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Results for “Genetic causality”

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At least 523 records · Page 29Linked to original sources
PubMed2026

Systemic Comorbidities of Keloid and Hypertrophic Scars: A Phenome-Wide Association Study in a Multiethnic U.S. Pediatric Cohort.

BACKGROUND: Excessive scarring (ES), including keloids and hypertrophic scars, impairs function, appearance, and quality of life in children. Its pediatric comorbidity spectrum is not well defined, limiting anticipatory guidance and multidisciplinary care. This research aims to investigate comorbidities of ES in a diverse pediatric cohort using a phenome-wide association study (PheWAS). METHODS: This population-based study leveraged longitudinal electronic health record (EHR) data from participants enrolled in the Children's Hospital of Philadelphia (CHOP) from 2006. Diagnosis codes (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] and Tenth Revision [ICD-10-CM]) were mapped to 3109 phenotype codes (PheCodes). PheWAS analyses were conducted using logistic regression, with Bonferroni correction applied to account for multiple testing. RESULTS: Among 86,092 pediatric participants, 662 (0.77%) were identified with ES; the remaining served as controls. Multivariable PheWAS screening identified 154 significant associations across 16 disease categories, of which 105 were not reported previously to our knowledge. Dermatologic phenotypes (n = 28; 18%) were most enriched, including acne and other follicular disorders, eczema, pigmentary changes, papulosquamous and granulomatous disorders, and cutaneous infections. Respiratory phenotypes (n = 21; 14%) included respiratory failure, pneumonia, asthma, allergic rhinitis, pharyngitis, and tonsillar hypertrophy. Sense organ disorders (n = 19; 12%) comprised conjunctivitis, refractive errors, otitis, and hearing impairment. Infection-related phenotypes (n = 14; 9%) highlighted susceptibility to viral (influenza, human papillomavirus [HPV], molluscum contagiosum), fungal (candidiasis, dermatophytosis), and bacterial infections. CONCLUSIONS: These findings suggest that ES in children indicates not only localized wound-healing impairment, but also systemic immune, developmental, and proliferative dysregulations, emphasizing the need for genetic and mechanistic studies to clarify causal pathways and multidisciplinary surveillance beyond dermatologic care.

Humans↗
PubMed1991

Sister-chromatid exchanges in lymphocytes from infants with Down's syndrome.

Sister-chromatid exchange (SCE) frequencies were studied in blood lymphocytes from 12 patients (3 females and 9 males) with Down's syndrome (DS). The mean frequency of SCE per metaphase for the patients (both sexes) was 9.2 +/- 0.8 which was significantly higher (P less than 0.01) than the mean SCE value (5.1 +/- 0.2) scored for 16 healthy infants (8 females and 8 males). A significant increase in the mean frequency of SCE in 12 parents of infants with DS (8.7 +/- 0.9 SCE/cell) was noticeable when compared with 20 parents of normal infants (6.3 +/- 0.1 SCE/cell). Increases in cellular division with reduction in their replication were also observed in patients with DS. Treatment with mitomycin C (0.05 micrograms/ml), hycanthone (0.1 micrograms/ml) and gamma-radiation (0.1 Gy) revealed a significant (P less than 0.01) increase in frequencies of SCE in DS lymphocytes and in those of their parents as compared to controls. These data may reveal a familial hypersensitivity reaction to these agents. The results indicate a genomic instability and deranged DNA-repair mechanisms which are accentuated by exposure to mutagenic agents, the underlying causal factor for which might be genetic.

Adult↗
PubMed2004

Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.

Parkinson's disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body inclusions. Parkinsonism is typically sporadic in nature; however, several rare familial forms are linked to genetic loci, and the identification of causal mutations has provided insight into the disease process. PARK8, identified in 2002 by Funayama and colleagues, appears to be a common cause of familial PD. We describe here the cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain. Because of the tremor observed in PD and because a number of the families are of Basque descent, we have named this protein dardarin, derived from the Basque word dardara, meaning tremor.

Aged↗
PubMed1994

A genetic analysis of relative weight among 4,020 twin pairs, with an emphasis on sex effects.

