RESUMEN
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.
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Infecciones Relacionadas con Catéteres/complicaciones , Sepsis/epidemiología , Infección de la Herida Quirúrgica/complicaciones , Centros de Atención Terciaria , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Finlandia/epidemiología , Hospitales Universitarios , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Factores de Riesgo , Sepsis/mortalidad , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To examine whether work stress is associated with a symptomatic status of the long QT syndrome (LQTS). METHODS: The sample comprised 173 KCNQ1, KCNH2, or SCN5A gene mutation carriers (70 symptomatic) and control groups of 203 relatives without the family mutation, and of 1209 population-based young Finns control subjects. Work stress was assessed using the Job Content Questionnaire and Occupational Stress Questionnaire. RESULTS: We found an association between the occurrence of symptoms in the LQTS and high work stress, higher job demands/effort, lower job control, and lower rewards compared with control subjects. We also found that symptomatic LQTS mutation carriers had higher work stress than asymptomatic LQTS mutation carriers. CONCLUSIONS: Higher work stress is related to arrhythmic risk in the LQTS. It may be useful to incorporate assessment of work conditions and stress interventions into management of high-risk patients.
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Síndrome de QT Prolongado/psicología , Recompensa , Estrés Psicológico/psicología , Carga de Trabajo/psicología , Adulto , Estudios de Casos y Controles , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/genética , Femenino , Finlandia , Heterocigoto , Humanos , Satisfacción en el Trabajo , Canal de Potasio KCNQ1/genética , Síndrome de QT Prolongado/genética , Masculino , Persona de Mediana Edad , Mutación , Canal de Sodio Activado por Voltaje NAV1.5/genética , Autonomía Profesional , Estrés Psicológico/fisiopatología , Lugar de Trabajo/psicología , Adulto JovenRESUMEN
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.
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Enfermedad Celíaca/enzimología , Enfermedad Celíaca/genética , Fucosiltransferasas/genética , Enfermedades Inflamatorias del Intestino/enzimología , Enfermedades Inflamatorias del Intestino/genética , Alelos , Secuencia de Bases , Estudios de Casos y Controles , Colitis Ulcerosa/enzimología , Colitis Ulcerosa/genética , Enfermedad de Crohn/enzimología , Enfermedad de Crohn/genética , Cartilla de ADN/genética , Dermatitis Herpetiforme/enzimología , Dermatitis Herpetiforme/genética , Finlandia , Genes Recesivos , Estudios de Asociación Genética , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
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.
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Enfermedad Celíaca/genética , Enfermedad Celíaca/inmunología , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Adulto , Estudios de Casos y Controles , Niño , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Finlandia , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , SueciaRESUMEN
Short telomeres are associated with aging and age-related diseases. Our aim was to determine whether short leukocyte telomere length is associated with risk factors and cardiovascular diseases in a high-risk hypertensive population. We measured leukocyte telomere lengths at recruitment in 1271 subjects with hypertension and left ventricular hypertrophy (LVH) participating in the Lifestyle Interventions and Independence for Elders (LIFE) study. At baseline, short mean telomere length was associated with coronary artery disease in males (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.39-0.95), and transient ischemic attack in females (OR 0.62 95% CI 0.39-0.99). Proportion of short telomeres (shorter than 5 kb) was associated with Framingham risk score (r=0.07, P<0.05), cerebrovascular disease (OR 1.18, 95% CI 1.01-1.15) and type 2 diabetes in men (OR 1.07, 95% CI 1.02-1.11). During follow-up, proportion of short telomeres was associated with combined cardiovascular mortality, stroke or angina pectoris (hazard ratio 1.04, 95% CI 1.01-1.07). Telomere length was not associated with smoking, body mass index, pulse pressure or self-reported use of alcohol. Our data suggest that reduced leukocyte telomere length is associated with cardiovascular risk factors and diseases as well as type 2 diabetes, and is a predictor of cardiovascular disease in elderly patients with hypertension and LVH.
