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1.
BMC Neurol ; 21(1): 201, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006233

RESUMO

BACKGROUND: Characterization of prediagnostic Parkinson's Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting. METHODS: We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window. RESULTS: We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300 days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles. CONCLUSIONS: Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.


Assuntos
Doença de Parkinson/diagnóstico , Marcha/fisiologia , Análise da Marcha , Humanos , Aprendizado de Máquina , Estudos Retrospectivos , Medição de Risco , Tremor
2.
PLoS Med ; 17(6): e1003149, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32559194

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. METHODS AND FINDINGS: We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (<5% or ≥5%) available for 1,514 participants. We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and random forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operating characteristic area under the curve (ROCAUC) of 0.84 (95% CI 0.82, 0.86; p < 0.001), which compared with a ROCAUC of 0.82 (95% CI 0.81, 0.83; p < 0.001) for a model including 9 clinically accessible variables. The IMI DIRECT prediction models outperformed existing noninvasive NAFLD prediction tools. One limitation is that these analyses were performed in adults of European ancestry residing in northern Europe, and it is unknown how well these findings will translate to people of other ancestries and exposed to environmental risk factors that differ from those of the present cohort. Another key limitation of this study is that the prediction was done on a binary outcome of liver fat quantity (<5% or ≥5%) rather than a continuous one. CONCLUSIONS: In this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see: https://www.predictliverfat.org/) and made it available to the community. TRIAL REGISTRATION: ClinicalTrials.gov NCT03814915.


Assuntos
Fígado Gorduroso/etiologia , Aprendizado de Máquina , Complicações do Diabetes/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de Risco
3.
Nature ; 490(7419): 267-72, 2012 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-22982992

RESUMO

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.


Assuntos
Índice de Massa Corporal , Variação Genética , Fenótipo , Proteínas/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Estatura/genética , Proteínas Correpressoras , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética
4.
Mol Genet Metab ; 121(1): 43-50, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28385534

RESUMO

Genome-wide association studies (GWAs) for type 2 diabetes (T2D) have been successful in identifying many loci with robust association signals. Nevertheless, there is a clear need for post-GWAs strategies to understand mechanism of action and clinical relevance of these variants. The association of several comorbidities with T2D suggests a common etiology for these phenotypes and complicates the management of the disease. In this study, we focused on the genetics underlying these relationships, using systems genomics to identify genetic variation associated with T2D and 12 other traits. GWAs studies summary statistics for pairwise comparisons were obtained for glycemic traits, obesity, coronary artery disease, and lipids from large consortia GWAs meta-analyses. We used a network medicine approach to leverage experimental information about the identified genes and variants with cross traits effects for biological function interpretation. We identified a set of 38 genetic variants with cross traits effects that point to a main network of genes that should be relevant for T2D and its comorbidities. We prioritized the T2D associated genes based on the number of traits they showed association with and the experimental evidence showing their relation to the disease etiology. In this study, we demonstrated how systems genomics and network medicine approaches can shed light into GWAs discoveries, translating findings into a more therapeutically relevant context.


Assuntos
Biologia Computacional/métodos , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Variação Genética , Obesidade/genética , Comorbidade , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Índice Glicêmico , Humanos , Modelos Genéticos , Locos de Características Quantitativas , Biologia de Sistemas
5.
J Transl Med ; 12: 34, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24502605

