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The p.(Tyr400_Phe402del) mutation in the LDL receptor (LDLR) gene is the most frequent cause of familial hypercholesterolaemia (FH) in Gran Canaria. The aim of this study was to determine the age and origin of this prevalent founder mutation and to explore its functional consequences. For this purpose, we obtained the haplotypic information of 14 microsatellite loci surrounding the mutation in one homozygous individual and 11 unrelated heterozygous family trios. Eight different mutation carrier haplotypes were identified, which were estimated to originate from a common ancestral haplotype 387 (110-1572) years ago. This estimation suggests that this mutation happened after the Spanish colonisation of the Canary Islands, which took place during the fifteenth century. Comprehensive functional studies of this mutation showed that the expressed LDL receptor was retained in the endoplasmic reticulum, preventing its migration to the cell surface, thus allowing us to classify this LDLR mutation as a class 2a, defective, pathogenic variant.
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Hiperlipoproteinemia Tipo II , Humanos , Espanha , Hiperlipoproteinemia Tipo II/genética , Mutação , Receptores de LDL/genética , HeterozigotoRESUMO
OBJECTIVES: Diagnosis of Wilson disease (WD) is difficult and, as early detection may prevent all symptoms, it is essential to know the exact prevalence to evaluate the cost-efficacy of a screening program. As the number of WD patients was high in our population, we wished to estimate prevalence by determining the carrier frequency for clinically relevant ATP7B mutations. METHODS: To estimate prevalence, screening for the most prevalent mutation was performed in 1661 individuals with ancestry in Gran Canaria, and the frequency of other mutations was estimated from patient records. Alternatively, ATP7B mutations were detected from exomes and genomes from 851 individuals with Canarian ancestry, 236 from Gran Canaria, and a public Spanish exome database. RESULTS: Estimated carrier frequencies in Gran Canaria ranged from 1 in 20 to 28, depending on the method used, resulting in prevalences of 1 case per 1547 to 3140 inhabitants. Alternatively, the estimated affected frequencies were 1 in 5985 to 7980 and 1 in 6278 to 16,510 in the archipelago or mainland Spain respectively. CONCLUSIONS: The number of carriers predicts much higher prevalences than reported, suggesting that WD is underdiagnosed; specific mutations may remain unnoticed due to low penetrance or no signs of disease at all; regional prevalence rather than national prevalence should be considered in cost-efficacy models to approach preventive screening in the asymptomatic population and genetic screening strategies will have to deal with the genetic heterogeneity of ATP7B in the general population and in patients.
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Degeneração Hepatolenticular , ATPases Transportadoras de Cobre/genética , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/epidemiologia , Degeneração Hepatolenticular/genética , Humanos , Mutação , Sistema de Registros , EspanhaRESUMO
BACKGROUND AND AIMS: Malnutrition is found frequently during chronic diseases, and its prevalence and relation to disease outcome in adult patients with congenital heart disease (CHD) remains unknown. METHODS AND RESULTS: A cohort of 393 consecutive stable congenital heart disease (CHD) patients was followed up in a single dedicated clinical unit. Demographic, clinical and laboratory parameters, along with a nutritional risk index (NRI), were studied, as well as major acute cardiovascular events (MACE), defined as arterial thrombotic events, heart failure requiring hospitalization or cardiovascular and non-cardiovascular mortality. The median age of the patients was 23 years (17-35) and 225 (57%) were males. Median plasma albumin concentration was 4.5 (4.2-4.7) g/dL, the body mass index was 23 (21-27) kg/m2, the NRI was 112 (106-118), and 33 (8%) patients showed malnutrition (NIR<100). A worse NYHA functional class (II and III), total cholesterol and serum glucose levels were significant risk factors associated with malnutrition (NRI<100) in CHD patients. During a median follow-up of 8 (5-10) years, 39 (10%) CHD patients suffered a MACE. Multivariable Cox regression analysis showed that older patients (years) [HR 1.06 (1.04-1.09), p < 0.001], CHD patients with great anatomical complexity [HR 4.24 (2.17-8.27), p < 0.001] and those with a lower NRI [HR 0.95 (0.93-0.98), p = 0.001] had a significant worse MACE-free survival, being the NRI a better predictor of MACE than albumin concentration. CONCLUSIONS: A low NRI is independently associated with a significant increased risk of MACE in CHD patients.