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Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Hipertensión/patología , Hipertrofia Ventricular Izquierda/patología , Leucocitos/patología , Telómero/patología , Anciano , Anciano de 80 o más Años , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Atenolol/farmacología , Atenolol/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipertrofia Ventricular Izquierda/epidemiología , Leucocitos/ultraestructura , Losartán/farmacología , Losartán/uso terapéutico , Masculino , Persona de Mediana Edad , Factores de Riesgo , Telómero/ultraestructura , Resultado del TratamientoRESUMEN
OBJECTIVE: To examine whether a history of stressful life events and prolonged mental stress are associated with arrhythmic events in inherited long QT syndrome (LQTS). METHODS: Participants who had a molecularly established mutation of KCNQ1, KCNH2 or SCN5A channel and were thus diagnosed as patients with LQT1, LQT2 and LQT3 (n=566), accordingly. The control group consisted of their 614 non-affected relatives. A history of stressful life events was indexed by the major stressful life events. Prolonged mental stress was indexed by vital exhaustion (VE), which was measured with the Maastricht Questionnaire. RESULTS: Multinomial logistic regression analysis including patients with LQTS with and without arrhythmic events and the control subjects showed an age- and sex-adjusted association of stressful life events OR=1.15 (95% CI 1.08 to 1.22) and VE (OR=3.33 (95% CI 1.63 to 6.78)) with symptomatic status of LQTS. Symptomatic patients with LQTS had experienced more stressful life events (OR=1.16 (95% CI 1.08 to 1.24)) and the level of VE (OR=3.40 (95% CI 1.44 to 8.03)) was more than three times higher among patients with LQTS with arrhythmic events than in asymptomatic LQTS mutation carriers. The association between stressful life events and arrhythmic events was independent of age, sex, specifically focused medication and LQTS subtype. CONCLUSIONS: A history of stressful life events and prolonged mental stress are associated with arrhythmic events in LQTS in this large sample of molecularly defined patients with LQTS. It is important for future studies to assess how strong these predisposing factors are for arrhythmic events in LQTS.
Asunto(s)
Acontecimientos que Cambian la Vida , Síndrome de QT Prolongado/etiología , Estrés Psicológico/complicaciones , Adolescente , Adulto , Factores de Edad , Anciano , Arritmias Cardíacas/etiología , Estudios de Casos y Controles , Femenino , Humanos , Síndrome de QT Prolongado/congénito , Síndrome de QT Prolongado/genética , Masculino , Persona de Mediana Edad , Mutación , Sistema de Registros , Factores de Riesgo , Adulto JovenRESUMEN
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.
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Proteínas Adaptadoras Transductoras de Señales/genética , Variación Genética/genética , Síndrome de QT Prolongado/genética , Polimorfismo de Nucleótido Simple , Canales de Potasio con Entrada de Voltaje/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis por Conglomerados , Muerte Súbita Cardíaca/etiología , Electrocardiografía , Canales de Potasio Éter-A-Go-Go/genética , Femenino , Finlandia/epidemiología , Genotipo , Humanos , Síndrome de QT Prolongado/epidemiología , Síndrome de QT Prolongado/fisiopatología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Mutations in the caspase-activating recruitment domain 15 (CARD15) gene are associated with Crohn disease (CD). CARD15 is an intracellular receptor for bacterial lipopolysaccharides (LPS). LPS-induced activation of transfectants containing the frameshift mutation (1007fs) of CARD15 is impaired. The aim of this study was to investigate whether the presence of CARD15 1007fs affects activation of CD patients' own cells. Patients (4 homozygotes, 6 heterozygotes, and 6 wild-type) were matched according to clinical picture and medication. METHODS: Immune inflammatory status was evaluated by measuring monocyte HLA-DR and CD11b densities and the proportion of CD14dimCD16+ monocytes, and was found to be comparable in the three groups. Blood mononuclear cells were cultured overnight in serum-free medium alone, or the medium supplemented with LPS (0.1-10.0 ng/mL), a combination of IFN-gamma (100 IU/mL) and granulocyte-macrophage colony stimulating factor (GM-CSF) (5 ng/mL), or both. TNF and IL-10 levels in the culture supernatant were determined. RESULTS: LPS 0.1 or 1.0 ng/mL alone did not increase TNF levels. IFN-gamma/GM-CSF induced TNF release, and co-culture with LPS 1.0 or 10.0 ng/mL was strongly synergistic. CARD15 1007fs mutation was linked in a gene-dose-dependent manner to low TNF release induced by IFN-gamma/GM-CSF (P value for linear trend = 0.001). The degree of synergism in co-culture was normal or high, suggesting that 1007fs did not depress responses to LPS. IL-10 levels were not related to CARD15 1007fs. CONCLUSIONS: In CD patients, CARD15 1007fs is associated in a gene-dose-dependent manner to low mononuclear cell TNF release by IFN-gamma/GM-CSF but does not impair TNF release by LPS. This type of immune dysregulation may influence susceptibility to and/or phenotype of CD.