RESUMO

BACKGROUND: Nephrolithiasis is more frequent and severe in obese patients from different western nations. This may be supported by higher calcium, urate, oxalate excretion in obese stone formers. Except these parameters, clinical characteristics of obese stone formers were not extensively explored. AIMS: In the present paper we studied the relationship between obesity and its metabolic correlates and nephrolithiasis. MATERIALS AND METHODS: We studied 478 Caucasian subjects having BMI ≥ 25 kg/m². The presence of nephrolithiasis, hypertension, diabetes mellitus and metabolic syndrome were noted. They underwent measurements of anthropometry (BMI and waist circumference, body composition), serum variables (fasting glucose, serum lipids and serum enzymes) and Mediterranean diet (MedDiet) nutritional questionnaire. RESULTS: 45 (9.4%) participants were stone formers. Subjects with high serum concentrations of triglycerides (≥ 150 mg/dl), fasting glucose (> 100 mg/dl) and AST (>30 U/I in F or >40 U/I in M) were more frequent among stone formers than non-stone formers.Multinomial logistic regression confirmed that kidney stone production was associated with high fasting glucose (OR = 2.6, 95% CI 1.2-5.2, P = 0.011), AST (OR = 4.3, 95% CI 1.1-16.7, P = 0.033) and triglycerides (OR = 2.7, 95% CI 1.3-5.7, P = 0.01). MedDiet score was not different in stone formers and non-stone formers. However, stone formers had a lower consumption frequency of olive oil and nuts, and higher consumption frequency of wine compared with non-stone formers. CONCLUSIONS: Overweight and obese stone formers may have a defect in glucose metabolism and a potential liver damage. Some foods typical of Mediterranean diet may protect against nephrolithiasis.


Assuntos
Dieta Mediterrânea , Glucose/metabolismo , Nefrolitíase/complicações , Nefrolitíase/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nefrolitíase/sangue , Obesidade/sangue , Azeite de Oliva , Óleos de Plantas , Análise de Regressão , Inquéritos e Questionários , Vinho
6.
NPJ Parkinsons Dis ; 10(1): 58, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38480700

RESUMO

Characterization of Parkinson's disease (PD) progression using real-world evidence could guide clinical trial design and identify subpopulations. Efforts to curate research populations, the increasing availability of real-world data, and advances in natural language processing, particularly large language models, allow for a more granular comparison of populations than previously possible. This study includes two research populations and two real-world data-derived (RWD) populations. The research populations are the Harvard Biomarkers Study (HBS, N = 935), a longitudinal biomarkers cohort study with in-person structured study visits; and Fox Insights (N = 36,660), an online self-survey-based research study of the Michael J. Fox Foundation. Real-world cohorts are the Optum Integrated Claims-electronic health records (N = 157,475), representing wide-scale linked medical and claims data and de-identified data from Mass General Brigham (MGB, N = 22,949), an academic hospital system. Structured, de-identified electronic health records data at MGB are supplemented using a manually validated natural language processing with a large language model to extract measurements of PD progression. Motor and cognitive progression scores change more rapidly in MGB than HBS (median survival until H&Y 3: 5.6 years vs. >10, p < 0.001; mini-mental state exam median decline 0.28 vs. 0.11, p < 0.001; and clinically recognized cognitive decline, p = 0.001). In real-world populations, patients are diagnosed more than eleven years later (RWD mean of 72.2 vs. research mean of 60.4, p < 0.001). After diagnosis, in real-world cohorts, treatment with PD medications has initiated an average of 2.3 years later (95% CI: [2.1-2.4]; p < 0.001). This study provides a detailed characterization of Parkinson's progression in diverse populations. It delineates systemic divergences in the patient populations enrolled in research settings vs. patients in the real-world. These divergences are likely due to a combination of selection bias and real population differences, but exact attribution of the causes is challenging. This study emphasizes a need to utilize multiple data sources and to diligently consider potential biases when planning, choosing data sources, and performing downstream tasks and analyses.

