrhythmias during a four-year follow-up. Resting ECGs were normal in affected subjects except a slight prolongation of the QT intervals adjusted for heart rate (QTc) (430 +/- 18 vs. 409 +/- 19 ms, affected vs. nonaffected, p < 0.01). Administration of flecainide did not induce ECG abnormalities encountered in familial idiopathic ventricular fibrillation. Ventricular volumes, contractility and wall measurements were normal by echocardiography, right ventricular cineangiography and MRI. Histopathological examination showed no fibrosis or fatty infiltration. The cumulative cardiac mortality by the age of 30 years was 31%. The disease locus was assigned to chromosome 1q42-q43, with a maximal pairwise lod score of 4.74 in the two families combined. Only one heterozygous carrier was clinically unaffected suggesting high disease penetrance in adulthood. CONCLUSIONS: A distinct cardiac disorder linked to chromosome 1q42-q43 causes exercise-induced polymorphic ventricular tachycardia in structurally normal hearts and is highly malignant. Delayed clinical manifestation necessitates repeated exercise electrocardiography to assure diagnosis in young individuals of the families.
Assuntos
Aberrações Cromossômicas/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Ligação Genética/genética , Miocárdio/patologia , Canais de Potássio de Domínios Poros em Tandem , Taquicardia Ventricular/genética , Adolescente , Adulto , Antiarrítmicos , Biópsia , Criança , Aberrações Cromossômicas/diagnóstico , Aberrações Cromossômicas/mortalidade , Transtornos Cromossômicos , Cineangiografia , Angiografia Coronária , Morte Súbita Cardíaca/patologia , Diagnóstico Diferencial , Ecocardiografia , Eletrocardiografia , Teste de Esforço , Feminino , Flecainida , Humanos , Escore Lod , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Contração Miocárdica , Linhagem , Canais de Potássio/genética , RNA/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/mortalidadeRESUMO
Analysis of the entire coding region of the HERG gene of 39 Finnish LQTS patients revealed eight mutations, six of which are hitherto unreported. All these mutations are located in the evolutionarily conserved regions of HERG, including the transmembrane domains (P451L, Y569H, 1631delAG, G584S, G601S, T613M) and the cytoplasmic N-terminus (453delC, R176W) of the channel. Our present and earlier results suggest that the LQT2 subtype accounts for approximately 20-30% of LQTS cases in Finland. We also report the first common amino acid polymorphism (K897T) of the HERG channel, with allele frequencies of 0.84 and 0.16. Investigation of 170 genetically homogenous LQT1 patients suggests that this polymorphism may influence QT interval in female individuals.
Assuntos
Substituição de Aminoácidos/genética , Proteínas de Transporte de Cátions , Proteínas de Ligação a DNA , Síndrome do QT Longo/genética , Mutação/genética , Polimorfismo Conformacional de Fita Simples , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Transativadores , Adulto , Idoso , Análise Mutacional de DNA , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Feminino , Humanos , Pessoa de Meia-Idade , Fenótipo , Canais de Potássio/análise , Deleção de Sequência , Regulador Transcricional ERGRESUMO
The mechanisms by which nonsteroidal antiandrogens such as flutamide (alpha, alpha, alpha-trifluoro-2-methyl-4'-nitro-m-propionotoluidide) influence androgen receptor distribution and androgen-regulated gene expression are poorly understood. Therefore, we studied acute and long-term effects of flutamide, administered alone or in combination with testosterone, on androgen receptor dynamics in mouse kidney. Nuclear androgen receptors were measured using 5 mM pyridoxal 5'-phosphate extracts of renal nuclei isolated with the hexylene glycol method. Androgen-regulated ornithine decarboxylase (ODC) and ODC-messenger RNA were used as biological markers for hormone action. A single dose of flutamide increased the measurable concentration of renal nuclear androgen receptors in a dose-dependent manner by 1 h after treatment, although to a lesser extent than a comparable dose of testosterone. When 5 mg flutamide was given concomitantly with a submaximal dose of testosterone (0.1 mg), nuclear androgen receptor concentration was similar to that achieved with flutamide alone; this inhibitory effect of the antiandrogen was reversed by a 10-fold higher dose of testosterone. The influence of flutamide on the steady-state receptor levels in renal nuclei achieved by continuous androgen administration was investigated by giving a single dose of this compound to mice with testosterone-releasing implants. In these animals, flutamide administration decreased nuclear androgen receptor concentration with an initial half-life of about 3.3 h. This half-life was similar to that after cycloheximide administration, but significantly longer than that measured (1.3 h) upon removal of the implant. During treatment of female mice for 8 days with testosterone-releasing implants (40 micrograms/day), both the immunoreactive and catalytically active ODC concentration increased about 300-fold. In contrast, there was no stimulation of ODC during the prolonged administration of flutamide, although this treatment resulted in a dose-dependent increase in the nuclear androgen receptor concentration. However, flutamide (up to 650 micrograms/day) given concomitantly with testosterone (40 micrograms/day) almost completely abolished the testosterone-induced increase in ODC. The changes in ODC-messenger RNA concentration, as measured by hybridization to a complementary DNA probe, paralleled those of the enzyme protein suggesting that flutamide action involves inhibition of transcription of androgen-regulated gene(s). We conclude that 1) nuclear androgen receptor turnover in mouse kidney is a relatively rapid process and 2) nonsteroidal antiandrogens such as flutamide have an intrinsic ability to form
