RESUMO
Coronary heart disease (CHD) is a multifactorial disease caused by environmental and genetic factors. CHD clusters in families, but it is not known whether susceptibility to early-onset CHD is associated with the clustering of cardiovascular risk factors. Therefore, we determined the levels of cardiovascular risk factors among siblings with and without severe early-onset CHD drawn from 101 Finnish families. Probands with CHD, compared with their siblings without CHD, had, respectively, higher 2-hour insulin levels (475.7 versus 331.8 pmol/L, P=0.011) and 2-hour insulin areas (796.2 versus 640.4 pmol/L per hour, P=0.031) in an oral glucose tolerance test, lower high density lipoprotein cholesterol levels (1.22 versus 1.42 mmol/L, P=0.001), higher total triglyceride levels (1.91 versus 1.68 mmol/L, P=0.018), higher very low density lipoprotein triglyceride levels (1.25 versus 1.06 mmol/L, P=0.011), and higher fibrinogen levels (3.8 versus 3.4 g/L, P= 0.008). No significant differences were found in cardiovascular risk factors between affected siblings and probands with CHD. Environmental or lifestyle factors did not differ between siblings with or without early-onset CHD. We conclude that cardiovascular risk factors associated with the insulin resistance syndrome (hyperinsulinemia, low high density lipoprotein cholesterol, high total and very low density lipoprotein triglycerides, and high fibrinogen) are likely to contribute indirectly to early-onset CHD.
Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Resistência à Insulina , Adulto , Idade de Início , Idoso , Arteriosclerose/genética , Doenças Cardiovasculares/sangue , HDL-Colesterol/sangue , Feminino , Fibrinogênio/metabolismo , Predisposição Genética para Doença , Humanos , Resistência à Insulina/genética , Lipoproteínas/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangueRESUMO
The endothelial nitric oxide synthase (eNOS) gene is responsible for constitutive nitric oxide synthesis and arterial vasodilatation. Recently two polymorphisms, the 27-bp repeat sequence in intron 4 and the Glu298Asp substitution in exon 7 of the eNOS gene have been reported to be related to coronary heart disease (CHD). We screened these polymorphisms of the eNOS gene in 308 unrelated nondiabetic subjects with CHD, in 251 unrelated patients with type 2 diabetes with CHD, and in 110 randomly selected healthy subjects without CHD. The 4a and Asp298 allele frequencies of the eNOS gene were 0.19 and 0.36 in nondiabetic patients with CHD, 0.21 and 0.27 in type 2 diabetic patients with CHD, and 0.16 and 0.31 in nondiabetic subjects without CHD (n.s. between the groups). The Asp298 allele in exon 7 of the eNOS gene was not associated with elevated blood pressure in any of the study groups. Among type 2 diabetic patients with CHD the 4a allele in intron 4 of the eNOS gene was associated with elevated levels of systolic (P=0.035) and mean arterial blood pressure (P=0.040). In nondiabetic subjects these associations were not statistically significant. When all study groups were pooled in statistical analysis the 4a allele of the eNOS gene was associated with elevated diastolic (P=0.032) and mean (P=0.030) arterial blood pressure even after adjustment for confounding factors. We conclude that the 4a allele of the eNOS gene is not associated with CHD or type 2 diabetes, but that it is related to elevated blood pressure levels particularly among type 2 diabetic patients with CHD.
Assuntos
Doença das Coronárias/complicações , Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Hipertensão/complicações , Hipertensão/genética , Óxido Nítrico Sintase/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Glicemia/análise , Pressão Sanguínea/genética , Éxons , Feminino , Genótipo , Técnica Clamp de Glucose , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Óxido Nítrico Sintase Tipo III , Reação em Cadeia da Polimerase , Fatores de RiscoRESUMO
The relationship of two apolipoprotein (apo) E gene polymorphisms and coronary heart disease (CHD) was investigated in 118 Finnish families with premature CHD and in 110 healthy control subjects. Affected siblings and probands with premature CHD had higher frequencies of the T allele of the -219G/T promoter polymorphism and the epsilon 4 allele (genotypes epsilon 4/3 or epsilon 4/4) of the apo epsilon 2/epsilon 3/ epsilon 4 polymorphism than those of healthy control subjects. Additionally, when the two apo E gene polymorphisms were combined, affected siblings and probands had a higher frequency of the -219T allele and the epsilon 4 allele combinations than did healthy controls. The -219T and the epsilon 4 alleles both separately and together were associated with higher levels of 2-h glucose in an oral glucose tolerance test. These results indicate that the two polymorphisms of the apo E gene have similar effects on the risk of coronary atherosclerosis in families with premature CHD. This risk was not explained by the effect of apo E gene polymorphisms on cholesterol metabolism, but their effect on cardiovascular risk factor clustering with insulin resistance may be of importance. We conclude that in addition to the epsilon 4 allele, also the -219G/T promoter polymorphism of the apo E gene is associated with early onset CHD.