7.
medRxiv ; 2024 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-38405736

RESUMO

Characterization of Parkinson's disease (PD) progression using real-world evidence could guide clinical trial design and identify subpopulations. Efforts to curate research populations, the increasing availability of real-world data and recent advances in natural language processing, particularly large language models, allow for a more granular comparison of populations and the methods of data collection describing these populations than previously possible. This study includes two research populations and two real-world data derived (RWD) populations. The research populations are the Harvard Biomarkers Study (HBS, N = 935), a longitudinal biomarkers cohort study with in-person structured study visits; and Fox Insights (N = 36,660), an online self-survey-based research study of the Michael J. Fox Foundation. Real-world cohorts are the Optum Integrated Claims-electronic health records (N = 157,475), representing wide-scale linked medical and claims data and de-identified data from Mass General Brigham (MGB, N = 22,949), an academic hospital system. Structured, de-identified electronic health records data at MGB are supplemented using natural language processing with a large language model to extract measurements of PD progression. This extraction process is manually validated for accuracy. Motor and cognitive progression scores change more rapidly in MGB than HBS (median survival until H&Y 3: 5.6 years vs. >10, p<0.001; mini-mental state exam median decline 0.28 vs. 0.11, p<0.001; and clinically recognized cognitive decline, p=0.001). In the real-world populations, patients are diagnosed more than eleven years later (RWD mean of 72.2 vs. research mean of 60.4, p<0.001). After diagnosis, in real-world cohorts, treatment with PD medications is initiated 2.3 years later on average (95% CI: [2.1-2.4]; p<0.001). This study provides a detailed characterization of Parkinson's progression in diverse populations. It delineates systemic divergences in the patient populations enrolled in research settings vs. patients in the real world. These divergences are likely due to a combination of selection bias and real population differences, but exact attribution of the causes is challenging using existing data. This study emphasizes a need to utilize multiple data sources and to diligently consider potential biases when planning, choosing data sources, and performing downstream tasks and analyses.

8.
Mar Environ Res ; 177: 105617, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35452902

RESUMO

Marine ecosystems are subject to global and local impacts, both contributing to dramatic changes in coastal communities. Assessing such changes requires time series or the revisitation of sites first surveyed in the past. In both cases, data are not necessarily collected by the same observers, which could lead to a bias in the results. In the Marine Protected Area (MPA) of Capo Carbonara (Sardinia, Italy), established in 1998, rocky reef communities were first assessed in 2000 by two diving scientists. Twenty years later, the same rocky reefs were resurveyed using the same method by two other diving scientists. In both surveys, semi-quantitative data on conspicuous species were collected at five sites in four depth zones, providing the possibility of assessing change over time. To explore the influence of climate and local pressures, existing data on sea surface temperature, resident population, tourism and diving activities were analysed. The reef communities of the Capo Carbonara MPA have distinctly changed over time, mostly under the effect of seawater warming, as highlighted by the occurrence of thermophilic species and by other climate-related indicators. On the other side, species vulnerable to local human pressures have increased over time, demonstrating the effectiveness of the protection measures undertaken by the MPA. Comparing data collected by four different observers in the two periods demonstrated that change over time was significantly greater than variability between the observers.


Assuntos
Antozoários , Ecossistema , Animais , Clima , Mudança Climática , Conservação dos Recursos Naturais , Recifes de Corais , Humanos , Itália , Água do Mar
9.
PeerJ ; 10: e12971, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35282273

RESUMO

Background: Marine protected areas (MPAs) usually have both positive effects of protection for the fisheries' target species and indirect negative effects for sea urchins. Moreover, often in MPAs sea urchin human harvest is restricted, but allowed. This study is aimed at estimating the effect of human harvest of the sea urchin Paracentrotus lividus within MPAs, where fish exploitation is restricted and its density is already controlled by a higher natural predation risk. The prediction we formulated was that the lowest densities of commercial sea urchins would be found where human harvest is allowed and where the harvest is restricted, compared to where the harvest is forbidden. Methods: At this aim, a collaborative database gained across five MPAs in Sardinia (Western Mediterranean, Italy) and areas outside was gathered collecting sea urchin abundance and size data in a total of 106 sites at different degrees of sea urchin exploitation: no, restricted and unrestricted harvest sites (NH, RH and UH, respectively). Furthermore, as estimates made in past monitoring efforts (since 2005) were available for 75 of the sampled sites, for each of the different levels of exploitation, the rate of variation in the total sea urchin density was also estimated. Results: Results have highlighted that the lowest sea urchin total and commercial density was found in RH sites, likely for the cumulative effects of human harvest and natural predation. The overall rate of change in sea urchin density over time indicates that only NH conditions promoted the increase of sea urchin abundance and that current local management of the MPAs has driven towards an important regression of populations, by allowing the harvest. Overall, results suggest that complex mechanisms, including synergistic effects between natural biotic interactions and human pressures, may occur on sea urchin populations and the assessment of MPA effects on P. lividus populations would be crucial to guide management decisions on regulating harvest permits. Overall, the need to ban sea urchin harvest in the MPAs to avoid extreme reductions is encouraged, as inside the MPAs sea urchin populations are likely under natural predation pressures for the trophic upgrading.