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Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Mutación del Sistema de Lectura , Péptidos y Proteínas de Señalización Intracelular/genética , Leucocitos Mononucleares/fisiología , Adulto , Estudios de Casos y Controles , Técnicas de Cultivo de Célula , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Humanos , Interferón gamma/fisiología , Interleucina-10/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/farmacología , Masculino , Persona de Mediana Edad , Proteína Adaptadora de Señalización NOD2 , Factor de Necrosis Tumoral alfa/metabolismoAsunto(s)
Hemocromatosis/genética , Homocigoto , Longevidad , Adulto , Anciano , Anciano de 80 o más Años , ADN/genética , Femenino , Finlandia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
BACKGROUND: Variants of the caspase activating recruitment domain 15/nucleotide oligomerisation domain 2 (CARD15/NOD2) gene have been associated with susceptibility to Crohn's disease (CD). AIM: Our aim was to evaluate the allele frequencies of the CARD15 variants R702W, G908R, and 1007fs in Finnish inflammatory bowel disease (IBD) patients and to search for possible associations between CARD15 variants and occurrence of familial forms of IBD or complicated forms of CD. PATIENTS AND METHODS: We investigated 198 sporadic CD patients, 46 probands with familial CD, 27 CD probands from mixed IBD families, 99 unrelated patients with ulcerative colitis (UC), and 300 control individuals for the occurrence of the CARD15 gene variants R702W, G908R, and 1007fs. RESULTS: In CD patients, the allele frequencies for the rare variants of these polymorphisms were 3.3%, 0.6%, and 4.8% (total 8.7%), and the corresponding frequencies in healthy controls were 1.8%, 0%, and 1.7% (total 3.5%) (8.7% v 3.5%; p<0.01). In UC patients allele frequencies were comparable with those in controls. The frequency of the 1007fs polymorphism variant allele was significantly higher among all CD patients than in controls (4.8% v 1.7%; p<0.01) but there was no significant difference in allele frequencies between the CD and UC groups. The 1007fs allele frequency was higher in familial CD than in non-familial cases with CD (10.9% v 3.5%; p<0.01). There were no significant differences in the allele frequencies of the R702W and G908R polymorphisms between CD patients, UC patients, and controls. We found that 15.5% of CD patients, 9.1% of UC patients, and 6.7% of controls carried at least one of the CARD15 variants. In CD patients carrying at least one of the three NOD2 variants, the ileum was affected more often than in non-carrier CD patients (90% v 73%; p<0.05), they had stricturing or penetrating disease more often than non-carriers (88% v 56%; p<0.01), and they had an increased need for bowel surgery. CONCLUSIONS: The frequency of NOD2 gene variants was lower in genetically homogenous Finns than in other populations. The 1007fs variant was associated with CD. The occurrence of CARD15 variants predicted ileal location as well as stricturing and penetrating forms of CD.