This study replicated previous findings showing a high heritability of obesity, as measured by body mass index (kg/m2), using a measure of relative weight that does not assume a constant regression of height on weight across different populations, and evaluated whether there are sex-limited genetic effects. Subjects were 4,020 adult twin pairs. Alternative causal structural equation models were fitted to variance-covariance matrices. The ADE model (additive genetic effects, dominant/nonadditive genetic effects, and unique environment) fit best. Allowing for sex-specific effects (common sex-limitation model) significantly improved the fit, X2(6) = 230.5, p < .001. The heritability of that portion of weight unrelated to height was large: .61 for men and .73 for women.

Adolescent↗
PubMed1999

Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly.

Holoprosencephaly (HPE) is a common, severe malformation of the brain that involves separation of the central nervous system into left and right halves. Mild HPE can consist of signs such as a single central incisor, hypotelorism, microcephaly, or other craniofacial findings that can be present with or without associated brain malformations. The aetiology of HPE is extremely heterogeneous, with the proposed participation of a minimum of 12 HPE-associated genetic loci as well as the causal involvement of specific teratogens acting at the earliest stages of neurulation. The HPE2 locus was recently characterized as a 1-Mb interval on human chromosome 2p21 that contained a gene associated with HPE. A minimal critical region was defined by a set of six overlapping deletions and three clustered translocations in HPE patients. We describe here the isolation and characterization of the human homeobox-containing SIX3 gene from the HPE2 minimal critical region (MCR). We show that at least 2 of the HPE-associated translocation breakpoints in 2p21 are less than 200 kb from the 5' end of SIX3. Mutational analysis has identified four different mutations in the homeodomain of SIX3 that are predicted to interfere with transcriptional activation and are associated with HPE. We propose that SIX3 is the HPE2 gene, essential for the development of the anterior neural plate and eye in humans.

Amino Acid Sequence↗
PubMed2002

Reorganization of human cortical maps caused by inherited photoreceptor abnormalities.

We describe a compelling demonstration of large-scale developmental reorganization in the human visual pathways. The developmental reorganization was observed in rod monochromats, a rare group of congenitally colorblind individuals who virtually lack cone photoreceptor function. Normal controls had a cortical region, spanning several square centimeters, that responded to signals initiated in the all-cone foveola but was inactive under rod viewing conditions; in rod monochromats this cortical region responded powerfully to rod-initiated signals. The measurements trace a causal pathway that begins with a genetic anomaly that directly influences sensory cells and ultimately results in a substantial central reorganization.

Adult↗
PubMed1997

Allelic loss determination in chronic lymphocytic leukemia by immunomagnetic bead sorting and microsatellite marker analysis.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. Details of the molecular mechanisms involved in the pathogenesis of this leukemia are unclear at present. In other malignancies tumorigenesis has been shown to proceed via a multistep progression model with a causal relation between the accumulation of genetic abnormalities and more aggressive clinical behavior. The loss of chromosomal segments in malignant cells has proven useful in mapping regions of DNA that contain candidate tumor suppressor genes. The detection of loss of heterozygosity (LOH) has been greatly facilitated by the analysis of highly polymorphic microsatellite markers enabling the identification of submicroscopic losses. Utilizing immunomagnetic bead sorting to separate leukemic from normal cells we identified at least one allelic losses in 8/29 (28%) of analysed CLL cases with a PCR-based assay. On chromosomal arm 3p we have identified homozygous deletions in 3/29 cases at locus D3S1284 residing in the vicinity of the newly described FHIT gene. Several cases of CLL manifested LOH at a locus telomeric to the p15 and p16 tumor suppressor genes, all being early to intermediate stage disease. Our findings suggest that losses at these loci may contribute to the development and/or progression of CLL in at least a subset of cases.

Adult↗
PubMed2000

Asthma.

