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1.
BMC Urol ; 16(1): 62, 2016 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-27769252

RESUMEN

BACKGROUND: Copy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population. METHODS: Genome wide genotyping were performed in 559 cases and 1772 controls (Group 1) using Illumina HumanHap550 v1, HumanHap550 v3 or Human610-Quad platforms and in 353 cases and 1149 controls (Group 2) using the Illumina Human OmniExpress 12v1 or Human OmniExpress 12v1-1. Signal intensity data including log R ratio (LRR) and B allele frequency (BAF) for each single nucleotide polymorphism (SNP) were used for CNV detection using PennCNV software. After sample quality control, gene- and CNV-based association tests were performed using cleaned data from Group 1 (493 cases and 1586 controls) and Group 2 (307 cases and 1102 controls) using ParseCNV software. Meta-analysis was performed using gene-based test results as input to identify significant genes, and CNVs in or around significant genes were identified in CNV-based association test results. Called CNVs passing quality control and signal intensity visualization examination were considered for validation using TaqMan CNV assays and QuantStudio® 3D Digital PCR System. RESULTS: The meta-analysis identified 373 genome wide significant (p < 5X10-4) genes/loci including 49 genes/loci with deletions and 324 with duplications. Among them, 17 genes with deletion and 1 gene with duplication were identified in CNV-based association results in both Group 1 and Group 2. Only 2 genes (NUCB2 and UPF2) containing deletions passed CNV quality control in both groups and signal intensity visualization examination, but laboratory validation failed to verify these deletions. CONCLUSIONS: Our data do not support that structural variation is a major cause of nonsyndromic cryptorchidism.


Asunto(s)
Criptorquidismo/genética , Variaciones en el Número de Copia de ADN , Población Blanca/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Programas Informáticos
2.
J Urol ; 193(5): 1637-45, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25390077

RESUMEN

PURPOSE: Based on a genome-wide association study of testicular dysgenesis syndrome showing a possible association with TGFBR3, we analyzed data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal. MATERIALS AND METHODS: We excluded samples based on strict quality control criteria, leaving 844 cases and 2,718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform (ie Illumina® HumanHap550, version 1 or 3, or Human610-Quad, version 1 BeadChip in group 1 and Human OmniExpress 12, version 1 BeadChip platform in group 2). Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of data for groups 1 and 2, and selective genotyping of independent cases (330) and controls (324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum. RESULTS: We identified suggestive (p ≤ 1× 10(-4)) association of markers in/near TGFBR3, including rs9661103 (OR 1.40; 95% CI 1.20, 1.64; p = 2.71 × 10(-5)) and rs10782968 (OR 1.58; 95% CI 1.26, 1.98; p = 9.36 × 10(-5)) in groups 1 and 2, respectively. In subgroup analyses we observed strongest association of rs17576372 (OR 1.42; 95% CI 1.24, 1.60; p = 1.67 × 10(-4)) with proximal and rs11165059 (OR 1.32; 95% CI 1.15, 1.38; p = 9.42 × 10(-4)) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior genome-wide association study signal (rs12082710) was marginal (OR 1.13; 95% CI 0.99, 1.28; p = 0.09 for group 1), and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild-type and cryptorchid rat fetal gubernaculum. CONCLUSIONS: These data suggest complex or phenotype specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFß signaling.


Asunto(s)
Criptorquidismo/genética , Proteoglicanos/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Niño , Preescolar , Humanos , Lactante , Masculino , Fenotipo
3.
Hum Reprod ; 30(10): 2439-51, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26209787