Assuntos
Conservação dos Recursos Naturais , Paracentrotus , Animais , Humanos , Conservação dos Recursos Naturais/métodos , Paracentrotus/fisiologia , Peixes/fisiologia , Dinâmica Populacional , Itália
10.
PeerJ ; 8: e10544, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362978

RESUMO

BACKGROUND: The Mediterranean subpopulation of fin whale Balaenoptera physalus (Linnaeus, 1758) has recently been listed as Vulnerable by the IUCN Red List of threatened species. The species is also listed as species in need of strict protection under the Habitat Directive and is one of the indicators for the assessment of Good Environmental Status under the MSFD. Reference values on population abundance and trends are needed in order to set the threshold values and to assess the conservation status of the population. METHODS: Yearly summer monitoring using ferries as platform of opportunity was performed since 2008 within the framework of the FLT Med Network. Data were collected along several fixed transects crossing the Western Mediterranean basin and the Adriatic and Ionian region. Species presence, expressed by density recorded along the sampled transects, was inspected for assessing interannual variability together with group size. Generalized Additive Models were used to describe density trends over a 11 years' period (2008-2018). A spatial multi-scale approach was used to highlight intra-basin differences in species presence and distribution during the years. RESULTS: Summer presence of fin whales in the western Mediterranean area showed a strong interannual variability, characterized by the alternance of rich and poor years. Small and large groups of fin whales were sighted only during rich years, confirming the favorable feeding condition influencing species presence. Trends highlighted by the GAM can be summarized as positive from 2008 to 2013, and slightly negative from 2014 to 2018. The sub-areas analysis showed a similar pattern, but with a more stable trend during the second period in the Pelagos Sanctuary sub-area, and a negative one in the other two sub-areas. Our findings further confirm the need for an integrated approach foreseeing both, large scale surveys and yearly monitoring at different spatial scales to correct and interpret the basin wide abundance estimates, and to correlate spatial and temporal trends with the ecological and anthropogenic drivers.

11.
Diabetes ; 68(1): 207-219, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352878

RESUMO

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/genética , Cardiopatias/diagnóstico por imagem , Cardiopatias/genética , Imageamento por Ressonância Magnética/métodos , Adiposidade/genética , Adiposidade/fisiologia , Adulto , Idoso , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Cardiopatias/fisiopatologia , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/genética , Hipertensão/fisiopatologia , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Obesidade/genética , Obesidade/fisiopatologia , Relação Cintura-Quadril
12.
J Am Heart Assoc ; 4(1): e001521, 2015 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-25622599