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Cardiopatias Congênitas/epidemiologia , Desnutrição/epidemiologia , Estado Nutricional , Sobreviventes , Adolescente , Adulto , Índice de Massa Corporal , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/mortalidade , Cardiopatias Congênitas/fisiopatologia , Fatores de Risco de Doenças Cardíacas , Humanos , Hipoalbuminemia/epidemiologia , Masculino , Desnutrição/diagnóstico , Desnutrição/mortalidade , Desnutrição/fisiopatologia , Avaliação Nutricional , Prevalência , Prognóstico , Estudos Prospectivos , Medição de Risco , Espanha/epidemiologia , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: To determine psychological distress in congenital heart disease (CHD) patients. METHODS: Cross-sectional study among consecutive CHD patients recruited from a single hospital outpatient clinic to determine anxiety and depression according to the Hospital Anxiety and Depression Scale (HADS) questionnaire. RESULTS: One hundred and sixty-nine CHD patients [29 (19-39) years old, 100 (59%) males] were studied. A total of 25% and 9% of CHD patients showed anxiety and depression symptoms, respectively. Patients with an HADS score ≥ 8 had a significantly worse New York Heart Association (NYHA) functional class, needed more psychological support, had more mental health history, and took more anxiolytic/antidepressant medication than the CHD patients with an HADS score below 8. A worse NYHA functional class [OR, 1.88 (1.01-3.52)] proved to be a predictor of a borderline/abnormal HADS score. CONCLUSION: Psychological distress has a high prevalence among CHD patients and having an NYHA Class II and III is a significant predictor of an HADS score ≥ 8.
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Cardiopatias Congênitas/psicologia , Angústia Psicológica , Adulto , Estudos Transversais , Feminino , Cardiopatias Congênitas/terapia , Humanos , Masculino , Prevalência , Fatores de Risco , Adulto JovemRESUMO
Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder. This study involves the entire known CMT patient registry in Gran Canaria, represented by 256 patients belonging to 79 unrelated families, who were clinically and genetically characterized, along with physical and neurophysiological evaluation on 181 and 165 patients, respectively. Complete genotyping showed an estimated prevalence of CMT disease of 30.08/100 000 (95% confidence interval [CI] = 26.5;33.9), corresponding mainly (78.5%) to CMT1A (23.6/100 000) and hereditary neuropathy with liability to pressure palsies [HNPP] 17.5%; 5.29/100 000). Most patients (198) with CMT1A carried the 17p11.2 duplication including the PMP22 gene, 45 patients with HNPP were all affected by deletion of the 17p11.2 locus, and 10 patients presented with axonal phenotypes: CMT2A (MFN2), CMT2N (AARS), and CMT1X (GJB1). Despite showing a classical CMT1A phenotype, we found a much earlier age of onset in our CMT1A patients, along with increased frequency of appearance of postural hand tremor. Bilateral tongue atrophy was an additional phenotype observed. Being this CMT1A group, one of the largest cohorts known to date, this study provided a unique opportunity to further define the clinical phenotype of CMT1A patients carrying the 17p11.2 duplication in a homogeneous ethnic group.
