RESUMEN
Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.
Asunto(s)
Sitios Genéticos , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Cromosomas Humanos , Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular/metabolismo , Población Blanca/genéticaRESUMEN
Cripto, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-ß, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. Cripto is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the CRIPTO gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides CRIPTO, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5'UTR of CRIPTO gene which is able to strongly modulate CRIPTO expression through an AP-1-mediate transcriptional regulation.
Asunto(s)
Proliferación Celular/genética , Proteínas Ligadas a GPI/genética , Estudio de Asociación del Genoma Completo , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Adulto , Anciano , Movimiento Celular/genética , Desarrollo Embrionario/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Proteínas Ligadas a GPI/sangre , Regulación de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Italia , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Neoplasias/sangre , Factor de Transcripción AP-1/genética , Factor de Crecimiento Transformador betaRESUMEN
Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
Asunto(s)
Exoma/genética , Tasa de Filtración Glomerular/genética , Riñón/embriología , Proteínas Tirosina Fosfatasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Son Of Sevenless/genética , Animales , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Pez CebraRESUMEN
Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
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Plaquetas/citología , Hematopoyesis/genética , Megacariocitos/citología , Animales , Plaquetas/metabolismo , Tamaño de la Célula , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Europa (Continente) , Perfilación de la Expresión Génica , Silenciador del Gen , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Humanos , Megacariocitos/metabolismo , Recuento de Plaquetas , Mapas de Interacción de Proteínas , Transcripción Genética/genética , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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Huesos/metabolismo , Calcio/sangre , Estudio de Asociación del Genoma Completo , Homeostasis/genética , Animales , Densidad Ósea/genética , Regulación de la Expresión Génica , Humanos , Riñón/metabolismo , Ratones , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Asunto(s)
Estudio de Asociación del Genoma Completo , Tasa de Filtración Glomerular/genética , Fallo Renal Crónico/genética , Riñón/fisiopatología , Pez Cebra/genética , ATPasas Asociadas con Actividades Celulares Diversas , Negro o Afroamericano/genética , Anciano , Animales , Caspasa 9/genética , Quinasas Ciclina-Dependientes/genética , ARN Helicasas DEAD-box/genética , ADN Helicasas/genética , Proteínas de Unión al ADN , Femenino , Estudios de Seguimiento , Técnicas de Silenciamiento del Gen , Humanos , Fallo Renal Crónico/patología , Masculino , Persona de Mediana Edad , Hidrolasas Diéster Fosfóricas/genética , Población Blanca/genéticaRESUMEN
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple/genética , Sistemas de Transporte de Aminoácidos Básicos/genética , Cadena Pesada de la Proteína-1 Reguladora de Fusión/genética , Predisposición Genética a la Enfermedad/genética , Tasa de Filtración Glomerular/genética , Tasa de Filtración Glomerular/fisiología , Humanos , Subunidades beta de Inhibinas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteínas de la Membrana/genéticaRESUMEN
Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
Asunto(s)
Variación Genética , Riñón/fisiología , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Insuficiencia Renal Crónica/genética , Población Blanca/genética , Bases de Datos Genéticas , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Humanos , FenotipoRESUMEN
BACKGROUND: Hearing is a complex trait, but until now only a few genes are known to contribute to variability of this process. In order to discover genes and pathways that underlie auditory function, a genome-wide association study was carried out within the International Consortium G-EAR. METHODS: Meta-analysis of genome-wide association study's data from six isolated populations of European ancestry for an overall number of 3417 individuals. RESULTS: Eight suggestive significant loci (p<10(-7)) were detected with a series of genes expressed within the inner ear such as: DCLK1, PTPRD, GRM8, CMIP. Additional biological candidates marked by a single nucleotide polymorphism (SNP) with a suggestive association (p<10(-6)) were identified, as well as loci encompassing 'gene desert regions'-genes of unknown function or genes whose function has not be linked to hearing so far. Some of these new loci map to already known hereditary hearing loss loci whose genes still need to be identified. Data have also been used to construct a highly significant 'in silico' pathway for hearing function characterised by a network of 49 genes, 34 of which are certainly expressed in the ear. CONCLUSION: These results provide new insights into the molecular basis of hearing function and may suggest new targets for hearing impairment treatment and prevention.