Assuntos
Apolipoproteínas E/genética , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Idade de Início , Idoso , Alelos , Doença das Coronárias/etiologia , Feminino , Finlândia/epidemiologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVE: Elevated HDL cholesterol and its principal carrier protein apolipoprotein a1 [apo(a1)] are associated with reduced risk of coronary heart disease (CHD). No studies are available on the impact of the -75-bp and/or +83-bp polymorphisms of the apo(a1) gene on HDL cholesterol and apo(a1) levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We determined the prevalence of the: -75-bp and +83-bp polymorphisms of the apo(a1) gene by restriction fragment length polymorphism analysis among 308 unrelated nondiabetic subjects with CHD and among 251 unrelated patients with type 2 diabetes with CHD and in randomly selected 82 healthy men (CHD-). RESULTS: The rare M1- and M2- allele frequencies of the apo(a1) gene were 23 and 1.8%, respectively, among control subjects; 20 and 1.5%, respectively, among nondiabetic subjects with CHD; and 22 and 2.6%, respectively, among patients with type 2 diabetes and CHD (NS). Nonsmoking nondiabetic subjects with CHD having the M2+- genotype had higher HDL cholesterol (1.48 +/- 0.19 vs. 1.23 +/- 0.02 mmol/l, P < 0.01) and apo(a1) (1.43 +/- 0.10 vs. 1.36 +/- 0.02 g/l, P < 0.05) levels than subjects with the M2++ genotype, even after adjustment for confounding factors. This association was not found among patients with type 2 diabetes and CHD. CONCLUSIONS: We conclude that the +83-bp polymorphism of the apo(a1) gene is associated with elevated HDL cholesterol and apo(a1) levels in Finnish nondiabetic subjects but not in patients with type 2 diabetes.
Assuntos
Apolipoproteína A-I/sangue , Apolipoproteína A-I/genética , HDL-Colesterol/sangue , Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/genética , Polimorfismo de Fragmento de Restrição , Apolipoproteínas B/sangue , Glicemia/metabolismo , Pressão Sanguínea , Doença das Coronárias/sangue , Doença das Coronárias/fisiopatologia , Desoxirribonuclease HpaII , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/fisiopatologia , Feminino , Genótipo , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Valores de Referência , Triglicerídeos/sangueRESUMO
Polymorphisms of the angiotensin-converting enzyme (ACE) (insertion/deletion (I/D) in intron 16) and of the plasminogen activator inhibitor-1 (PAI-1) (promoter 4G/5G) genes have been linked with coronary heart disease (CHD) and/or myocardial infarction (MI). We studied the association of polymorphisms in these genes with CHD with linkage and association analyses in 118 families with premature and severe CHD and in 110 healthy controls. In linkage analysis there was no evidence for a linkage of the ACE or PAI-1 loci with CHD. However, in quantitative linkage analysis the ACE locus was linked with fasting glucose (P=0. 047) and fasting free fatty acid levels (P=0.029). In association analysis the ACE genotype frequencies of probands with CHD did not differ from those of healthy controls. Normoglycemic probands with MI and with the ACE polymorphism DD genotype had characteristics of the insulin resistance syndrome. They had higher levels of 1-h glucose (P=0.008) and 2-h free fatty acids (P=0.011) in an oral glucose tolerance test and higher levels of total (P=0.005) and very-low-density lipoprotein triglycerides (P=0.006) than probands with the ID or the II genotypes. The PAI-1 gene polymorphism was not associated with any of the variables of glucose or lipid metabolism. In conclusion, the ACE and PAI-1 gene polymorphisms are not linked with early-onset CHD. However, the ACE gene polymorphism is associated with features of the insulin resistance syndrome.