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Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Adolescente , Adulto , Idade de Início , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Proteínas da Mielina/genética , Linhagem , Fenótipo , Espanha/epidemiologia , Trissomia/genética , Adulto JovemRESUMO
The airway epithelium forms a barrier between the internal and external environments. Epithelial dysfunction is critical in the pathology of many respiratory diseases, including cystic fibrosis. Ets homologous factor (EHF) is a key member of the transcription factor network that regulates gene expression in the airway epithelium in response to endogenous and exogenous stimuli. EHF, which has altered expression in inflammatory states, maps to the 5' end of an intergenic region on Chr11p13 that is implicated as a modifier of cystic fibrosis airway disease. Here we determine the functions of EHF in primary human bronchial epithelial (HBE) cells and relevant airway cell lines. Using EHF ChIP followed by deep sequencing (ChIP-seq) and RNA sequencing after EHF depletion, we show that EHF targets in HBE cells are enriched for genes involved in inflammation and wound repair. Furthermore, changes in gene expression impact cell phenotype because EHF depletion alters epithelial secretion of a neutrophil chemokine and slows wound closure in HBE cells. EHF activates expression of the SAM pointed domain-containing ETS transcription factor, which contributes to goblet cell hyperplasia. Our data reveal a critical role for EHF in regulating epithelial function in lung disease.
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Brônquios/metabolismo , Fibrose Cística/metabolismo , Células Epiteliais/metabolismo , Células Caliciformes/metabolismo , Fatores de Transcrição/metabolismo , Brônquios/patologia , Linhagem Celular , Quimiocinas/genética , Quimiocinas/metabolismo , Fibrose Cística/genética , Fibrose Cística/patologia , Células Epiteliais/patologia , Células Caliciformes/patologia , Humanos , Hiperplasia , Neutrófilos/metabolismo , Neutrófilos/patologia , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Wilson's disease (WD) is a rare condition resulting from autosomal recessive mutations in ATP7B, a copper transporter, manifesting with hepatic, neurological, and psychiatric symptoms. Timely diagnosis and appropriate treatment yield a positive prognosis, while delayed identification and/or insufficient therapy lead to a poor outcome. Our aim was to establish a prognostic method for WD by characterising biomarkers based on circulating microRNAs. METHODS: We conducted investigations across three cohorts: discovery, validation (comprising unrelated patients), and follow-up (revisiting the discovery cohort 3 years later). All groups were compared to age- and gender-matched controls. Plasma microRNAs were analysed via RNA sequencing in the discovery cohort and subsequently validated using quantitative PCR in all three cohorts. To assess disease progression, we examined the microRNA profile in Atp7b-/- mice, analysing serum samples from 6 to 44 weeks of age and liver samples at three time points: 20, 30, and 40 weeks of age. RESULTS: In patients, elevated levels of the signature microRNAs (miR-122-5p, miR-192-5p, and miR-885-5p) correlated with serum activities of aspartate transaminase, alanine aminotransferase and gamma-glutamyl transferase. In Atp7b-/- mice, levels of miR-122-5p and miR-192-5p (miR-885-5p lacking a murine orthologue) increased from 12 weeks of age in serum, while exhibiting fluctuations in the liver, possibly attributable to hepatocyte regenerative capacity post-injury and the release of hepatic microRNAs into the bloodstream. CONCLUSIONS: The upregulation of the signature miR-122-5p, miR-192-5p, and miR-885-5p in patients and their correlation with liver disease progression in WD mice support their potential as biomarkers of WD.
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OBJECTIVES: The aim of the study was to characterize a group of 11 pediatric patients, ages 3 to 13 years, affected by Wilson disease (WD) in the island of Gran Canaria, Spain. PATIENTS AND METHODS: Genetic, biochemical, and pathological features, together with their response to treatment and clinical evolution, have been analyzed for this group of patients. RESULTS: Genetically, the group was rather homogeneous, with an extremely high prevalence of the L708P mutation (4 homozygotes and 5 heterozygotes). Despite being initially screened because of asymptomatic hypertransaminemia, all of the patients presented with some degree of liver damage that was never accompanied by any neurological manifestation. Hepatic damage was most severe in a compound heterozygote with a novel mutation, G1266W, affecting a motif in the ATP7B polypeptide that is greatly conserved in similar proteins among metazoans. Ceruloplasmin and copper serum levels, together with the determination of hepatic copper content, were found to be of great diagnostic value, whereas urine copper measurements were found to be much less conclusive. All of the patients responded well to treatment with D-penicillamine with no documented adverse reactions. CONCLUSIONS: The patients in Gran Canaria constitute, overall, one of the largest groups of patients with WD with a high incidence of a single mutation, allowing us to define the early clinical symptoms and the evolution of the disease in patients carrying the ATP7B L708P mutant allele, and the study of WD in a genetically homogeneous background.
