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1.
Nat Genet ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

2.
Sci Rep ; 8(1): 18048, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30575761

RESUMO

Inconsistencies between published estimates of dominance heritability between studies of human genetic isolates and human outbred populations incite investigation into whether such differences result from particular trait architectures or specific population structures. We analyse simulated datasets, characteristic of genetic isolates and of unrelated individuals, before analysing the isolate of Cilento for various commonly studied traits. We show the strengths of using genetic relationship matrices for variance decomposition over identity-by-descent based methods in a population isolate and that heritability estimates in isolates will avoid the downward biases that may occur in studies of samples of unrelated individuals; irrespective of the simulated distribution of causal variants. Yet, we also show that precise estimates of dominance in isolates are demonstrably problematic in the presence of shared environmental effects and such effects should be accounted for. Nevertheless, we demonstrate how studying isolates can help determine the existence or non-existence of dominance for complex traits, and we find strong indications of non-zero dominance for low-density lipoprotein level in Cilento. Finally, we recommend future study designs to analyse trait variance decomposition from ensemble data across multiple population isolates.

3.
Nat Commun ; 9(1): 4228, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315176

RESUMO

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.

4.
Genet Epidemiol ; 42(2): 201-213, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29319195

RESUMO

In the search for genetic associations with complex traits, population isolates offer the advantage of reduced genetic and environmental heterogeneity. In addition, cost-efficient next-generation association approaches have been proposed in these populations where only a subsample of representative individuals is sequenced and then genotypes are imputed into the rest of the population. Gene mapping in such populations thus requires high-quality genetic imputation and preliminary phasing. To identify an effective study design, we compare by simulation a range of phasing and imputation software and strategies. We simulated 1,115,604 variants on chromosome 10 for 477 members of the large complex pedigree of Campora, a village within the established isolate of Cilento in southern Italy. We assessed the phasing performance of identical by descent based software ALPHAPHASE and SLRP, LD-based software SHAPEIT2, SHAPEIT3, and BEAGLE, and new software EAGLE that combines both methodologies. For imputation we compared IMPUTE2, IMPUTE4, MINIMAC3, BEAGLE, and new software PBWT. Genotyping errors and missing genotypes were simulated to observe their effects on the performance of each software. Highly accurate phased data were achieved by all software with SHAPEIT2, SHAPEIT3, and EAGLE2 providing the most accurate results. MINIMAC3, IMPUTE4, and IMPUTE2 all performed strongly as imputation software and our study highlights the considerable gain in imputation accuracy provided by a genome sequenced reference panel specific to the population isolate.


Assuntos
Efeito Fundador , Genética Populacional , Haplótipos/genética , Projetos de Pesquisa , Software , Algoritmos , Cromossomos Humanos Par 10/genética , Feminino , Genoma Humano/genética , Humanos , Itália , Desequilíbrio de Ligação/genética , Masculino , Modelos Genéticos , Linhagem , Fenótipo
7.
Sci Rep ; 7: 45040, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28452372

RESUMO

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.


Assuntos
Biologia Computacional/métodos , Loci Gênicos , Rim/fisiologia , Frequência do Gene , Genoma Humano , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Polimorfismo de Nucleotídeo Único
8.
PLoS Genet ; 12(2): e1005874, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26910538

RESUMO

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.


Assuntos
Loci Gênicos , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genética , Cromossomos Humanos , Grupo com Ancestrais do Continente Europeu/genética , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Hum Mol Genet ; 24(19): 5655-64, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26188009

RESUMO

Hearing loss and individual differences in normal hearing both have a substantial genetic basis. Although many new genes contributing to deafness have been identified, very little is known about genes/variants modulating the normal range of hearing ability. To fill this gap, we performed a two-stage meta-analysis on hearing thresholds (tested at 0.25, 0.5, 1, 2, 4, 8 kHz) and on pure-tone averages (low-, medium- and high-frequency thresholds grouped) in several isolated populations from Italy and Central Asia (total N = 2636). Here, we detected two genome-wide significant loci close to PCDH20 and SLC28A3 (top hits: rs78043697, P = 4.71E-10 and rs7032430, P = 2.39E-09, respectively). For both loci, we sought replication in two independent cohorts: B58C from the UK (N = 5892) and FITSA from Finland (N = 270). Both loci were successfully replicated at a nominal level of significance (P < 0.05). In order to confirm our quantitative findings, we carried out RT-PCR and reported RNA-Seq data, which showed that both genes are expressed in mouse inner ear, especially in hair cells, further suggesting them as good candidates for modulatory genes in the auditory system. Sequencing data revealed no functional variants in the coding region of PCDH20 or SLC28A3, suggesting that variation in regulatory sequences may affect expression. Overall, these results contribute to a better understanding of the complex mechanisms underlying human hearing function.