RESUMO

BACKGROUND: Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment. METHODS AND RESULTS: We conducted a genome-wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study is a double-blind, placebo-controlled cross-over study where each subject received amlodipine, bisoprolol,hydrochlorothiazide, and losartan, each as a monotherapy, in a randomized order. Replication analyses were performed in 4 studies with patients of European ancestry (PEAR Study, N=386; GERA I and II Studies, N=196 and N=198; SOPHIA Study, N=372). We identified 3 single-nucleotide polymorphisms within the ACY3 gene that showed associations with bisoprolol response reaching genome-wide significance (P<5x10(-8))however, this could not be replicated in the PEAR Study using atenolol. In addition, 39 single-nucleotide polymorphisms showed P values of 10(-5) to 10(-7). The 20 top-associated single-nucleotide polymorphisms were different for each antihypertensive drug. None of these top single-nucleotide polymorphisms co-localized with the panel of >40 genes identified in genome-wide association studies of hypertension. Replication analyses of GENRES results provided suggestive evidence for a missense variant (rs3814995) in the NPHS1 (nephrin) gene influencing losartan response, and for 2 variants influencing hydrochlorothiazide response, located within or close to the ALDH1A3 (rs3825926) and CLIC5 (rs321329) genes. CONCLUSIONS: These data provide some evidence for a link between biology of the glomerular protein nephrin and antihypertensive action of angiotensin receptor antagonists and encourage additional studies on aldehyde dehydrogenase­mediated reactions in antihypertensive drug action.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/genética , Proteínas de Membrana/genética , Farmacogenética/métodos , Adulto , Aldeído Oxirredutases/genética , Anlodipino/uso terapêutico , Anti-Hipertensivos/farmacologia , Benzimidazóis/uso terapêutico , Compostos de Bifenilo , Bisoprolol/uso terapêutico , Monitorização Ambulatorial da Pressão Arterial , Canais de Cloreto/genética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Hipertensão Essencial , Finlândia , Estudo de Associação Genômica Ampla , Humanos , Hidroclorotiazida/uso terapêutico , Hipertensão/diagnóstico , Losartan/uso terapêutico , Masculino , Metanálise como Assunto , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Tetrazóis/uso terapêutico , Resultado do Tratamento
13.
J Hypertens ; 33(6): 1301-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25695618

RESUMO

BACKGROUND: Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects. METHODS AND RESULTS: We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2. CONCLUSION: This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study.


Assuntos
Anti-Hipertensivos/uso terapêutico , Proteínas de Ligação a DNA/genética , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Adulto , Idoso , Aldosterona/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Estudos de Casos e Controles , Dioxigenases , Hipertensão Essencial , Estudo de Associação Genômica Ampla , Humanos , Itália , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Farmacogenética , Sístole/genética , Proteínas Supressoras de Tumor , População Branca
14.
PLoS One ; 9(3): e91237, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24651212

RESUMO

The peculiar position of Sardinia in the Mediterranean sea has rendered its population an interesting biogeographical isolate. The aim of this study was to investigate the genetic population structure, as well as to estimate Runs of Homozygosity and regions under positive selection, using about 1.2 million single nucleotide polymorphisms genotyped in 1077 Sardinian individuals. Using four different methods--fixation index, inflation factor, principal component analysis and ancestry estimation--we were able to highlight, as expected for a genetic isolate, the high internal homogeneity of the island. Sardinians showed a higher percentage of genome covered by RoHs>0.5 Mb (F(RoH%0.5)) when compared to peninsular Italians, with the only exception of the area surrounding Alghero. We furthermore identified 9 genomic regions showing signs of positive selection and, we re-captured many previously inferred signals. Other regions harbor novel candidate genes for positive selection, like TMEM252, or regions containing long non coding RNA. With the present study we confirmed the high genetic homogeneity of Sardinia that may be explained by the shared ancestry combined with the action of evolutionary forces.


Assuntos
Genoma Humano/genética , Seleção Genética , Pareamento de Bases/genética , Geografia , Homozigoto , Humanos , Endogamia , Itália , Mar Mediterrâneo , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal , Software
15.
Pharmacogenomics ; 15(13): 1643-52, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25410890

RESUMO

BACKGROUND: Essential hypertension arises from the combined effect of genetic and environmental factors. A pharmacogenomics approach could help to identify additional molecular mechanisms involved in its pathogenesis. AIM: The aim of SOPHIA study was to identify genetic polymorphisms regulating blood pressure response to the angiotensin II receptor blocker, losartan, with a whole-genome approach. MATERIALS & METHODS: We performed a genome-wide association study on blood pressure response in 372 hypertensives treated with losartan and we looked for replication in two independent samples. RESULTS: We identified a peak of association in CAMK1D gene (rs10752271, effect size -5.5 ± 0.94 mmHg, p = 1.2 × 10(-8)). CAMK1D encodes a protein that belongs to the regulatory pathway involved in aldosterone synthesis. We tested the specificity of rs10752271 for losartan in hypertensives treated with hydrochlorothiazide and we validated it in silico in the GENRES cohort. CONCLUSION: Using a genome-wide approach, we identified the CAMK1D gene as a novel locus associated with blood pressure response to losartan. CAMK1D gene characterization may represent a useful tool to personalize the treatment of essential hypertension.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/genética , Estudo de Associação Genômica Ampla , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Humanos , Hidroclorotiazida/uso terapêutico , Hipertensão/genética , Hipertensão/fisiopatologia , Losartan/farmacologia , Masculino , Pessoa de Meia-Idade
16.
Hypertension ; 62(5): 844-52, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24019403