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Adenosina Trifosfatases/genética , Proteínas de Transporte de Cátions/genética , Cobre/metabolismo , Degeneração Hepatolenticular/genética , Fígado/patologia , Mutação , Adolescente , Ceruloplasmina/metabolismo , Quelantes/uso terapêutico , Criança , Pré-Escolar , ATPases Transportadoras de Cobre , Progressão da Doença , Feminino , Genótipo , Degeneração Hepatolenticular/metabolismo , Degeneração Hepatolenticular/patologia , Humanos , Fígado/metabolismo , Masculino , Penicilamina/uso terapêuticoRESUMO
The therapeutic efficacy of clopidogrel as an antiplatelet drug varies among individuals, being the mainstream hypothesis that its bioavailability depends on the individual genetic background and/or interactions with other drugs. A total of 477 patients receiving double antiaggregation therapy with aspirin and clopidogrel, after suffering a first event, were followed for 1 year to record relapse, as a surrogate end point to measure their therapeutic response, as defined by presenting with an acute coronary event (unstable angina, ST-segment-elevation myocardial infarction, or non-ST-segment-elevation myocardial infarction), stent thrombosis/restenosis, or cardiac mortality. Anthropometric, clinical, and pharmacological variables along with CYP2C19 genotypes were analyzed for their association with the disease relapse phenotype. Only 75 patients (15%) suffered a relapse, which occurred during the first 6 months of therapy, with a peak at 4.5 months. An initial univariate analysis identified that patients in the relapse group were significantly older (67.4 ± 11.0 vs 61.6 ± 12.3 years old) and presented with diffuse coronary disease, insulin-dependent type 2 diabetes mellitus dyslipidemia, and arterial hypertension. A poor clinical response to the platelet antiaggregation regime also occurred more frequently among patients taking acenocoumarol and calcium channel blockers, along with aspirin and clopidogrel, while no association was found according to CYP2C19 genotypes. A retrospective multivariate analysis indicated that patients belonging to the nonresponder phenotype to treatment with aspirin and clopidogrel were older, presented with diffuse coronary disease, a group largely overlapping with type 2 insulin-dependent diabetes mellitus, and were taking dihidropyrimidinic calcium channel blockers.
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Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Infarto do Miocárdio , Síndrome Coronariana Aguda/tratamento farmacológico , Aspirina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária , Recidiva , Estudos Retrospectivos , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous disease with relatively high morbidity and mortality rates. The lack of effective therapies, high recurrence rates and drug resistance driven in part, by tumor heterogeneity, contribute to the poor prognosis for patients diagnosed with this cancer. This problem is further exacerbated by the fact that key regulatory factors contributing to the disease diversity remains largely elusive. Here, we have identified EHF as an important member of the ETS family of transcription factors that is highly expressed in normal oral tissues, but lost during HNSCC progression. Interestingly, HNSCC tumors and cell lines exhibited a dichotomy of high and low EHF expression, and patients whose tumors retained EHF expression showed significantly better prognosis, suggesting a potential tumor suppressive role for EHF. To address this, we have performed gain and loss of function studies and leveraged bulk and single-cell cancer genomic datasets to identify global EHF targets by RNA-sequencing (RNA-seq) and Chromatin Immunoprecipitation and next generation sequencing (ChIP-seq) experiments of HNSCC cell lines. These mechanistic studies have revealed that EHF, acts as a regulator of a broad spectrum of metabolic processes, specifically targeting regulators of redox homeostasis such as NRF2 and SOX2. Our immunostaining results confirm the mutually exclusive expression patterns of EHF and SOX2 in HNSCC tumors and suggest a possible role for these two factors in establishing discrete metabolic states within the tumor microenvironment. Taken together, EHF may serve as a novel prognostic marker for classifying HNSCC patients for actionable and targeted therapeutic intervention.
