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Biomedical subjects

Karen Walker

Publications and source records attributed to Karen Walker.

14 recordsLinked to original sources
PubMed2006

Complex gene-gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes.

The complex inheritance involved in multiple sclerosis (MS) risk has been extensively investigated, but our understanding of MS genetics remains rudimentary. In this study, we explore 51 single nucleotide polymorphisms (SNPs) in 36 candidate genes from the inflammatory pathway and test for gene-gene interactions using complementary case-control, discordant sibling pair, and trio family study designs. We used a sample of 421 carefully diagnosed MS cases and 96 unrelated, healthy controls; discordant sibling pairs from 146 multiplex families; and 275 trio families. We used multifactor dimensionality reduction to explore gene-gene interactions. Based on our analyses, we have identified several statistically significant models including both main effect models and two-locus, three-locus, and four-locus epistasis models that predict MS disease risk with between approximately 61% and 85% accuracy. These results suggest that significant epistasis, or gene-gene interactions, may exist even in the absence of statistically significant individual main effects.

Case-Control Studies↗
PubMed2006

Association of endothelial nitric oxide synthase genotypes with bone mineral density, bone loss, hip structure, and risk of fracture in older women: the SOF study.

Nitric oxide (NO) is an important bone-signaling molecule. We examined the associations between the Glu298Asp polymorphism of NOS3, indices of bone strength, and the incidence of fracture among 6691 women aged 65 years and older enrolled in the Study of Osteoporotic Fractures. Calcaneal BMD was measured at an initial exam and after an average of 5.9 years of follow-up. Hip BMD was measured at an initial exam and after 3.7 years of follow-up. Baseline spine BMD and hip structural parameters were measured. Incident hip fractures were confirmed by review of radiographic reports; follow-up was greater than 98% complete. Incident vertebral fractures were defined by morphometry using lateral spine radiography at baseline and an average of 3.7 years later. The frequencies of the NOS3 Glu298Asp genotypes were Glu/Glu=46.2%, Glu/Asp=42.7%, and Asp/Asp=11.1%. There were no significant associations between NOS3 genotypes and initial calcaneal BMD, hip BMD, or rate of change in hip or calcaneal BMD. None of the hip structural parameters differed substantially by genotype. NOS3 genotype was not significantly associated with either incident or prevalent radiographic vertebral fractures. Women with the heterozygous Glu/Asp genotype had a borderline statistically significantly lower rate of hip fracture than either the Glu/Glu genotype (HR=0.87, 95% CI: 0.74, 1.01) or the Asp/Asp genotype (HR=0.78, 95% CI: 0.62, 0.98). In conclusion, the Glu298Asp polymorphism does not contribute substantially or consistently to indices of bone strength in this sample of older white women, although our findings suggest allelic variation at the NOS3 locus maybe associated with hip fracture risk. Confirmation of these findings is needed in other populations and with additional markers within and flanking the NOS3 gene region.

Age Factors↗
PubMed2006

A population-based study of congenital diaphragmatic hernia outcome in New South Wales and the Australian Capital Territory, Australia, 1992-2001.

PURPOSE: The aim of the study was to describe the incidence and survival of infants born with congenital diaphragmatic hernia (CDH) in the state of New South Wales (NSW) and the Australian Capital Territory (ACT), Australia. METHODS: A population-based cohort study of all infants inclusive up to 1 month of age diagnosed with CDH in NSW and the ACT between 1992 and 2001 was conducted. Data sources were the NSW and ACT Neonatal Intensive Care Data Collection (Neonatal Intensive Care Units Study), NSW Birth Defects Register, Population Health Research Centre of ACT Health, and NSW Midwives Data Collection. Individual risk factors for mortality were assessed using the chi(2) test with P < .05 being considered statistically significant. Multivariate analysis was performed using logistic regression to adjust for potential confounding variables. RESULTS: From the databases used, the incidence of CDH in NSW and the ACT was 1 per 3800 births. Of 242 infants identified with CDH, 8% underwent termination of pregnancy, 10% were stillborn after 20 weeks' gestation, and 82% were liveborn. Most liveborn infants (70%) were delivered at term with a 64% survival, whereas 30% were preterm with a 35% survival. For liveborn infants, the overall preoperative mortality was 35% with 56% surviving to discharge. Logistic regression identified a low 5-minute Apgar score, prematurity, and air leak as independent risk factors for mortality. CONCLUSIONS: This population-based study of CDH provides us with baseline data for our states. Mortality is high in preterm infants and in the preoperative period. Avoiding preterm delivery and improving preoperative stabilization are the measures most likely to improve survival.