From an epidemiological point of view four issues are briefly emphasized here: the definition of asthma, time trends and regional differences, and risk factors for asthma. Furthermore, I will focus upon a few aspects regarding the relation between exercise and asthma. The definition of asthma has presented problems for those involved in studying the disease in general populations, where the estimates rely solely on reported asthma and respiratory symptoms. A standardized questionnaire does not fully overcome differences in languages and interpretations of the concepts of asthma and wheeze over time and in different communities. Although the belief of an upward trend of childhood asthma seems to be widely accepted, studies with the proper methodology to investigate this issue are scarce. The prevalence of asthma varies within and between countries. There is no clear urban rural gradient, and the prevalence of atopy appears to be higher in western than in eastern Europe. Amazingly little is still known about genetic and environmental factors that are causally related to the manifestation of allergic disorders in previously asymptomatic individuals. The effect of exercise on asthma may be many-sided. Children with asthma can actively take part in sport. However, to what extent extensive exercise may affect the occurrence of bronchial responsiveness is unclear, and among athletes exercise may be a risk factor for the development of "athlete's asthma". In conclusion, epidemiological studies have to date not reached their potential due to the lack of longitudinal studies including objective measures of exposures and health outcomes. Causal inference is limited, and further studies designed to answer specific research questions are needed.

Asthma↗
PubMed1987

Genetic transformation of the fungal pathogen responsible for rice blast disease.

The analysis of complex genetic determinants that control the ability of a fungus to colonize its host has been impaired by the lack of sophisticated genetic tools for characterizing important pathogens. We have developed a system for the genetic transformation of Magnaporthe grisea, the causal agent of rice blast disease, to overcome this limitation. A M. grisea arginine auxotroph was shown to contain a mutation (arg3-12) that abolishes ornithine carbamoyltransferase activity. M. grisea strains that contain arg3-12 were used as recipients in transformation experiments with plasmid pMA2, which carries the ArgB(+) gene from Aspergillus nidulans. Stable prototrophic transformants arose at a frequency of about 35 per microgram of plasmid DNA. Integration of single or multiple plasmid copies occurred at a single site in the genome of each transformant; rearrangements were often created during integration. When M. grisea genomic segments were incorporated into pMA2, the presence of any one of five different M. grisea segments did not greatly affect the efficiency of transformation. Integration via homologous recombination occurred when the donor plasmid was linearized by cleaving at a unique restriction site within the M. grisea segment.

Journal Article↗
PubMed2001

Theories of musculoskeletal injury causation.

Based on the scientific evidence in published literature about precipitation of musculoskeletal injuries in the workplace, four theories have been proposed to explain these afflictions. Central to all theories is the presupposition that all occupational musculoskeletal injuries are biomechanical in nature. Disruption of mechanical order of a biological system is dependent on the individual components and their mechanical properties. These common denominators will be causally affected by the individual's genetic endowment, morphological characteristics and psychosocial makeup, and by the occupational biomechanical hazards. This phenomenon is explained by the Multivariate Interaction Theory. Differential Fatigue Theory accounts for unbalanced and asymmetric occupational activities creating differential fatigue and thereby a kinetic and kinematic imbalance resulting in injury precipitation. Cumulative Load Theory suggests a threshold range of load and repetition product beyond which injury precipitates, as all material substances have a finite life. Finally, Overexertion Theory claims that exertion exceeding the tolerance limit precipitates occupational musculoskeletal injury. It is also suggested that while these theories may explain the immediate mechanism of precipitation of injuries, they all operate simultaneously and interact to modulate injuries to varying degrees in different cases.

Biomechanical Phenomena↗
PubMedDate not supplied

Oxidative DNA damage and human cancer: need for cohort studies.

Research of the role of oxidative DNA damage is well established in experimental carcinogenesis. A large number of human studies on biomarkers of oxidative DNA damage, in particular related to guanine oxidation, have been published. The level of oxidative DNA damage and repair activity can be quite different between tumor and normal tissues; case-control studies have shown increased levels of oxidative DNA damage and decreased repair capacity in leukocytes from cases. Similarly, the urinary biomarkers of oxidative DNA damage may be elevated in patients with cancer. However, such studies are likely to be associated with reverse causality. Case-control studies of genetic polymorphisms in DNA repair enzymes suggest that the common variant Ser326Cys in OGG1 may be a risk factor for lung cancer, whereas a rare variant in OGG1 and germ line mutations in the corresponding mismatch repair gene MYH are risk factors for hereditary colon cancer. Cohort studies are required to provide evidence that a high level of oxidative DNA damage implies a high risk of cancer. However, this represents a real challenge considering the large number of subjects and long followup time required with likely spurious oxidation of DNA during collection, assay and/or storage of samples.