Asunto(s)
Proteínas Portadoras/genética , Enfermedad de Crohn/genética , Predisposición Genética a la Enfermedad , Péptidos y Proteínas de Señalización Intracelular , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Colitis Ulcerosa/genética , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/patología , Femenino , Frecuencia de los Genes , Variación Genética , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Proteína Adaptadora de Señalización NOD2 , Fenotipo , Estudios RetrospectivosRESUMEN
BACKGROUND: Linkage and knock-out mice studies suggest that the melanocortin-3-receptor (MC3R) is a candidate gene for obesity. OBJECTIVE: To evaluate whether MC3R mutations underlie morbid obesity. SUBJECTS AND METHODS: MC3R coding and 5(')-flanking regions were sequenced in 48 subjects and the detected variants genotyped in 252 morbidly obese (BMI>/=40 kg/m(2)) Finns. Gel shifts were used to examine whether a mutation in the putative promoter alters GATA-factor binding. RESULTS: Three common MC3R variants were found: a 17C>A variant, changing Thr6-->Lys in 16%, a 241G>A variant changing Val81-->Ile in 15%, and a -239A>G substitution in the GATA binding site in 21% of the subjects. Four other variants were detected in the 5(') flanking region. Frequencies of the three common variants did not differ between obese and contol subjects. Among the obese, the 17C>A and 241G>A variants were coinherited and associated with increased insulin-glucose ratios (P<0.05) and leptin levels (P<0.05). GATA-4 bound efficiently to wild type oligonucleotide, but only weakly to the oligonucleotide with the -239A>G mutation. CONCLUSIONS: MC3R gene variants are common and do not explain human morbid obesity. These variants associated with subtle changes in onset of weight gain, hyperleptinemia and insulin-glucose ratios. The -239A>G mutation abolishes binding of GATA-4 to the MC3R promoter region.
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Obesidad Mórbida/genética , Receptores de Corticotropina/genética , Adulto , Anciano , Estudios de Cohortes , Proteínas de Unión al ADN/metabolismo , Femenino , Factor de Transcripción GATA4 , Frecuencia de los Genes , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Receptor de Melanocortina Tipo 3 , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: The familial occurrence of inflammatory bowel disease (IBD) and the clinical features of familial and sporadic IBD in the genetically homogeneous Finnish population are evaluated. METHODS: 257 patients with Crohn disease (CD) and 436 with ulcerative colitis (UC) participated in the study. They were asked whether IBD was present (familial IBD) or absent (sporadic IBD) in their first-degree relatives. Data on the clinical course of the disease were collected from the patient records. Antibodies to Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) were determined from serum samples. RESULTS: Affected first-degree relatives were found in 15.6% of patients with CD and in 13.8% of patients with UC. In familial cases CD was more often located in the ileum (38% versus 21%) and less often in the ileocolon (35% versus 50%) (P< 0.05) than in sporadic cases. A greater percentage of CD patients than UC patients were smokers (47% versus 13%; P < 0.01). An elevated level of IgA and/or IgG antibodies for ASCA was found more often in CD patients than in UC patients (59% versus 14%; P < 0.01), while pANCA were found more often in UC than in CD patients (48% versus 12%; P < 0.01). The combination of pANCA-ASCA+ yielded a sensitivity, specificity and positive predictive value of 48%, 92% and 90%, respectively, for CD, and the combination of pANCA + ASCA- of 55%, 94% and 90%, respectively, for UC. CONCLUSIONS: The percentage of familial IBD cases in Finland is comparable to that reported elsewhere in Europe. No important clinical differences between patients with familial and sporadic forms of the disease were found. ASCA is associated with both familial and sporadic CD and pANCA with UC, but low sensitivity diminishes their value as a serological marker of IBD or as a differential diagnostic test between CD and UC.