RESUMO

A case-control study revealed association between hypertension and rs3918226 in the endothelial nitric oxide synthase (eNOS) gene promoter (minor/major allele, T/C allele). We aimed at substantiating these preliminary findings by target sequencing, cell experiments, and a population study. We sequenced the 140-kb genomic area encompassing the eNOS gene. In HeLa and HEK293T cells transfected with the eNOS promoter carrying either the T or the C allele, we quantified transcription by luciferase assay. In 2722 randomly recruited Europeans (53.0% women; mean age 40.1 years), we studied blood pressure change and incidence of hypertension in relation to rs3918226, using multivariable-adjusted models. Sequencing confirmed rs3918226, a binding site of E-twenty six transcription factors, as the single nucleotide polymorphism most closely associated with hypertension. In T compared with C transfected cells, eNOS promoter activity was from 20% to 40% (P<0.01) lower. In the population, systolic/diastolic blood pressure increased over 7.6 years (median) by 9.7/6.8 mm Hg in 28 TT homozygotes and by 3.8/1.9 mm Hg in 2694 C allele carriers (P≤0.0004). The blood pressure rise was 5.9 mm Hg systolic (confidence interval [CI], 0.6-11.1; P=0.028) and 4.8 mm Hg diastolic (CI, 1.5-8.2; P=0.0046) greater in TT homozygotes, with no differences between the CT and CC genotypes (P≥0.90). Among 2013 participants normotensive at baseline, 692 (34.4%) developed hypertension. The hazard ratio and attributable risk associated with TT homozygosity were 2.04 (CI, 1.24-3.37; P=0.0054) and 51.0%, respectively. In conclusion, rs3918226 in the eNOS promoter tags a hypertension susceptibility locus, TT homozygosity being associated with lesser transcription and higher risk of hypertension.


Assuntos
Pressão Sanguínea/genética , Predisposição Genética para Doença , Hipertensão/genética , Óxido Nítrico Sintase Tipo III/genética , Regiões Promotoras Genéticas , Adulto , Alelos , Estudos de Casos e Controles , Endotélio Vascular/fisiopatologia , Feminino , Genótipo , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , População Branca/genética
17.
PLoS One ; 7(9): e43759, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22984441

RESUMO

In spite of the common belief of Europe as reasonably homogeneous at genetic level, advances in high-throughput genotyping technology have resolved several gradients which define different geographical areas with good precision. When Northern and Southern European groups were considered separately, there were clear genetic distinctions. Intra-country genetic differences were also evident, especially in Finland and, to a lesser extent, within other European populations. Here, we present the first analysis using the 125,799 genome-wide Single Nucleotide Polymorphisms (SNPs) data of 1,014 Italians with wide geographical coverage. We showed by using Principal Component analysis and model-based individual ancestry analysis, that the current population of Sardinia can be clearly differentiated genetically from mainland Italy and Sicily, and that a certain degree of genetic differentiation is detectable within the current Italian peninsula population. Pair-wise F(ST) statistics Northern and Southern Italy amounts approximately to 0.001 between, and around 0.002 between Northern Italy and Utah residents with Northern and Western European ancestry (CEU). The Italian population also revealed a fine genetic substructure underscoring by the genomic inflation (Sardinia vs. Northern Italy = 3.040 and Northern Italy vs. CEU = 1.427), warning against confounding effects of hidden relatedness and population substructure in association studies.