Assuntos
Anilidas/farmacologia , Flutamida/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/metabolismo , Ornitina Descarboxilase/genética , Receptores Androgênicos/metabolismo , Receptores de Esteroides/metabolismo , Animais , Núcleo Celular/metabolismo , Cicloeximida/farmacologia , Feminino , Rim/efeitos dos fármacos , Masculino , Camundongos , Hibridização de Ácido Nucleico , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos , Receptores Androgênicos/efeitos dos fármacos , Testosterona/farmacologiaRESUMO
Circulating human lymphocytes contain glucocorticoid receptors (GR). To see if adrenocortical imbalance is associated with changes in the level of GR, several patients with hypo- and hypercortisolism were studied. Peripheral lymphocytes were prepared by Ficoll-Hypaque gradients and were then subjected to a whole cell-binding assay measuring the total cellular receptor pool, with [3H]dexamethasone as the ligand. There were no significant differences in the cellular content of GR among healthy controls, 10 patients with Cushing's syndrome, and 3 patients suffering from Addison's disease; the absolute levels of GR were 4850 +/- 1340, 4900 +/- 2160, and 5640 +/- 1110 (mean +/- SD) receptors/cell, respectively. The mean equilibrium dissociation constants of the interaction of [3H]dexamethasone with the receptor were also about the same in the 3 groups (1-2 X 10(-8) M). Thus, aberrations in glucocorticoid balance strong enough to produce clear-cut clinical symptoms do not result in major alterations in the level of the peripheral GR. We also studied an additional patient who had hypercortisolism due to an adrenal adenoma but only slight clinical signs of hypercortisolism; interestingly, her cellular GR level was only 30% of normal. The lymphocytic GR content was also below normal in 2 patients with anorexia nervosa.
Assuntos
Doença de Addison/sangue , Síndrome de Cushing/sangue , Linfócitos/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Esteroides/metabolismo , Adulto , Anorexia Nervosa/fisiopatologia , Dexametasona/metabolismo , Feminino , Humanos , Hidrocortisona/sangue , Pessoa de Meia-IdadeRESUMO
Glucocorticoids have been postulated to directly inhibit adrenocortical steroid production in laboratory animals. To investigate this in the human, we measured specific [3H]dexamethasone-binding sites in cytosol samples from normal and neoplastic human adrenal tissues. All nine normal adrenocortical samples, six adenomas (four cortisol-producing and two aldosterone-producing), and two hyperplastic adrenocortical samples studied were devoid of measurable specific glucocorticoid-binding activity. In contrast, steroid binding with characteristics of the glucocorticoid receptor (concentration of binding sites, 32-146 fmol/mg cytosol protein; Kd, 1.7-3.1 X 10(-9) M) was readily detectable in cytosol of all three adrenocortical carcinomas and all three pheochromocytomas examined. To elucidate the in vivo role of glucocorticoids as direct regulators of adrenocortical function, five patients with hypopituitarism receiving varying oral maintenance doses of dexamethasone were given ACTH iv. Increasing the orally administered dexamethasone dose from 1 to 8 mg/day did not alter the plasma cortisol response to a 4-h infusion of 250 micrograms synthetic ACTH in these patients. Collectively, these data cast doubt on the proposal that synthetic glucocorticoids directly suppress adrenocortical function in the human. Whether glucocorticoid receptors in tumor tissue could mediate the dexamethasone-induced suppression of hypercortisolism occasionally reported in patients with adrenocortical neoplasia remains to be investigated.
Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Esteroides/metabolismo , Adolescente , Hormônio Adrenocorticotrópico , Adulto , Idoso , Citosol/metabolismo , Dexametasona/metabolismo , Feminino , Humanos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
Obesity is a multifactorial trait with evidence of a genetic component. Obesity is very common in all westernized countries, including Finland, where 10% of the adult population has a body mass index of 32 kg/m2 or more. Here we report results from a three-stage genome-wide scan of obesity in 188 affected subjects (body mass index, > or =32 kg/m2) from 87 Finnish families. Initially, 374 markers with an average density of 10 centimorgans were genotyped. The strongest evidence for linkage to obesity was detected on chromosome Xq24, with the marker DXS6804 providing a maximum likelihood score (MLS) 3.14 in a model-free 2-point sibpair analysis. Fine-mapping in an extended sample set of 367 affected subjects from 166 families yielded a multipoint MLS of 3.48 over this X-chromosomal region. The Xq24 region contains a plausible candidate gene, serotonin 2C receptor, variants of which have been shown to predispose to obesity and type II diabetes in mice. Another chromosomal region also provided suggestive evidence of linkage, an area on 18q21, flanking the melanocortin-4 receptor, where a 2-point MLS of 2.42 with marker D18S1155 was obtained with a set of 367 affected subjects. In conclusion, our results in this Finnish study sample suggest that a locus on chromosome Xq24 influences the risk of obesity.