Biomarkers↗
PubMed1999

Power and sample size calculations in case-control studies of gene-environment interactions: comments on different approaches.

Power and sample size considerations are critical for the design of epidemiologic studies of gene-environment interactions. Hwang et al. (Am J Epidemiol 1994;140:1029-37) and Foppa and Spiegelman (Am J Epidemiol 1997;146:596-604) have presented power and sample size calculations for case-control studies of gene-environment interactions. Comparisons of calculations using these approaches and an approach for general multivariate regression models for the odds ratio previously published by Lubin and Gail (Am J Epidemiol 1990; 131:552-66) have revealed substantial differences under some scenarios. These differences are the result of a highly restrictive characterization of the null hypothesis in Hwang et al. and Foppa and Spiegelman, which results in an underestimation of sample size and overestimation of power for the test of a gene-environment interaction. A computer program to perform sample size and power calculations to detect additive or multiplicative models of gene-environment interactions using the Lubin and Gail approach will be available free of charge in the near future from the National Cancer Institute.

Case-Control Studies↗
PubMed1991

Craniofacial anomalies in twins.

Studies of twins provide insight into the relative contribution of genetic and environmental factors in the causality of structural anomalies. Thirty-five affected twin pairs were identified from a group of 1114 patients with congenital craniofacial deformities evaluated from 1972 to 1989. Forty-three of these 70 twins exhibited one or more craniofacial anomalies; these were analyzed for dysmorphic characteristics, zygosity, concordance, and family history. The anomalies were categorized into two groups: malformations and deformations. The malformations (n = 36) included hemifacial microsomia (n = 10), cleft lip and palate (n = 8), cleft palate (n = 4), rare facial cleft (n = 2), craniosynostosis (n = 2), Binder syndrome (n = 2), Treacher Collins syndrome (n = 2), craniopagus (n = 2), CHARGE association (n = 1), frontonasal dysplasia (n = 2), and constricted ears (n = 1). The deformations (n = 7) included plagiocephaly (n = 5), hemifacial hypoplasia (n = 1), and micrognathia (n = 1). Twenty-one monozygotic and 14 dizygotic twin pairs were identified. The concordance rate was 33 percent for monozygotic twins and 7 percent for dizygotic twins.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Multiple↗
PubMed2025

Genomic signatures of innovation and selection in the extremotolerant yeast Kluyveromyces marxianus.

Extremophiles can be the product of millions of years of evolutionary engineering and refinement. The underlying mechanisms can be quite distinct from the ones operating at earlier stages of trait innovation. In this work, we have developed the compost yeast Kluyveromyces marxianus, which diverged from its closest relative >20 million years ago, as a model for interspecies comparative biology and genomics. We applied a battery of growth assays to species of the Kluyveromyces genus and found that K. marxianus outperformed its relatives in a battery of heat and chemical stress conditions. We then generated and analyzed genomes from across the genus, to find derived genetic features associated with, and potentially causal for, K. marxianus traits. We found robust expansions in gene families in the K. marxianus genome, most notably among genes annotated as transmembrane transporters and in metabolism. In molecular-evolution tests, we identified adaptive protein variants at hundreds of genes, among which plasma membrane transporters were over-represented. Together, these signals enable a model for the molecular mechanisms and evolutionary pressures underlying K. marxianus traits, including gains in transporter function mediating stress resistance, and metabolic variants contributing to its capacity for rapid growth in challenging conditions. Such oligogenic architectures may be the rule rather than the exception in phenotypes that have evolved over long timescales.

Journal Article↗