Assuntos
Doença das Coronárias/genética , Resistência à Insulina/genética , Peptidil Dipeptidase A/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Idoso , Alelos , Doença das Coronárias/etiologia , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras GenéticasAssuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/genética , Polimorfismo Genético , Receptores Imunológicos/genética , Substituição de Aminoácidos , Feminino , Finlândia , Glicina , Humanos , Masculino , Pessoa de Meia-Idade , Receptor para Produtos Finais de Glicação Avançada , Valores de Referência , SerinaRESUMO
The incidence of Lyme borreliosis was studied prospectively in 165 patients with acute idiopathic sensorineural hearing loss. The prevalence of positive levels of antibodies against Borrelia burgdorferi was sixfold higher in patients with sensorineural hearing loss than in the general population in Finland. Four patients fulfilled the criteria for Lyme borreliosis. No specific risk factors were found with which to predict the occurrence of Lyme borreliosis among patients with hearing loss. In logistic regression modeling the poor outcome of hearing loss was best explained by advanced age, high-frequency or flat-type hearing loss, and absence of positive levels of antibodies against B. burgdorferi. Although the causal relationship between Lyme borreliosis and sensorineural hearing loss is difficult to verify, we suggest that Lyme borreliosis is a rare but potentially treatable cause of sudden deafness. We propose that in endemic areas antibodies against Lyme borreliosis should be determined in patients with idiopathic sensorineural hearing loss.
Assuntos
Perda Auditiva Neurossensorial/microbiologia , Neuroborreliose de Lyme/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Bactérias/análise , Audiometria de Tons Puros , Grupo Borrelia Burgdorferi/imunologia , Feminino , Finlândia/epidemiologia , Perda Auditiva Neurossensorial/epidemiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prevalência , Estações do AnoRESUMO
BACKGROUND: There has been no previous study to determine the severity and extent of coronary artery disease (CAD) in subjects with no diagnosis or symptoms of CAD at the time of the angiography. METHODS: Fifty-three subjects, who were siblings of patients with early onset CAD, underwent coronary angiography. Indices to describe per-patient characteristics of CAD were calculated, based on computer-aided quantitative coronary angiography. Clinical and laboratory characteristics were correlated to the angiographic parameters. RESULTS: Serum total homocysteine (rho = 0.29, P < 0.05) and creatinine (rho = 0.47, P = 0.001) levels were related to the global atheroma burden index. The median of the atheroma burden index was two times higher in the top homocysteine quartile compared to the lowest quartile. The overall atheroma burden index correlated significantly with the fasting blood glucose level in all subjects. Diabetes, especially when albuminuria was present, was a powerful risk factor. In a multivariate analysis, only age and sex were independent predictors of atheroma burden. CONCLUSIONS: Serum homocysteine and creatinine concentrations, and diabetes with albuminuria were found to be markers of the severity and extent of CAD in subjects of high-risk families without symptoms of CAD.
Assuntos
Glicemia/análise , Doença das Coronárias/diagnóstico , Creatinina/sangue , Homocisteína/sangue , Biomarcadores/sangue , Angiografia Coronária , Doença das Coronárias/sangue , Doença das Coronárias/etiologia , Complicações do Diabetes , Diabetes Mellitus/sangue , Diagnóstico por Computador , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de RiscoRESUMO
Coronary heart disease (CHD) is a complex disorder constituting a major health problem in Western societies. To assess the genetic background of CHD, we performed a genomewide linkage scan in two study samples from the genetically isolated population of Finland. An initial study sample consisted of family material from the northeastern part of Finland, settled by a small number of founders approximately 300 years ago. A second study sample originated from the southwestern region of Finland, settled approximately 2,000 years ago. Families were ascertained through probands exhibiting premature CHD, defined as >50% stenosis of at least two coronary arteries at a young age, as verified by coronary angiography. Both study samples and the pooled data set provided evidence for linkage in two chromosomal regions. A region on chromosome 2q21.1-22 yielded two-point LOD scores of 3.2, 1.9, and 3.7, in the affected sib-pair (ASP) analyses of the northeastern, southwestern, and pooled study samples. The corresponding multipoint maximum-likelihood scores (MLSs) for these three study samples were 2.4, 1.3, and 3.0. In addition, a region on chromosome Xq23-26 resulted in two-point LOD scores of 1.9, 3.5, and 2.9 and in multipoint MLSs of 3.4, 3.1, and 2.5, respectively. In conclusion, this study identifies two loci likely to contribute to premature CHD: one on chromosome 2q21.1-22 and another on chromosome Xq23-26.