Assuntos
Caderinas/genética , Estudo de Associação Genômica Ampla/métodos , Audição/fisiologia , Proteínas de Membrana Transportadoras/genética , Proteínas do Tecido Nervoso/genética , Animais , Ásia Central , Caderinas/metabolismo , Surdez/genética , Predisposição Genética para Doença , Células Ciliadas Auditivas Internas/metabolismo , Audição/genética , Humanos , Itália , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência de RNA/métodos
10.
PLoS Genet ; 11(1): e1004976, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25629528

RESUMO

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.


Assuntos
Proliferação de Células/genética , Proteínas Ligadas por GPI/genética , Estudo de Associação Genômica Ampla , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Adulto , Idoso , Movimento Celular/genética , Desenvolvimento Embrionário/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Proteínas Ligadas por GPI/sangue , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Itália , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Neoplasias/sangue , Fator de Transcrição AP-1/genética , Fator de Crescimento Transformador beta
11.
Hum Mol Genet ; 23(23): 6407-18, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25060954

RESUMO

Hearing function is known to be heritable, but few significant and reproducible associations of genetic variants have been identified to date in the adult population. In this study, genome-wide association results of hearing function from the G-EAR consortium and TwinsUK were used for meta-analysis. Hearing ability in eight population samples of Northern and Southern European ancestry (n = 4591) and the Silk Road (n = 348) was measured using pure-tone audiometry and summarized using principal component (PC) analysis. Genome-wide association analyses for PC1-3 were conducted separately in each sample assuming an additive model adjusted for age, sex and relatedness of subjects. Meta-analysis was performed using 2.3 million single-nucleotide polymorphisms (SNPs) tested against each of the three PCs of hearing ability in 4939 individuals. A single SNP lying in intron 6 of the salt-inducible kinase 3 (SIK3) gene was found to be associated with hearing PC2 (P = 3.7×10(-8)) and further supported by whole-genome sequence in a subset. To determine the relevance of this gene in the ear, expression of the Sik3 protein was studied in mouse cochlea of different ages. Sik3 was expressed in murine hair cells during early development and in cells of the spiral ganglion during early development and adulthood. Our results suggest a developmental role of Sik3 in hearing and may be required for the maintenance of adult auditory function.


Assuntos
Audição/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Fatores Etários , Animais , Cóclea/crescimento & desenvolvimento , Cóclea/metabolismo , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Humanos , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único
12.
Hum Hered ; 78(1): 27-37, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24969533

RESUMO

BACKGROUND: Linkage analysis on extended pedigrees is often challenged by the high computational demand of exact identity-by-descent (IBD) matrix reconstruction. When such an analysis becomes not feasible, two alternative solutions are contrasted: a full pedigree analysis based on approximate IBD estimation versus a pedigree splitting followed by exact IBD estimation. A multiple splitting (MS) approach, which combines linkage results across different splitting configurations, has been proposed to increase the power of single-split solutions. METHODS: To assess whether MS can achieve a comparable power to a full pedigree analysis, we compared the power of linkage on a very large pedigree in both simulated and real-case scenarios, using variance components linkage analysis of a dense SNP array. RESULTS: Our results confirm that the power to detect linkage is affected by the pedigree size. The MS approach showed higher power than the single-split analysis, but it was substantially less powerful than the full pedigree approach in both scenarios, at any level of significance and variance explained by a quantitative trait locus. CONCLUSION: The MS approach should always be preferred to analyses based on a single split but, when adequate computational resources are available, a full pedigree analysis is better than the MS analysis. Rather than focusing on how to best split a pedigree, it might be more valuable to identify computational solutions that can make the IBD estimation of dense-marker maps practically feasible, thus allowing a full pedigree analysis.


Assuntos
Mapeamento Cromossômico/métodos , Ligação Genética , Linhagem , Polimorfismo de Nucleotídeo Único , Simulação por Computador , Feminino , Genética Populacional/métodos , Genótipo , Humanos , Escore Lod , Masculino , Modelos Genéticos , Locos de Características Quantitativas/genética
13.
PLoS One ; 8(1): e54289, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23382888

RESUMO

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.