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Monocytes participate in the development of atherosclerosis through the action of cytokines and other inflammatory mediators. Among them, CCR2 and its ligands, CCL2 and CCL7 play an important role, so the main objective of this work was to determine whether genetic variants affecting their activity were associated with cardiovascular disease. A cohort of 519 patients that have suffered coronary events was analyzed under a propensity score-matching protocol selecting a homogeneous set of cases and controls, according to age, sex, smoking status, dyslipidemia, arterial hypertension and type 2 diabetes as risk factors. While dyslipidemia and arterial hypertension were more prevalent among patients with angina pectoris, current smoking status and elevated inflammatory markers, including total leukocyte and monocyte counts, were more likely associated with acute coronary events. Propensity score matching analysis, performed to eliminate the influence of these risk factors and highlight genetic modifiers, revealed that a single nucleotide variant, rs17735770 at the 3'untranslated region of the CCL7 gene transcript, was associated with decreased cardiovascular risk in a group represented mostly by men, with an average age of 57, and without significant differences in traditional risk factors. Furthermore, the presence of this variant altered the local mRNA structure encompassing a binding site for miR-23ab, resulting in increased translation of a reporter gene in a miR23 independent fashion. The rs17735770 genetic variant led to increased expression of CCL7, a potential antagonist of CCR2 at inflammatory sites, where it could play a meaningful role during the evolution of atherosclerosis.
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In isolated populations rare genetic diseases are important and relatively frequent. The objective of this study is to determine the geographical aggregates of maternal and paternal ancestors of patients with congenital heart disease (CHD) to determine whether there is an association between the different areas and types of cardiac defects. Descriptive, observational, and cross-sectional study of patients with CHD obtained consecutively in a single adult CHD unit between January 2018 and December 2019 in Gran Canaria (Canary Islands, Spain). To be included in the study, at least one of the grandparents (maternal or paternal) should be born in Gran Canaria. 258 out of 353 CHD patients met the inclusion criteria. 58% of CHD patients were male and the median age was of 28 (21-40) years old. The most frequent types of CHD were cardiac septal defects (76 patients), right side cardiac outflow tract anomalies (74 patients) and left side cardiac outflow tract anomalies (58 patients). 13% of the patients had a family history of CHD, 11% showed consanguinity and 7% had an associated polymalformative syndrome. 20% of the four ancestors were born in the same municipality and a significant association was seen between two areas of Gran Canaria, orographically related, and right-side cardiac outflow tract anomalies (P<0.001). In conclusion in patients with tetralogy of Fallot and/or pulmonary valve stenosis/atresia an ancestry's geographic aggregation was seen.
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COVID-19 outbreak has brought tremendous psychological pressure to the general population, especially to those with associated cardiovascular disease. An online Patient Health Questionnaire (PHQ-9) survey on consecutive congenital heart disease (CHD) patients, was carried out to determine depression during the Spanish coronavirus disease (COVID-19) quarantine. Two-hundred forty-two out of 407 (59%) CHD patients answered the survey, 123 (51%) had mild defects, 88 (36%) moderate and 31 (13%) great defects, most of them between 18 and 24 years old and 51% were male. Patients were dichotomized to no or mild (PHQ-9 < 10) and moderate to severe (≥ 10) depressive symptoms. Thirty-four (14%) patients showed a PHQ-9 ≥ 10 and 10 of them (29%) were under anxiolytic or antidepressant treatment during the quarantine. During the study period, 9 (4%) patients had COVID-19 symptoms. Patients with a NYHA above 2 (P=0.025), living in houses without garden or balcony (P=0.014), needing psychological/psychiatric evaluation/medication in the previous 12 months or being under anxiolytic/antidepressant treatment during the confinement had, significantly, a PHQ-9 score ≥ 10 (P < 0.001). Being under anxiolytic/antidepressant treatment during the coronavirus pandemic [OR 3.92 (95% CI 1.05-14.66), P=0.043] and having previous psychological/psychiatric evaluation in the previous 12 months to the quarantine [OR 3.82 (95% CI 1.16-12.54), P=0.027] were the only variables that reached statistical significance, in the multivariable analysis, as predictors of a pathological PHQ-9 questionnaire (score ≥ 10). In conclusion depression was frequent during the COVID-19 quarantine among CHD patients, with only a third of them being under anxiolytic or antidepressant treatment. Needing psychological/psychiatric evaluation/treatment during the previous 12 months to the lockdown was a predictive factor for an abnormal PHQ-9 score.