RESUMEN

STUDY QUESTION: What are the genetic loci that increase susceptibility to nonsyndromic cryptorchidism, or undescended testis? SUMMARY ANSWER: A genome-wide association study (GWAS) suggests that susceptibility to cryptorchidism is heterogeneous, with a subset of suggestive signals linked to cytoskeleton-dependent functions and syndromic forms of the disease. WHAT IS KNOWN ALREADY: Population studies suggest moderate genetic risk of cryptorchidism and possible maternal and environmental contributions to risk. Previous candidate gene analyses have failed to identify a major associated locus, although variants in insulin-like 3 (INSL3), relaxin/insulin-like family peptide receptor 2 (RXFP2) and other hormonal pathway genes may increase risk in a small percentage of patients. STUDY DESIGN, SIZE, DURATION: This is a case-control GWAS of 844 boys with nonsyndromic cryptorchidism and 2718 control subjects without syndromes or genital anomalies, all of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS: All boys with cryptorchidism were diagnosed and treated by a pediatric specialist. In the discovery phase, DNA was extracted from tissue or blood samples and genotyping performed using the Illumina HumanHap550 and Human610-Quad (Group 1) or OmniExpress (Group 2) platform. We imputed genotypes genome-wide, and combined single marker association results in meta-analyses for all cases and for secondary subphenotype analyses based on testis position, laterality and age, and defined genome-wide significance as P = 7 × 10(-9) to correct for multiple testing. Selected markers were genotyped in an independent replication group of European cases (n = 298) and controls (n = 324). We used several bioinformatics tools to analyze top (P < 10(-5)) and suggestive (P < 10(-3)) signals for significant enrichment of signaling pathways, cellular functions and custom gene lists after multiple testing correction. MAIN RESULTS AND THE ROLE OF CHANCE: In the full analysis, we identified 20 top loci, none reaching genome-wide significance, but one passing this threshold in a subphenotype analysis of proximal testis position (rs55867206, near SH3PXD2B, odds ratio = 2.2 (95% confidence interval 1.7, 2.9), P = 2 × 10(-9)). An additional 127 top loci emerged in at least one secondary analysis, particularly of more severe phenotypes. Cytoskeleton-dependent molecular and cellular functions were prevalent in pathway analysis of suggestive signals, and may implicate loci encoding cytoskeletal proteins that participate in androgen receptor signaling. Genes linked to human syndromic cryptorchidism, including hypogonadotropic hypogonadism, and to hormone-responsive and/or differentially expressed genes in normal and cryptorchid rat gubernaculum, were also significantly overrepresented. No tested marker showed significant replication in an independent population. The results suggest heterogeneous, multilocus and potentially multifactorial susceptibility to nonsyndromic cryptorchidism. LIMITATIONS, REASONS FOR CAUTION: The present study failed to identify genome-wide significant markers associated with cryptorchidism that could be replicated in an independent population, so further studies are required to define true positive signals among suggestive loci. WIDER IMPLICATIONS OF THE FINDINGS: As the only GWAS to date of nonsyndromic cryptorchidism, these data will provide a basis for future efforts to understand genetic susceptibility to this common reproductive anomaly and the potential for additive risk from environmental exposures. STUDY FUNDING/COMPETING INTERESTS: This work was supported by R01HD060769 (the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD)), P20RR20173 (the National Center for Research Resources (NCRR), currently P20GM103464 from the National Institute of General Medical Sciences (NIGMS)), an Institute Development Fund to the Center for Applied Genomics at The Children's Hospital of Philadelphia, and Nemours Biomedical Research. The authors have no competing interests to declare.


Asunto(s)
Criptorquidismo/diagnóstico , Citoesqueleto/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Criptorquidismo/genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Insulina/genética , Masculino , Oportunidad Relativa , Fenotipo , Estructura Terciaria de Proteína , Proteínas/genética , Receptores Acoplados a Proteínas G/genética , Transducción de Señal , Testículo/patología
4.
Birth Defects Res A Clin Mol Teratol ; 94(11): 900-7, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23081935

