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Palmer LJ Buxbaum SG Larkin E Patel SR Elston RC Tishler PV Redline S 《American journal of human genetics》2003,72(2):340-350
Obstructive sleep apnea (OSA) is a common, chronic, complex disease associated with serious cardiovascular and neuropsychological sequelae and with substantial social and economic costs. Along with male gender, obesity is the most characteristic feature of OSA in adults. To identify susceptibility loci for OSA, we undertook a 9-cM genome scan in 66 white pedigrees (n=349 subjects) ascertained on the basis of either an affected individual with laboratory-confirmed OSA or a proband who was a neighborhood control individual. Multipoint variance-component linkage analysis was performed for the OSA-associated quantitative phenotypes apnea-hypopnea index (AHI) and body mass index (BMI). Candidate regions on chromosomes 1p (LOD score 1.39), 2p (LOD score 1.64), 12p (LOD score 1.43), and 19p (LOD score 1.40) gave the most evidence for linkage to AHI. BMI was also linked to multiple regions, most significantly to markers on chromosomes 2p (LOD score 3.08), 7p (LOD score 2.53), and 12p (LOD score 3.41). Extended modeling indicated that the evidence for linkage to AHI was effectively removed after adjustment for BMI, with the exception of the candidate regions on chromosomes 2p (adjusted LOD score 1.33) and 19p (adjusted LOD score 1.45). After adjustment for AHI, the primary linkages to BMI remained suggestive but were roughly halved. Our results suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity and that the interrelationship of OSA and obesity in white individuals may be partially explained by a common causal pathway involving one or more genes regulating both AHI and BMI levels. 相似文献
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Parental origin and phenotype of triploidy in spontaneous abortions: predominance of diandry and association with the partial hydatidiform mole 总被引:13,自引:0,他引:13 下载免费PDF全文
Zaragoza MV Surti U Redline RW Millie E Chakravarti A Hassold TJ 《American journal of human genetics》2000,66(6):1807-1820
The origin of human triploidy is controversial. Early cytogenetic studies found the majority of cases to be paternal in origin; however, recent molecular analyses have challenged these findings, suggesting that digynic triploidy is the most common source of triploidy. To resolve this dispute, we examined 91 cases of human triploid spontaneous abortions to (1) determine the mechanism of origin of the additional haploid set, and (2) assess the effect of origin on the phenotype of the conceptus. Our results indicate that the majority of cases were diandric in origin because of dispermy, whereas the maternally-derived cases mainly originated through errors in meiosis II. Furthermore, our results indicate a complex relationship between phenotype and parental origin: paternally-derived cases predominate among "typical" spontaneous abortions, whereas maternally-derived cases are associated with either early embryonic demise or with relatively late demise involving a well-formed fetus. As the cytogenetic studies relied on analyses of the former type of material and the molecular studies on the latter sources, the discrepancies between the data sets are explained by differences in ascertainment. In studies correlating the origin of the extra haploid set with histological phenotype, we observed an association between paternal-but not maternal-triploidy and the development of partial hydatidiform moles. However, only a proportion of paternally derived cases developed a partial molar phenotype, indicating that the mere presence of two paternal genomes is not sufficient for molar development. 相似文献
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Intrauterine infection plays a pivotal role in preterm birth (PTB) and is characterized by inflammation. Currently, there is no effective therapy available to treat or prevent bacterial-induced PTB. Using Fusobacterium nucleatum, a Gram-negative anaerobe frequently associated with PTB, as a model organism, the mechanism of intrauterine infection was investigated. Previously, it was shown that F. nucleatum induced preterm and term stillbirth in mice. Fusobacterial-induced placental infection was characterized by localized bacterial colonization, inflammation, and necrosis. In this study, F. nucleatum was shown to activate both TLR2 and TLR4 in vitro. In vivo, the fetal death rate was significantly reduced in TLR4-deficient mice (C57BL/6 TLR4(-/-) and C3H/HeJ (TLR4(d/d))), but not in TLR2-deficient mice (C57BL/6 TLR2(-/-)), following F. nucleatum infection. The reduced fetal death in TLR4-deficient mice was accompanied by decreased placental necroinflammatory