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INTRODUCTION: Gran Canaria is a region of genetic isolation of familial hypercholesterolemia due to a founder mutation, p. [Tyr400_Phe402del], in the LDL receptor (LDLR) gene. Initial data suggest that its carriers could have a high prevalence of diabetes. MATERIAL AND METHODS: Patients over 30 years of age with familial hypercholesterolemia and a confirmed mutation in LDLR were recruited from a tertiary hospital in Gran Canaria. The prevalence of diabetes and other clinical data were compared among carriers of p. [Tyr400_Phe402del] and those with other LDLR mutations. RESULTS: 76.4% of the 89 participants were carriers of p.[Tyr400_Phe402del]. The prevalence of diabetes in this group was significantly higher (25 vs. 4%, P=.045). These cases also had a higher prevalence of cardiovascular disease and higher levels of LDL cholesterol and triglycerides. There were no differences in age, weight, body mass index, waist, age of onset, and time of statin treatment. However, they required PCSK9 inhibitors more often (51.5 vs 24%, P=.027). CONCLUSIONS: The mutation p.[Tyr400_Phe402del] is associated with a high prevalence of diabetes, not explained by classic risk factors, such as age, obesity, or long-term use of statins.
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Diabetes Mellitus , Hiperlipoproteinemia Tipo II , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Humanos , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Mutação , Inibidores de PCSK9 , Fenótipo , Pró-Proteína Convertase 9/genética , Receptores de LDL/genéticaRESUMO
As physical activity contributes to quality of life and health, we evaluated its association, as measured by the Global physical activity (GPAQ) questionnaire, on the quality of life (QoL) and serum glucose and cholesterol levels of patients with congenital heart disease (CHD). This cross-sectional study was carried out in 200 adult patients with CHD (17 to 58 years old), of whom 45 had simple defects, 122 moderate defects and 33 great anatomical complexity defects. Physiological complexity was defined as stage A in 74 patients, stage B in 29, stage C in 86 and stage D in 11. The energy expenditure was below 600 Metabolic Equivalent of Task (MET)-minutes per week in 56 (28%) patients, while 144 (72%) were above 600 MET-minutes per week. Physically inactive patients with CHD were significantly more dyslipidemic than active ones, but no significant differences in serum glucose and cholesterol levels were observed. Logistic regression analysis showed that physical activity was associated with a better QoL rating [0.28 (0.10-0.17), P=0.014] and health satisfaction [0.24 (0.09-0.62), P=0.003]. Physically active patients with CHD scored 7.7 and 8.9 points higher, on a 100-point scale, in the physical and social relationships domains respectively, than physically inactive ones. No significant differences were seen in the psychological and the environment domains associated with physical activity. Additionally, a worse New York Heart Association (NYHA) functional class (≥ 2) was identified as a risk factor for dissatisfaction with health [OR 7.48, 95% CI (1.55-47.14), P=0.020], having a significantly negative impact of 8.5 and 7.6, on a 100-point scale, in the physical and psychological domains respectively. In conclusion, physically active patients with CHD had a better QoL assessment, were more satisfied with their health and scored higher in the physical and social relationships domains.