RESUMEN

BACKGROUND: Genetic and environmental factors likely influence susceptibility to nonsyndromic cryptorchidism, a common disease presenting at birth or in later childhood. We compared cases and controls to define differential risk factors for congenital versus acquired cryptorchidism. METHODS: We compared questionnaire and clinical data from cases of congenital cryptorchidism (n = 230), acquired cryptorchidism (n = 182) and hernia/hydrocele (n = 104) with a group of healthy male controls (n = 358). Potential predictor variables (p < 0.2 in univariable analysis) were included in stepwise multivariable logistic regression models. RESULTS: Temporary (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.4-0.8) or exclusive (OR, 0.6; 95% CI, 0.4-0.9) breastfeeding was reduced and soy formula feeding increased (OR, 1.8; 95% CI, 1.2-2.9) in acquired but not congenital or hernia/hydrocele groups. The highest risk estimates were observed for primary soy formula feeding with limited or no breastfeeding (OR 2.5; 95% CI, 1.4-4.3; adjusted OR, 2.7; 95% CI, 1.4-5.4) in the acquired group. Primary feeding risk estimates were equivalent or strengthened when multivariable models were limited to age greater than 2 years, full-term or not small for gestational age, or Caucasian subjects. Pregnancy complications and increased maternal exposure to cosmetic or household chemicals were not consistently associated with either form of cryptorchidism in these models. CONCLUSIONS: Our data support reduced breastfeeding and soy formula feeding as potential risk factors for acquired cryptorchidism. Although additional studies are needed, hormonally active components of breast milk and soy formula could influence the establishment of normal testis position in the first months of life, leading to apparent ascent of testes in childhood. Birth Defects Research (Part A), 2012.


Asunto(s)
Lactancia Materna , Criptorquidismo/etiología , Conducta Alimentaria , Alimentos de Soja/efectos adversos , Hidrocele Testicular/etiología , Adolescente , Adulto , Enfermedades Asintomáticas , Estudios de Casos y Controles , Niño , Preescolar , Criptorquidismo/clasificación , Criptorquidismo/epidemiología , Femenino , Humanos , Lactante , Fórmulas Infantiles , Modelos Logísticos , Masculino , Leche Humana/química , Embarazo , Factores de Riesgo , Encuestas y Cuestionarios , Hidrocele Testicular/epidemiología , Testículo/patología , Estados Unidos/epidemiología
6.
Pediatr Pulmonol ; 47(10): 979-86, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22431368

RESUMEN

BACKGROUND: It is common practice during one lung ventilation (OLV) to use 100% oxygen, although this may cause hyperoxia- and oxidative stress-related lung injury. We hypothesized that lower oxygen (FiO(2) ) during OLV will result in less inflammatory and oxidative lung injury and improved lung function. METHODS: Twenty pigs (8.88 ± 0.84 kg; 38 ± 4.6 days) were assigned to either the hyperoxia group (n = 10; FiO(2) = 100%) or the normoxia group (n = 10; FiO(2) < 50%). Both groups were subjected to 3 hr of OLV. Blood samples were tested for pro-inflammatory cytokines and lung tissue was tested for these cytokines and oxidative biomarkers. RESULTS: There were no differences between groups for partial pressure of CO(2) , tidal volume, end-tidal CO(2) , plasma cytokines, or respiratory compliance. Total respiratory resistance was greater in the hyperoxia group (P = 0.02). There were higher levels of TNF-α, IL-1ß, and IL-6 in the lung homogenates of the hyperoxia group than in the normoxia group (P ≤ 0.01, 0.001, and 0.001, respectively). Myeloperoxidase and protein carbonyls (PC) were higher (P = 0.03 and P = 0.01, respectively) and superoxide dismutase (SOD) was lower in the lung homogenates of the hyperoxia group (P ≤ 0.001). CONCLUSION: Higher myeloperoxidase, PC, and cytokine levels, and lower SOD availability indicate a greater degree of injury in the lungs of the hyperoxia animals, possibly from using 100% oxygen. In this translational study using a pig model, FiO(2) ≤ 50% during OLV reduced hyperoxic injury and improved function in the lungs.


Asunto(s)
Hiperoxia/etiología , Hiperoxia/fisiopatología , Inflamación/fisiopatología , Pulmón/fisiología , Ventilación Unipulmonar/efectos adversos , Estrés Oxidativo , Oxígeno/efectos adversos , Lesión Pulmonar Aguda/enzimología , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/fisiopatología , Animales , Dióxido de Carbono/sangre , Citocinas/sangre , Hiperoxia/sangre , Inflamación/sangre , Pulmón/enzimología , Peroxidasa/análisis , Carbonilación Proteica/fisiología , Superóxido Dismutasa/análisis , Porcinos
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