Abortion, Induced↗
PubMed2006

Visual side-effects from transdermal scopolamine (hyoscine).

Transdermal scopolamine may be used to reduce drooling in children with disabilities. Side-effects include dilated pupils and a reduction in the near point of accommodation (the closest point at which clear vision is possible). Two male children with epilepsy, one with spinal dysraphism (aged 7y 6mo) and one with cerebral palsy (aged 5y 8mo), who have undergone treatment for drooling with transdermal scopolamine are described. Near visual acuity was reduced, and both children showed dilated pupils with reduced or no response to light. These responses became normal on cessation of the scopolamine patch. As the effect of this drug may be cumulative, and many patients are unable to communicate difficulties, clinicians need to be aware of these possible side-effects.

Administration, Cutaneous↗
PubMed2006

Neurodevelopmental outcomes and surgery in neonates.

A neonate requiring major surgery in 2006 has a greater prospect of survival than ever before. Increasingly, however, there is awareness that critical illness may affect later neurodevelopment. Pre-existing conditions in addition to the physiologic stresses associated with cardiac and general surgery are implicated but remain unavoidable in the case of significant structural abnormalities such as transposition of the great arteries or congenital diaphragmatic hernia. For those affected by neurodevelopmental impairment, there is a significant cost to the child, family and society. Current research focuses on the preventable causes of brain injury, before, during and after the intervention, and the rate of impairment in apparently uncomplicated procedures. In contrast to the quantity of neurodevelopmental outcome data following cardiac surgery, there remain few outcome studies dealing with non-cardiac surgery despite such intervention being two to three times more common. There appear to be compelling clinical and economic arguments for the instigation of formalised population-based developmental assessments for all infants undergoing major surgery.

Australia↗
PubMed2005

Gene-environment interaction effects on the development of immune responses in the 1st year of life.

Asthma is a common disease that results from both genetic and environmental risk factors. Children attending day care in the 1st year of life have lower risks for developing asthma, although the mechanism for this "day care" effect is largely unknown. We investigated the interactions between day care exposure in the 1st 6 mo of life and genotypes for 72 polymorphisms at 45 candidate loci and their effects on cytokine response profiles and on the development of atopic phenotypes in the 1st year of life in the Childhood Onset of Asthma (COAST) cohort of children. Six interactions (at four polymorphisms in three loci) with "day care" that had an effect on early-life immune phenotypes were significant at P<.001. The estimated false-discovery rate was 33%, indicating that an estimated four P values correspond to true associations. Moreover, the "day care" effect at some loci was accounted for by the increased number of viral infections among COAST children attending day care, whereas interactions at other loci were independent of the number of viral infections, indicating the presence of additional risk factors associated with day care environment. This study identified significant gene-environment interactions influencing the early patterning of the immune system and the subsequent development of asthma and highlights the importance of considering environmental risk factors in genetic analyses.

Asthma↗
PubMed2004

Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis.