Assuntos
Bases de Dados Genéticas , Genética Populacional , Genoma Humano/genética , Estudo de Associação Genômica Ampla , População Negra , Análise por Conglomerados , Genealogia e Heráldica , Humanos , Itália , Oriente Médio , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Software , População Branca/genética
18.
Hypertension ; 59(2): 248-55, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22184326

RESUMO

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.


Assuntos
Predisposição Genética para Doença/genética , Hipertensão/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipertensão/etnologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
19.
PLoS One ; 6(5): e19620, 2011 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-21573014

RESUMO

The importance of excess salt intake in the pathogenesis of hypertension is widely recognized. Blood pressure is controlled primarily by salt and water balance because of the infinite gain property of the kidney to rapidly eliminate excess fluid and salt. Up to fifty percent of patients with essential hypertension are salt-sensitive, as manifested by a rise in blood pressure with salt loading. We conducted a two-stage genetic analysis in hypertensive patients very accurately phenotyped for their salt-sensitivity. All newly discovered never treated before, essential hypertensives underwent an acute salt load to monitor the simultaneous changes in blood pressure and renal sodium excretion. The first stage consisted in an association analysis of genotyping data derived from genome-wide array on 329 subjects. Principal Component Analysis demonstrated that this population was homogenous. Among the strongest results, we detected a cluster of SNPs located in the first introns of PRKG1 gene (rs7897633, p = 2.34E-05) associated with variation in diastolic blood pressure after acute salt load. We further focused on two genetic loci, SLC24A3 and SLC8A1 (plasma membrane sodium/calcium exchange proteins, NCKX3 and NCX1, respectively) with a functional relationship with the previous gene and associated to variations in systolic blood pressure (the imputed rs3790261, p = 4.55E-06; and rs434082, p = 4.7E-03). In stage 2, we characterized 159 more patients for the SNPs in PRKG1, SLC24A3 and SLC8A1. Combined analysis showed an epistatic interaction of SNPs in SLC24A3 and SLC8A1 on the pressure-natriuresis (p interaction = 1.55E-04, p model = 3.35E-05), supporting their pathophysiological link in cellular calcium homeostasis. In conclusions, these findings point to a clear association between body sodium-blood pressure relations and molecules modulating the contractile state of vascular cells through an increase in cytoplasmic calcium concentration.


Assuntos
Hipertensão/genética , Hipertensão/fisiopatologia , Cloreto de Sódio na Dieta/farmacologia , Vasoconstrição/genética , Vasodilatação/genética , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Natriurese/genética , Polimorfismo de Nucleotídeo Único/genética , Cloreto de Sódio na Dieta/administração & dosagem , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
20.
Pharmacogenomics ; 11(3): 319-25, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20235788

RESUMO

AIMS: To analyze the association of haplotypes of the adrenergic system with essential hypertension and with the blood pressure response to beta-blockers. MATERIALS & METHODS: In 1112 never-treated essential hypertension patients and 203 normotensive controls, tightly linked SNPs of beta-adrenergic receptors (ADRB1 - Ser49Gly and Arg389Gly; ADRB2 - Cys19Arg, Gly16Arg and Gln27Glu) and the G-protein beta3-subunit (GNB3 - A3882C, G5249A and C825T) were genotyped. Association of haplotypes with essential hypertension and with the blood pressure response to atenolol 50 mg twice daily in a subgroup of essential hypertension patients (n = 340) was evaluated (Haploview 3.2). RESULTS: No SNPs or haplotypes were associated with essential hypertension. In females only, GNB3 SNPs and haplotypes were associated with the blood pressure response (p < 0.05). CONCLUSION: Our study confirmed the sex-specific association of GNB3 with the blood pressure response to atenolol with no substantial advantage of the analysis of haplotypes over SNPs.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Haplótipos , Proteínas Heterotriméricas de Ligação ao GTP/genética , Hipertensão/tratamento farmacológico , Hipertensão/genética , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Adulto , Idoso , Atenolol/farmacologia , Sequência de Bases , Estudos de Casos e Controles , Primers do DNA/genética , Feminino , Estudos de Associação Genética , Humanos , Hipertensão/fisiopatologia , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo Único
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