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Anticuerpos Anticitoplasma de Neutrófilos/análisis , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/genética , Adolescente , Adulto , Distribución por Edad , Anciano , Biomarcadores/análisis , Niño , Estudios de Cohortes , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/epidemiología , Colitis Ulcerosa/genética , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Finlandia/epidemiología , Humanos , Incidencia , Enfermedades Inflamatorias del Intestino/diagnóstico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Probabilidad , Pronóstico , Medición de Riesgo , Distribución por SexoRESUMEN
BACKGROUND: Variants of the lipoprotein lipase (LPL) gene have been shown to influence serum lipid levels, risk of coronary heart disease and, as found recently, risk of clinical ischaemic cerebrovascular disease. Here we tested for an association between brain infarction and two common polymorphisms of the LPL gene, Ser447Ter and Asn291 Ser. METHOD: To avoid ascertainment and selection bias involved in many association studies, we compared the distribution of these polymorphisms in neuropathologically verified patients (n = 119) vs controls (n = 133) derived from a prospective, population-based study (the Vantaa 85+ study). RESULTS: The LPL Ter447 variant was negatively associated with neuropathologically verified brain infarcts (P = 0.006), and even more strongly with small brain infarcts (P = 0.004). In addition, we found that the Ter447 variant was associated with higher serum HDL chblesterol (P = 0.004) and lower triglyceride levels (P= 0.003), and that it was negatively associated with pathologically verified severe coronary artery disease (P=0.001) in the Vantaa 85+ study sample. The Asn291Ser polymorphism was not significantly associated with brain infarction. CONCLUSION: The Ter447 variant of LPL is associated with decreased risk of brain infarction and coronary artery disease in our very elderly population.
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Infarto Cerebral/genética , Infarto Cerebral/patología , Lipoproteína Lipasa/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Marcadores Genéticos/genética , Genotipo , Humanos , Modelos Logísticos , Masculino , Vigilancia de la Población , Probabilidad , Valores de Referencia , Sensibilidad y Especificidad , Estadísticas no ParamétricasRESUMEN
Familial hypercholesterolaemia (FH) is an autosomal co-dominantly inherited condition resulting from mutations of the low-density lipoprotein (LDL) receptor which occur in heterozygous form in approximately one in 500 individuals. Clinically, FH is characterized by 2-3-fold elevation of serum LDL cholesterol levels, accelerated development of atherosclerotic vascular disease, and, if untreated, shortened lifespan. The Finnish population, which represents a genetic isolate, offers exceptional possibilities for genetic-epidemiological studies on FH, as a handful of founder gene mutations account for the majority of FH cases in Finland. This review summarizes data from our FH studies carried out since 1985. We wish to emphasize the continuum of genotype-phenotype relationships, the importance of molecular diagnosis, the detection of novel risk factors of vascular disease, and innovations inhibiting cholesterol absorption for the modern treatment of FH.
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Hiperlipoproteinemia Tipo II/genética , Mutación Puntual , Receptores de LDL/genética , Edad de Inicio , Deleción Cromosómica , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/genética , Análisis Mutacional de ADN , Finlandia/epidemiología , Genotipo , Humanos , Epidemiología Molecular , Linaje , FenotipoRESUMEN
BACKGROUND: The majority of patients with inherited haemochromatosis carry two mutant alleles of the recently discovered HFE gene. Individuals heterozygous for the HFE mutation could be predisposed to end-stage liver disease due to other causes. METHODS: The frequencies of the HFE gene mutations C282Y and H63D were determined in DNA samples obtained from 189 liver transplant patients and 225 healthy Finnish blood donors. RESULTS: 5% of the 189 liver transplant recipients were heterozygotes and 0.5% homozygotes for the C282Y mutation, while 16% were heterozygotes and 0.5% homozygotes for the H63D mutation. These figures were not increased in comparison to controls, of whom 11% were C282Y heterozygotes, 16% H63D heterozygotes and 0.9% H63D homozygotes. Among recipients with acute non-A-E hepatitis (n = 31), the frequency of the H63D allele was higher than in controls (21% versus 9.1%, P < 0.01). Perls' stain for iron in explanted liver specimens was positive in 28% of recipients with alcoholic cirrhosis, 26% of patients with acute non-A-E hepatitis and 14% in the rest of the recipients. The HFE genotypes did not correlate with the iron status. CONCLUSION: Individuals heterozygous for either the C282Y or H63D mutation of the HFE gene are not at increased risk of developing chronic end-stage liver disease. However, subjects heterozygous for the H63D mutation may have an increased risk to develop fulminant non-A-E hepatitis.