A large body of research supports a multifactorial cause in multiple sclerosis (MS), with an underlying genetic susceptibility likely acting in concert with undefined environmental exposures. Here, we used a highly efficient multilocus genotyping assay to study single nucleotide polymorphisms representing variation in 34 genes from inflammatory pathways in a well-characterized MS familial data set. Evidence of transmission distortion was present for several polymorphisms. Results for the NOS2A locus (exon 10 C/T, D346D) on chromosome 17q11 remained significant after correction for multiple testing and were reproduced in a second independent African American MS data set. In addition, linkage to a NOS2A promoter region polymorphism, (CCTTT)(n), was present in a third data set of multicase MS families. Our results provide strong evidence for linkage and association to a new candidate disease gene on chromosome 17q11 in MS and suggest that variation within NOS2A or a nearby locus contributes to disease susceptibility.

Adult↗
PubMed2004

Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy.

BACKGROUND: Asthma is a chronic respiratory disease that often originates in early childhood. Although candidate gene studies have identified many potential asthma susceptibility genes in adult populations, few have studied associations with immune phenotypes in the first year that might be early clinical markers of asthma. OBJECTIVE: The aim of this study was to assess the contribution of genetic variation to cytokine response profiles and atopic phenotypes in the first year of life in the Childhood Origin of Asthma cohort. METHODS: Two hundred seven European American children participating in the Childhood Origin of Asthma study were genotyped for 61 single nucleotide polymorphisms in 35 genes involved in immune regulation. We examined the relationship between these single nucleotide polymorphisms and PHA-induced cytokine (IL-5, IL-10, IL-13, and IFN-gamma) response profiles at birth and at year 1, respiratory syncytial virus-induced wheezing and atopic dermatitis in the first year of life, and total IgE levels, peripheral blood eosinophil counts, and allergic sensitization at age 1 year. The data were analyzed by using censored regression for quantitative measurements and logistic regression for qualitative phenotypes. RESULTS: The 237Gly allele of the high-affinity IgE receptor beta chain (FCER1B) and a silent substitution in the nitric oxide synthase (NOS)2A gene were associated with reduced IL-13 responses in cord blood (P = .0025 and P = .0062, respectively). A significant gene-gene interaction between FCER1B 237Gly and NOS2A D346D was detected, with individuals carrying the minor allele for both polymorphisms having the lowest cord blood IL-13 levels. Furthermore, the IL13 110Gln allele showed an association with increased IgE levels at year 1 (P = .0026), and the colony-stimulating factor 2 (CSF2) 117Thr allele showed an association with a greater increase in IL-5 responses during the first year (P = .0092). The TGF-beta1 (TGFB1) -509T allele was associated with respiratory syncytial virus-related wheezing in the first year (P = .0005). None of the polymorphisms included in this study were associated with atopic dermatitis during the first year or a positive RAST result at 1 year of age. CONCLUSION: These data suggest that variations in genes involved in immune regulation are associated with biologic and clinical phenotypes in the first year of life that might increase the risk for the subsequent development of childhood asthma.

Alleles↗
PubMed2004

Are common disease susceptibility alleles the same in outbred and founder populations?

Founder populations have been the subjects of complex disease studies because of their decreased genetic heterogeneity, increased linkage disequilibrium and more homogeneous environmental exposures. However, it is possible that disease alleles identified in founder populations may not contribute significantly to susceptibility in outbred populations. In this study we examine the Hutterites, a founder population of European descent, for 103 polymorphisms in 66 genes that are candidates for cardiovascular or inflammatory diseases. We compare the frequencies of alleles at these loci in the Hutterites to their frequencies in outbred European-American populations and test for associations with cardiovascular disease-associated phenotypes in the Hutterites. We show that alleles at these loci are found at similar frequencies in the Hutterites and in outbred populations. In addition, we report associations between 39 alleles or haplotypes and cardiovascular disease phenotypes (P<0.05), with five loci remaining significant after adjusting for multiple comparisons. These data indicate that this founder population is informative and offers considerable advantages for genetic studies of common complex diseases.

Cardiovascular Diseases↗
PubMed2003

Novel case-control test in a founder population identifies P-selectin as an atopy-susceptibility locus.