responses in both C57BL/6 TLR4(-/-) and C3H/HeJ. Decreased bacterial colonization in the placenta was observed in C3H/HeJ, but not in C57BL/6 TLR4(-/-). These results suggest that inflammation, rather than the bacteria per se, was the likely cause of fetal loss. TLR2 did not appear to be critically involved, as no difference in bacterial colonization, inflammation, or necrosis was observed between C57BL/6 and C57BL/6 TLR2(-/-) mice. A synthetic TLR4 antagonist, TLR4A, significantly reduced fusobacterial-induced fetal death and decidual necrosis without affecting the bacterial colonization in the placentas. TLR4A had no bactericidal activity nor did it affect the birth outcome in sham-infected mice. TLR4A could have promise as an anti-inflammatory agent for the treatment or prevention of bacterial-induced preterm birth. 相似文献
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Xiaofeng Zhu Tao Feng Bamidele?O. Tayo Jingjing Liang J.?Hunter Young Nora Franceschini Jennifer?A. Smith Lisa?R. Yanek Yan?V. Sun Todd?L. Edwards Wei Chen Mike Nalls Ervin Fox Michele Sale Erwin Bottinger Charles Rotimi The COGENT BP Consortium Yongmei Liu Barbara McKnight Kiang Liu Donna?K. Arnett Aravinda Chakravati Richard?S. Cooper Susan Redline 《American journal of human genetics》2015,96(1):21-36
Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple—even distinct—traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10−8) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10−7) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes. 相似文献
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OBJECTIVE: To address human papillomavirus (HPV) testing on negative Pap tests preceded by atypical squamous cells of undetermined significance (ASC-US) without reflex HPV testing. STUDY DESIGN: Positive HPV test results with concurrent negative Pap tests over 1 year were identified. Pathology records for all patients diagnosed with ASCUS without reflex HPV testing in the previous year were reviewed; all cytologic and surgical specimens over the subsequent 2 years were evaluated for squamous abnormalities. RESULTS: Fifty patients had positive HPV DNA (HPV-DNA) test result combined with a negative Pap test. Twenty-three had a previous Pap test interpretation of ASC-US (without HPV testing) within the preceding year. On follow-up, 8 of 23 developed a squamous intraepithelial lesion (SIL) within 1 year. Four additional cases developed SIL in the second year after positive HPV testing. All dysplasias in the first year of follow-up were low grade; 1 of 4 developing in the second year was high grade. CONCLUSION: Negative Pap smear following an ASC-US interpretation without a concurrent HPV test is associated with significant false negative rate. We suggest consideration of combining HPV-DNA testing to all initial follow-up negative Pap tests of patients with previous ASC-US, if reflex HPV testing has not been performed. 相似文献
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Influence of upper airway sensory receptors on respiratory muscle activation in humans 总被引:4,自引:0,他引:4
We reasoned that neural information from upper airway (UA) sensory receptors could influence the relationship between UA and diaphragmatic neuromuscular responses to hypercapnia. In this study, the electromyographic (EMG) activities of the alae nasi (AN), genioglossus (GG), and chest wall (CW) or diaphragm (Di) to ventilatory loading were assessed in six laryngectomized, tracheostomized human subjects and in six subjects breathing with an intact UA before and after topical UA anesthesia. The EMG activities of the UA and thoracic muscles increased at similar rates with increasing hypercapnia in normal subjects, in subjects whose upper airways were anesthetized, and in laryngectomized subjects breathing with a cervical tracheostomy. Furthermore, in the laryngectomized subjects, respiratory muscle EMG activation increased with resistive inspiratory loading (15 cmH2O X l-1 X s) applied at the level of a cervical tracheostomy. At an average expired CO2 fraction of 7.0%, resistive loading resulted in a 93 +/- 26.3% (SE) increase in peak AN EMG activity, a 39 +/- 2.0% increase in peak GG EMG activity, and a 43.2 +/- 16.5% increase in peak CW (Di) EMG activity compared with control values. We conclude that the ventilatory responses of the UA and thoracic muscles to ventilatory loading are not substantially influenced by laryngectomy or UA anesthesia. 相似文献
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Naresh M. Punjabi Brian S. Caffo James L. Goodwin Daniel J. Gottlieb Anne B. Newman George T. O'Connor David M. Rapoport Susan Redline Helaine E. Resnick John A. Robbins Eyal Shahar Mark L. Unruh Jonathan M. Samet 《PLoS medicine》2009,6(8)