Assuntos
Plaquetas/citologia , Contagem de Plaquetas , Trombocitopenia/diagnóstico , Trombocitose/diagnóstico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Lactente , Recém-Nascido , Itália , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas/métodos , Contagem de Plaquetas/normas , Valores de Referência , Fatores Sexuais , Trombocitopenia/sangue , Trombocitose/sangue
14.
Nature ; 492(7429): 369-75, 2012 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-23222517

RESUMO

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.


Assuntos
Eritrócitos/metabolismo , Loci Gênicos , Estudo de Associação Genômica Ampla , Fenótipo , Animais , Ciclo Celular/genética , Citocinas/metabolismo , Drosophila melanogaster/genética , Eritrócitos/citologia , Feminino , Regulação da Expressão Gênica/genética , Hematopoese/genética , Hemoglobinas/genética , Humanos , Masculino , Camundongos , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único/genética , Interferência de RNA , Transdução de Sinais/genética
15.
PLoS One ; 7(8): e42537, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22916133

RESUMO

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.


Assuntos
Genética Populacional , Proteínas da Gravidez/genética , Dinamarca , Feminino , Genótipo , Humanos , Masculino , Fator de Crescimento Placentário , Polimorfismo de Nucleotídeo Único , Controle de Qualidade
16.
Am J Med Genet B Neuropsychiatr Genet ; 159B(2): 192-200, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22213687

RESUMO

Human longevity and personality traits are both heritable and are consistently linked at the phenotypic level. We test the hypothesis that candidate genes influencing longevity in lower organisms are associated with variance in the five major dimensions of human personality (measured by the NEO-FFI and IPIP inventories) plus related mood states of anxiety and depression. Seventy single nucleotide polymorphisms (SNPs) in six brain expressed, longevity candidate genes (AFG3L2, FRAP1, MAT1A, MAT2A, SYNJ1, and SYNJ2) were typed in over 1,000 70-year old participants from the Lothian Birth Cohort of 1936 (LBC1936). No SNPs were associated with the personality and psychological distress traits at a Bonferroni corrected level of significance (P < 0.0002), but there was an over-representation of nominally significant (P < 0.05) SNPs in the synaptojanin-2 (SYNJ2) gene associated with agreeableness and symptoms of depression. Eight SNPs which showed nominally significant association across personality measurement instruments were tested in an extremely large replication sample of 17,106 participants. SNP rs350292, in SYNJ2, was significant: the minor allele was associated with an average decrease in NEO agreeableness scale scores of 0.25 points, and 0.67 points in the restricted analysis of elderly cohorts (most aged >60 years). Because we selected a specific set of longevity genes based on functional genomics findings, further research on other longevity gene candidates is warranted to discover whether they are relevant candidates for personality and psychological distress traits.


Assuntos
Marcadores Genéticos/genética , Longevidade/genética , Transtornos da Personalidade/genética , Transtornos da Personalidade/psicologia , Monoéster Fosfórico Hidrolases/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Transtornos de Ansiedade/genética , Estudos de Coortes , Depressão/genética , Feminino , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos da Personalidade/diagnóstico , Testes de Personalidade , Fenótipo , Reação em Cadeia da Polimerase , Adulto Jovem
17.
Nutrition ; 28(3): 262-6, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22113066

RESUMO

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.


Assuntos
Biomarcadores/sangue , Índice de Massa Corporal , Inflamação/sangue , Neovascularização Patológica/sangue , Adolescente , Composição Corporal , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/fisiopatologia , Criança , Pré-Escolar , Colesterol/sangue , Estudos Transversais , Feminino , Humanos , Inflamação/fisiopatologia , Entrevistas como Assunto , Itália , Lipoproteínas HDL/sangue , Masculino , Peptídeo Natriurético Encefálico/sangue , Obesidade/fisiopatologia , Fatores de Risco , Triglicerídeos/sangue , Troponina T/sangue , Fator A de Crescimento do Endotélio Vascular/sangue
19.
J Med Genet ; 48(6): 369-74, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21493956

RESUMO

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.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Efeito Fundador , Estudo de Associação Genômica Ampla/métodos , Perda Auditiva/genética , Audição/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Limiar Auditivo , Proteínas de Transporte/genética , Bases de Dados Genéticas , Europa (Continente)/epidemiologia , Feminino , Ligação Genética , Perda Auditiva/etnologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Receptores de Glutamato Metabotrópico/genética
20.
PLoS One ; 6(2): e16982, 2011 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-21347390

RESUMO

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.


Assuntos
Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genética , Cromossomos Humanos Par 6/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/diagnóstico , Neoplasias/genética , Prognóstico
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