Asunto(s)
Efecto Fundador , Estudio de Asociación del Genoma Completo/métodos , Pérdida Auditiva/genética , Audición/genética , Población Blanca/genética , Proteínas Adaptadoras Transductoras de Señales , Animales , Umbral Auditivo , Proteínas Portadoras/genética , Bases de Datos Genéticas , Quinasas Similares a Doblecortina , Europa (Continente)/epidemiología , Femenino , Ligamiento Genético , Pérdida Auditiva/etnología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones , Fenotipo , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Receptores de Glutamato Metabotrópico/genéticaRESUMEN
Gingival recessions (GR) are often associated with the presence of non-carious cervical lesions (NCCL). The latter result in the disappearance of the cement-enamel junction (CEJ), with consequent difficulties both in measuring the recession itself and in performing root coverage techniques. The restoration of cervical lesions is consequently an important aspect in the treatment of GR, with the re-establishment of a "new" CEJ. This pilot study aimed to verify whether restorative therapy alone, with the execution of a restoration that mimics the convexity of the natural CEJ and thanks to a slight horizontal over-contour, can stabilize a clot in the intrasulcular site and consequently is able to change the position of the gingival margin in a coronal direction. In periodontally healthy patients, with a non-thin gingival phenotype, 10 GR-associated NCCL restorations were performed using a protocol inspired by concepts of prosthetic conditioning, with a progressively reduced convexity ("coronally dynamic restoration") and de-epithelialization of the gingival sulcus. We observed that 70% of the treated teeth showed a reduction in crown length after 15 days (-0.267 mm), without an increase in probing depth. While considering the limitations of the sample and the need to evaluate the different parameters that can affect the result, the coronally dynamic restoration of NCCL with GR was able to influence the position of the gingival margin in a coronal direction.
RESUMEN
Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10-56) and SLC2A9 (p = 4.5 × 10-7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10-3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.
Asunto(s)
Exoma/genética , Ácido Úrico/sangre , Predisposición Genética a la Enfermedad , Proteínas Facilitadoras del Transporte de la Glucosa/química , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Pruebas de Función Renal , Metaanálisis como Asunto , Transportadores de Anión Orgánico/química , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/química , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Estructura Secundaria de ProteínaRESUMEN
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.
Asunto(s)
Albuminuria/genética , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Túbulos Renales/metabolismo , Adulto , Anciano , Albuminuria/etiología , Animales , Catepsina C/genética , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/etiología , Femenino , Técnicas de Inactivación de Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Ratas , Receptores de Superficie Celular/genética , Sulfotransferasas/genética , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismoRESUMEN
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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Predisposición Genética a la Enfermedad , Insuficiencia Renal Crónica/genética , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , HumanosRESUMEN
BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
Asunto(s)
Cardiomegalia/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Animales , HumanosRESUMEN
BACKGROUND AND OBJECTIVES: Although several studies demonstrated that platelet count is higher in women, decreases with age, and is influenced by genetic background, most clinical laboratories still use the reference interval 150-400×10(9) platelets/L for all subjects. The present study was to identify age- and sex-specific reference intervals for platelet count. METHODS: We analysed electronic records of subjects enrolled in three population-based studies that investigated inhabitants of seven Italian areas including six geographic isolates. After exclusion of patients with malignancies, liver diseases, or inherited thrombocytopenias, which could affect platelet count, reference intervals were estimated from 40,987 subjects with the non parametric method computing the 2.5° and 97.5° percentiles. RESULTS: Platelet count was similar in men and women until the age of 14, but subsequently women had steadily more platelets than men. The number of platelets decreases quickly in childhood, stabilizes in adulthood, and further decreases in oldness. The final result of this phenomenon is that platelet count in old age was reduced by 35% in men and by 25% in women compared with early infancy. Based on these findings, we estimated reference intervals for platelet count ×10(9)/L in children (176-452), adult men (141-362), adult women (156-405), old men (122-350) and, old women (140-379). Moreover, we calculated an "extended" reference interval that takes into account the differences in platelet count observed in different geographic areas. CONCLUSIONS: The age-, sex-, and origin-related variability of platelet count is very wide, and the patient-adapted reference intervals we propose change the thresholds for diagnosing both thrombocytopenia and thrombocytosis in Italy.