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BACKGROUND: Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. An early diagnosis is crucial to prevent evolution of the disease, as implantation of early therapeutic measures fully prevents its symptoms. As population genetics data predict a higher than initially expected prevalence, it was important to define the basic diagnostic tools to approach population screening. METHODS: A highly genetically homogeneous cohort of 70 patients, belonging to 50 unrelated families, has been selected as a framework to analyze all their clinical, biochemical and genetic characteristics, to define the disease in our population, with an estimated prevalence of 1 in 12,369, and determine the most useful features that reach diagnostic value. RESULTS: Serum ceruloplasmin below 11.5 mg/dL and cupremia below 60 µg/mL, were the best analytical predictors of the disease in asymptomatic individuals, while cupruria or hepatic copper determination were less powerful. Genetic analysis reached a conclusive diagnosis in all 65 patients available for complete testing. Of them, 48 were carriers of at least one p.Leu708Pro mutant allele, with 24 homozygotes. Nine patients carried a promoter deletion mutation, revealing that extended sequencing beyond the ATP7B gene-coding region is essential. All mutations caused hepatic damage since early ages, increasing its severity as diagnosis was delayed, and neurological symptoms appear. CONCLUSION: Serum ceruloplasmin determination followed by genetic screening would reduce costs and favor the prioritization of non-invasive procedures to reach a definitive diagnosis, even for asymptomatic cases.
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Ceruloplasmina/metabolismo , ATPases Transportadoras de Cobre/genética , Testes Genéticos/métodos , Degeneração Hepatolenticular/diagnóstico , Programas de Rastreamento/métodos , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Criança , Pré-Escolar , Cobre/metabolismo , Diagnóstico Tardio , Diagnóstico Precoce , Feminino , Marcadores Genéticos , Degeneração Hepatolenticular/sangue , Degeneração Hepatolenticular/epidemiologia , Degeneração Hepatolenticular/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Prognóstico , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Espanha/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Red blood cell distribution width (RDW) is a predictor of adverse outcomes in patients with heart disease. AIM: To establish predictors of high RDW values in patients with congenital heart disease (CHD), and their relationship with cardiovascular events. METHODS: Overall, 561 patients with stable CHD who attended a single outpatient clinic and a matched control population of 2128 patients were studied. Exclusion criteria were renal failure, anaemia, receiving iron therapy and cyanosis. Blood tests included glucose, creatinine, iron, apoferritin, liver enzymes and a complete blood count. C-reactive protein and N-terminal prohormone of B-type natriuretic peptide (NT-pro-BNP) concentrations were also measured in patients with CHD. Major adverse cardiac events (MACE) were defined as cardiovascular/total mortality, arterial thrombotic events, arrhythmias, major bleedings, pulmonary embolism or heart failure needing hospital admission. RESULTS: The median age in patients with CHD was 23 (17-36) years and the median follow-up time was 5.8 (3.2-8.7) years; 103 (4.8%) controls and 40 (7.1%) patients with CHD had an RDW>15% (P=0.032). During follow-up, MACE were reported in 48 patients. CHD of great complexity, cardiovascular risk factors, low haemoglobin concentration and high NT-pro-BNP concentration were risk factors for an RDW>15%. Kaplan-Meier analysis showed a significantly worse cardiovascular outcome in patients with CHD with an RDW>15% (P<0.001). The multivariable survival analysis determined that age, CHD of great complexity, high NT-pro-BNP concentration and an RDW>15% were independent predictive factors for MACE. CONCLUSION: RDW and NT-pro-BNP concentration are independent analytical predictors of MACE in patients with CHD.