To avoid problems related to unknown population substructure, association studies may be conducted in founder populations. In such populations, however, the relatedness among individuals may be considerable. Neglecting such correlations among individuals can lead to seriously spurious associations. Here, we propose a method for case-control association studies of binary traits that is suitable for any set of related individuals, provided that their genealogy is known. Although we focus here on large inbred pedigrees, this method may also be used in outbred populations for case-control studies in which some individuals are relatives. We base inference on a quasi-likelihood score (QLS) function and construct a QLS test for allelic association. This approach can be used even when the pedigree structure is far too complex to use an exact-likelihood calculation. We also present an alternative approach to this test, in which we use the known genealogy to derive a correction factor for the case-control association chi2 test. We perform analytical power calculations for each of the two tests by deriving their respective noncentrality parameters. The QLS test is more powerful than the corrected chi2 test in every situation considered. Indeed, under certain regularity conditions, the QLS test is asymptotically the locally most powerful test in a general class of linear tests that includes the corrected chi2 test. The two methods are used to test for associations between three asthma-associated phenotypes and 48 SNPs in 35 candidate genes in the Hutterites. We report a highly significant novel association (P=2.10-6) between atopy and an amino acid polymorphism in the P-selectin gene, detected with the QLS test and also, but less significantly (P=.0014), with the transmission/disequilibrium test.

Alleles↗
PubMed2003

Functional rating for knee arthroplasty: comparison of three scoring systems.

This study evaluated the reliability of three rating systems for total knee arthroplasty. Twenty-nine patients were assessed by six observers with the American Knee Society Score, the British Orthopaedic Association Score, and the Oxford 12-item questionnaire. The inter- and intraobserver variations were calculated for the American Knee Society Score and the British Orthopaedic Association Score, as was the reproducibility of the Oxford 12-item questionnaire. Components of the scores were evaluated for agreement using Kappa statistics. The British Orthopaedic Association Score had smaller interobserver variation compared to the American Knee Society Score, and the greatest reproducibility of the three systems. This was attributed to the equal weighting of its component variables. The Oxford 12-item questionnaire, a self-administered questionnaire that eliminates interobserver error, emerged as the most reliable system. Observer experience affected the reliability of the American Knee Society Score and the British Orthopaedic Association Score. Subjective variables were more reliable and reproducible than the objective components.

Activities of Daily Living↗
PubMed2003

"Mad for Fitness": an exercise group to combat a high incidence of postnatal depression.

Health visitors working in a socially and economically deprived area of the Wirral, Merseyside wanted to find innovative ways to address the high incidence of postnatal depression in their caseloads. Believing that exercise may have a beneficial effect on depression, they set up a project to make fitness activities more affordable and available to their client base. After an initial survey of local mothers had indicated support, a pilot "swim, gym and crèche" scheme was set up in a Leisure Centre in partnership with other agencies. The response from the pilot group was positive and suggested that the participants were benefiting mentally and physically from the exercise and the social aspects of the group. Parents began to take a greater part in running the group and funding was obtained to continue the scheme. Further evaluation is in progress and there are plans to replicate the scheme in other areas of the local Primary Care Trust.

Attitude to Health↗
PubMed2002

Cutaneous lesions showing giant yeast forms of Blastomyces dermatitidis.

BACKGROUND: The yeast forms of Blastomyces dermatitidis usually range from 8 to 15-20 micro m in diameter. Larger yeast forms have previously been reported only twice in immunosuppressed patients. In both patients these large forms were seen within the lung. CASE REPORT: We present a 14-year-old cardiac transplant patient, who presented 36 days following his transplantation with acute respiratory distress followed a few days later by erythematous cutaneous papules. RESULTS: Biopsy of a skin lesion showed yeast forms, some greater than 40 micro m in diameter, within and surrounding dermal vessels. Cultures later grew Blastomyces dermatitidis. CONCLUSIONS: To our knowledge this is the first reported case of giant forms of Blastomyces dermatitidis within the skin. With increased iatrogenic immunosuppression, we may expect to see more diverse morphologic forms with deep fungal infections.

Adolescent↗