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Plaquetas/citología , Recuento de Plaquetas , Trombocitopenia/diagnóstico , Trombocitosis/diagnóstico , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Italia , Masculino , Persona de Mediana Edad , Recuento de Plaquetas/métodos , Recuento de Plaquetas/normas , Valores de Referencia , Factores Sexuales , Trombocitopenia/sangre , Trombocitosis/sangre , Población BlancaRESUMEN
OBJECTIVES: Childhood obesity is associated with an increased risk of atherosclerosis, which can be mediated by an increase in angiogenesis and inflammation. The objective was to investigate the association between body mass index (BMI) and circulating biomarkers of angiogenesis, inflammation, and cardiac dysfunction in children and adolescents. METHODS: The Genetic Park Study is a highly inclusive survey conducted in three isolated villages of southern Italy. One hundred fifty-one children and adolescents (age range 5-17 y, 45% male) were included and categorized as obese (BMI z-score ≥ 1.64, n = 38) or non-obese (n = 113). Metabolic and cardiovascular biomarkers included glucose, triacylglycerol, total cholesterol, high-density lipoprotein, vascular endothelial growth factor (VEGF), placental growth factor, soluble feline sarcoma virus (fms)-like tyrosine kinase-1, highly sensitive C reactive protein (hs-CRP), highly sensitive troponin T (hs-TnT), and N-terminal prohormone brain natriuretic peptide (NT-proBNP). RESULTS: Obese subjects had higher levels of triacylglycerol (P = 0.03) and hs-CRP (P = 0.02) after adjustment for age and gender. Circulating levels of VEGF were directly associated with BMI z-score (r = 0.22, P = 0.007) and hs-CRP (r = 0.33, P < 0.001). BMI z-score was not associated with biomarkers of cardiac dysfunction (hs-TnT and NT-proBNP). CONCLUSION: Increasing BMI was associated with plasma levels hs-CRP and VEGF, which are involved in the initiation and progression of atherosclerosis. The lack of association between BMI and markers of cardiac damage (hs-TnT) or ventricular volume overload (NT-proBNP) suggest that atherosclerotic risk may still at a preclinical stage in this population of obese but otherwise healthy young individuals. Collectively, this suite of biomarkers could provide mechanistic insights into the physiopathologic progression of cardiovascular risk associated with childhood obesity.
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Biomarcadores/sangre , Índice de Masa Corporal , Inflamación/sangre , Neovascularización Patológica/sangre , Adolescente , Composición Corporal , Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Niño , Preescolar , Colesterol/sangre , Estudios Transversales , Femenino , Humanos , Inflamación/fisiopatología , Entrevistas como Asunto , Italia , Lipoproteínas HDL/sangre , Masculino , Péptido Natriurético Encefálico/sangre , Obesidad/fisiopatología , Factores de Riesgo , Triglicéridos/sangre , Troponina T/sangre , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Placental Growth Factor (PGF) is a key molecule in angiogenesis. Several studies have revealed an important role of PGF primarily in pathological conditions (e.g.: ischaemia, tumour formation, cardiovascular diseases and inflammatory processes) suggesting its use as a potential therapeutic agent. However, to date, no information is available regarding the genetics of PGF variability. Furthermore, even though the effect of environmental factors (e.g.: cigarette smoking) on angiogenesis has been explored, no data on the influence of these factors on PGF levels have been reported so far. Here we have first investigated PGF variability in two cohorts focusing on non-genetic risk factors: a study sample from two isolated villages in the Cilento region, South Italy (N=871) and a replication sample from the general Danish population (N=1,812). A significant difference in PGF mean levels was found between the two cohorts. However, in both samples, we observed a strong correlation of PGF levels with ageing and sex, men displaying PGF levels significantly higher than women. Interestingly, smoking was also found to influence the trait in the two populations, although differently. We have then focused on genetic risk factors. The association between five single nucleotide polymorphisms (SNPs) located in the PGF gene and the plasma levels of the protein was investigated. Two polymorphisms (rs11850328 and rs2268614) were associated with the PGF plasma levels in the Cilento sample and these associations were strongly replicated in the Danish sample. These results, for the first time, support the hypothesis of the presence of genetic and environmental factors influencing PGF plasma variability.
Asunto(s)
Genética de Población , Proteínas Gestacionales/genética , Dinamarca , Femenino , Genotipo , Humanos , Masculino , Factor de Crecimiento Placentario , Polimorfismo de Nucleótido Simple , Control de CalidadRESUMEN
Vascular Endothelial Growth Factor (VEGF) is the main player in angiogenesis. Because of its crucial role in this process, the study of the genetic factors controlling VEGF variability may be of particular interest for many angiogenesis-associated diseases. Although some polymorphisms in the VEGF gene have been associated with a susceptibility to several disorders, no genome-wide search on VEGF serum levels has been reported so far. We carried out a genome-wide linkage analysis in three isolated populations and we detected a strong linkage between VEGF serum levels and the 6p21.1 VEGF region in all samples. A new locus on chromosome 3p26.3 significantly linked to VEGF serum levels was also detected in a combined population sample. A sequencing of the gene followed by an association study identified three common single nucleotide polymorphisms (SNPs) influencing VEGF serum levels in one population (Campora), two already reported in the literature (rs3025039, rs25648) and one new signal (rs3025020). A fourth SNP (rs41282644) was found to affect VEGF serum levels in another population (Cardile). All the identified SNPs contribute to the related population linkages (35% of the linkage explained in Campora and 15% in Cardile). Interestingly, none of the SNPs influencing VEGF serum levels in one population was found to be associated in the two other populations. These results allow us to exclude the hypothesis that the common variants located in the exons, intron-exon junctions, promoter and regulative regions of the VEGF gene may have a causal effect on the VEGF variation. The data support the alternative hypothesis of a multiple rare variant model, possibly consisting in distinct variants in different populations, influencing VEGF serum levels.
Asunto(s)
Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Cromosomas Humanos Par 6/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Italia , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/diagnóstico , Neoplasias/genética , PronósticoRESUMEN
Large-scale population studies have established that genetic factors contribute to individual differences in smoking behavior. Linkage and genome-wide association studies have shown many chromosomal regions and genes associated with different smoking behaviors. One study was the association of single-nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 gene cluster to nicotine addiction. Here, we report a replication of this association in the Italian population represented by three genetically isolated populations. One, the Val Borbera, is a genetic isolate from North-Western Italy; the Cilento population, is located in South-Western Italy; and the Carlantino village is located in South-Eastern Italy. Owing to their position and their isolation, the three populations have a different environment, different history and genetic structure. The variant A of the rs1051730 SNP was significantly associated with smoking quantity in two populations, Val Borbera and Cilento, no association was found in Carlantino population probably because difference in LD pattern in the variant region.
Asunto(s)
Estudio de Asociación del Genoma Completo , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Receptores Nicotínicos/genética , Fumar/genética , Tabaquismo/genética , Predisposición Genética a la Enfermedad , Humanos , Italia , Familia de MultigenesRESUMEN
OBJECTIVE: Obesity is a complex trait with a variety of genetic susceptibility variants. Several loci linked to obesity and/or obesity-related traits have been identified, and relatively few regions have been replicated. Studying isolated populations can be a useful approach to identify rare variants that will not be detected with whole-genome association studies in large populations. RESEARCH DESIGN AND METHODS: Random individuals were sampled from Campora, an isolated village of the Cilento area in South Italy, phenotyped for BMI, and genotyped using a dense microsatellite marker map. An efficient pedigree-breaking strategy was applied to perform genome-wide linkage analyses of both BMI and obesity. Significance was assessed with ad hoc simulations for the two traits and with an original local false discovery rate approach to quantitative trait linkage analysis for BMI. A genealogy-corrected association test was performed for a single nucleotide polymorphism located in one of the linkage regions. A replication study was conducted in the neighboring village of Gioi. RESULTS: A new locus on chr1q24 significantly linked to BMI was identified in Campora. Linkage at the same locus is suggested with obesity. Three additional loci linked to BMI were also detected, including the locus including the INSIG2 gene region. No evidence of association between the rs7566605 variant and BMI or obesity was found. In Gioi, the linkage on chr1q24 was replicated with both BMI and obesity. CONCLUSIONS: Overall, our results confirm that successful linkage studies can be accomplished in these populations both to replicate known linkages and to identify novel quantitative trait linkages.