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Índices de Eritrócitos , Cardiopatias Congênitas/diagnóstico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
INTRODUCTION: Certain polymorphisms in the non-muscle myosin IIA (MYH9) and apolipoprotein L1 (APOL1) genes have been associated to chronic kidney disease (CKD) in different populations. This study examined the association between the MHY9 rs2032487 and APOL1 rs73885319 polymorphisms and advanced CKD related to type 2 diabetes mellitus (T2DM) in a population of Gran Canaria (Canary Islands, Spain). PATIENTS AND METHODS: Polymorphisms were genotyped in 152 patients with advanced CKD (estimated glomerular filtration rate [eGFR]<30mL/min/1.73 m2) secondary to T2DM, 110 patients with T2DM onset ≥ 20 years before without advanced CKD (eGFR ≥ 45mL/min/1.73 m2 and no proteinuria), and 292 healthy blood donors over 50 years of age without CKD or diabetes. RESULTS: The frequency of the risk allele for rs2032487 was 10.7% in patients with diabetes and advanced CKD, 7.1% in those with diabetes but without advanced CKD, and 6.1% in healthy subjects, with significant differences between the first and third groups (P=.015). Among subjects with advanced CKD, 78.5% were homozygous for the protective allele, as compared to 87.9% in the other two groups (P=.015 and P=.016 respectively). The frequency of the risk allele for the rs73885319 polymorphism did not exceed 0.5% in any of the three groups. CONCLUSIONS: These data suggest that polymorphism rs2032487 is associated to advanced CKD related to T2DM in the population of Gran Canaria.
Assuntos
Apolipoproteína L1/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Cadeias Pesadas de Miosina/genética , Polimorfismo Genético , Insuficiência Renal Crônica/etiologia , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , EspanhaRESUMO
BACKGROUND: Genetic diagnosis of familial hypercholesterolemia (FH) has not been universally performed in the Canary Islands (Spain). OBJECTIVES: This study aimed to genetically characterize a cohort of patients with FH in the island of Gran Canaria. METHODS: Study subjects were 70 unrelated index cases attending a tertiary hospital in Gran Canaria, with a clinical diagnosis of FH, according to the criteria of the Dutch Lipid Clinic Network. Given that 7 of the first 10 cases with positive genetic study were carriers of a single mutation in the LDLR gene [p.(Tyr400_Phe402del)], a specific polymerase chain reaction-based assay was developed for the detection of this variant as a first screening step on the remaining subjects. In those without this mutation, molecular diagnosis was completed using a next-generation sequencing panel including LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, and LIPA genes and incorporating copy number variation detection in LDLR. RESULTS: On the whole, 44 subjects (62%) had a positive genetic study, of whom 30 (68%) were heterozygous carriers of the p.(Tyr400_Phe402del) variant. Eleven subjects carried other mutations in LDLR, including the novel mutation NM_000527.4: c.877dupG; NP_000518.1: p.(Asp293Glyfs*8). An unclassified PCSK9 gene variant was found in one subject [(NM_174936.3:c.1496G>A; NP_777596.2: p.(Arg499His)]. Other single patients had mutations in APOB (heterozygous) and in LIPA (homozygous). All identified variants co-segregated with the disease phenotype. CONCLUSIONS: These findings suggest a founder effect for the p.(Tyr400_Phe402del) LDLR mutation in Gran Canaria. A cost-effective local screening strategy for genetic diagnosis of FH could be implemented in this region.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , Adulto , Idoso , Apolipoproteína B-100/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Heterozigoto , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9/genética , Espanha , Esterol Esterase/genéticaRESUMO
Along with aspirin, clopidogrel has been a widely used antiplatelet therapeutic regimen. Although generally well tolerated, its efficacy varies among individuals, with the main hypothesis that its bioavailability relies on its bioconversion to the active compound, which, in turn, depends on the genetic background and/or interactions with other drugs. To determine which factors influenced response in our patients, 368 patients receiving combined antiaggregation therapy with aspirin and clopidogrel were followed for 1 year to record 30 novel cardiovascular acute events. This clinical relapse was considered a surrogate end point to measure therapeutic response under the influence of the CYP2C19*2, *3, and *17 and CYP3A5*3 alleles, as well as the effects of concomitant medication and the presence of known cardiovascular risk factors and comorbidity. We show that either single CYP2C19 or CYP3A5 genotyping or combined were not useful to predict clinical efficacy in this cohort. Rather than genetic testing, we have found that clinical observations such as suffering type 2 diabetes mellitus requiring insulin, having several vessels affected, and concurrent medication with calcium channel blockers, regardless of CYP3A5 genotype or drug class were, in that order, the strongest independent predictors of disease relapse.