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Antígenos HLA/genética , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Trasplante de Hígado , Proteínas de la Membrana , Mutación , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Análisis Mutacional de ADN/métodos , Cartilla de ADN , Femenino , Hemocromatosis/patología , Proteína de la Hemocromatosis , Humanos , Hígado/patología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To study and compare the effects of mental and physical stress on long QT syndrome (LQTS) patients. DESIGN: Case-control study. MAIN OUTCOME MEASURES: QT intervals were measured from lead V3. Serum potassium and plasma catecholamine concentrations were also monitored. PATIENTS: 16 patients with type 1 LQTS (LQT1), 14 with type 2 LQTS (LQT2), both groups asymptomatic, and 14 healthy control subjects. INTERVENTIONS: Three types of mental stress tests and a submaximal exercise stress test. RESULTS: Heart rate responses to mental stress and exercise were similar in all groups. During mental stress, the mean QT interval shortened to a similar extent in controls (-29 ms), LQT1 patients (-34 ms), and LQT2 patients (-30 ms). During exercise, the corresponding QT adaptation to exercise stress was more pronounced (p < 0.01) in healthy controls (-47 ms) than in LQT1 (-38 ms) or LQT2 patients (-38 ms). During exercise changes in serum potassium concentrations were correlated to changes in QT intervals in controls, but not in LQTS patients. LQT1 and LQT2 patients did not differ in serum potassium, catecholamine or heart rate responses to mental or physical stress. CONCLUSIONS: QT adaptation to mental and exercise stress in healthy people and in patients with LQTS is different. In healthy people QT adaptation is more sensitive to physical than to mental stress while no such diverging pattern was seen in asymptomatic LQTS patients.
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Electrocardiografía , Síndrome de QT Prolongado/fisiopatología , Estrés Fisiológico/fisiopatología , Adolescente , Adulto , Biomarcadores/sangre , Epinefrina/sangre , Prueba de Esfuerzo , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Síndrome de QT Prolongado/sangre , Síndrome de QT Prolongado/psicología , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Potasio/sangre , Estrés Fisiológico/sangre , Estrés Fisiológico/psicología , Estrés Psicológico/sangre , Estrés Psicológico/fisiopatologíaRESUMEN
BACKGROUND: No previous autopsy-controlled, prospective, and population-based studies are available on the prevalence of AD in very elderly people. OBJECTIVE: To study the point prevalence of neuropathologically defined AD in a population of people at least 85 years of age, stratified according to their APOE genotype. METHODS: A population-based sample of 532 (of a total population of 601) elderly Finnish individuals, aged 85 years or more, were clinically tested for dementia in 1991 (with follow-up studies of the survivors in 1994, 1996, and 1999) and genotyped for APOE. An autopsy involving neuropathologic diagnosis of AD according to modified consensus criteria was performed in 118 of 198 deceased subjects who had been demented on April 1, 1991, and in 62 of 201 nondemented individuals. RESULTS: The prevalence of neuropathologically defined AD was 33%, whereas the prevalence of clinically diagnosed AD was 16%. There was a highly significant (p < 0.001) association between the APOE epsilon4 allele and AD: Sixty-three percent of APOE epsilon4 carriers and 20% of noncarriers had neuropathologic AD. The respective figures in subjects aged 90 years or more were 71 and 22%. CONCLUSIONS: The prevalence of neuropathologically defined AD is higher than that reported in most previous studies based on clinical diagnosis. The discrepancy between the neuropathologic and clinical diagnoses of AD in very elderly subjects may affect the results of population-based studies. The APOE genotype has a strong effect on the prevalence of neuropathologically defined AD, even after 90 years of age.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteínas E/genética , Anciano , Anciano de 80 o más Años , Finlandia , Genotipo , Humanos , Masculino , Prevalencia , Estudios ProspectivosRESUMEN
In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (P=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor alpha-subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32-bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL4RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD.