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Biomedical subjects

E Dawson

Publications and source records attributed to E Dawson.

At least 37 records · Page 2Linked to original sources
PubMed2000

The extent of linkage disequilibrium in four populations with distinct demographic histories.

The design and feasibility of whole-genome-association studies are critically dependent on the extent of linkage disequilibrium (LD) between markers. Although there has been extensive theoretical discussion of this, few empirical data exist. The authors have determined the extent of LD among 38 biallelic markers with minor allele frequencies >.1, since these are most comparable to the common disease-susceptibility polymorphisms that association studies aim to detect. The markers come from three chromosomal regions-1,335 kb on chromosome 13q12-13, 380 kb on chromosome 19q13.2, and 120 kb on chromosome 22q13.3-which have been extensively mapped. These markers were examined in approximately 1,600 individuals from four populations, all of European origin but with different demographic histories; Afrikaners, Ashkenazim, Finns, and East Anglian British. There are few differences, either in allele frequencies or in LD, among the populations studied. A similar inverse relationship was found between LD and distance in each genomic region and in each population. Mean D' is.68 for marker pairs <5 kb apart and is.24 for pairs separated by 10-20 kb, and the level of LD is not different from that seen in unlinked marker pairs separated by >500 kb. However, only 50% of marker pairs at distances <5 kb display sufficient LD (delta>.3) to be useful in association studies. Results of the present study, if representative of the whole genome, suggest that a whole-genome scan searching for common disease-susceptibility alleles would require markers spaced < or = 5 kb apart.

Africa↗
PubMed2000

An SNP map of human chromosome 22.

The human genome sequence will provide a reference for measuring DNA sequence variation in human populations. Sequence variants are responsible for the genetic component of individuality, including complex characteristics such as disease susceptibility and drug response. Most sequence variants are single nucleotide polymorphisms (SNPs), where two alternate bases occur at one position. Comparison of any two genomes reveals around 1 SNP per kilobase. A sufficiently dense map of SNPs would allow the detection of sequence variants responsible for particular characteristics on the basis that they are associated with a specific SNP allele. Here we have evaluated large-scale sequencing approaches to obtaining SNPs, and have constructed a map of 2,730 SNPs on human chromosome 22. Most of the SNPs are within 25 kilobases of a transcribed exon, and are valuable for association studies. We have scaled up the process, detecting over 65,000 SNPs in the genome as part of The SNP Consortium programme, which is on target to build a map of 1 SNP every 5 kilobases that is integrated with the human genome sequence and that is freely available in the public domain.

Cell Line↗
PubMed2000

Refinement of an ovarian cancer tumour suppressor gene locus on chromosome arm 22q and mutation analysis of CYP2D6, SREBP2 and NAGA.

Loss of heterozygosity on chromosome 22q was detected in 53% of 123 ovarian carcinomas, suggesting the presence of at least one tumour suppressor gene. We have refined the location of one possible tumour suppressor gene to the region between the microsatellite markers D22S299 and CYP2D. Located within this region are the genes SREBP2 (sterol regulatory element binding protein 2) and NAGA (N-acetyl-alpha-D-galactosaminidase). Investigation of the coding exons of these genes by single stranded conformational polymorphism/heteroduplex analysis failed to identify any somatic genetic alterations in 57 ovarian tumours which exhibited LOH on 22q13. The CYP2D gene locus straddles the distal boundary of the candidate region. Germline variants of the active CYP2D6 gene with differing abilities to metabolise specific substrates have been implicated in the development of various cancers. Comparison of the frequency of the two common germline mutations among 258 ovarian tumours and 231 non-cancer controls did not reveal any significant differences between the two groups. This suggests that the known polymorphic variants of CYP2D6 are not involved in ovarian cancer predisposition. We also conclude that neither NAGA nor SREBP2 are likely to be mutated in ovarian carcinomas.

Chromosome Mapping↗
PubMed1999

Autosome search for schizophrenia susceptibility genes in multiply affected families.

We have analysed 298 polymorphic markers in 13 families multiply affected with schizophrenia and related disorders using a combination of radiolabelled and fluorescent-based methodologies. The markers were distributed throughout the autosomes at an average spacing of 12.8 cM. The data were analysed with two-point linkage analysis (MLINK) and heterogeneity testing (HOMOG). Several genetic models were used ranging from near dominant to fully recessive. Multi-point analysis was performed for 27 regions demonstrating either contiguously positive lod scores in two or more consecutive markers, and in regions with two-point lod score(s) of 1.0 or above in a single marker. A proportion of the multi-point regions have been implicated in previous studies, thereby decreasing risk of false-positive results. However neither our two-point, nor multi-point scores reached the threshold value for significance of 3. 6. Nevertheless three regions were suggestive of linkage.

Chromosome Mapping↗
PubMed1998

Transmission disequilibrium analysis of a triplet repeat within the hKCa3 gene using family trios with schizophrenia.

hKCa3 is a neuronal small conductance calcium-activated potassium channel which contains a polyglutamine tract, encoded by a polymorphic CAG repeat in the gene. Since an association between longer alleles of the CAG repeat and schizophrenia has been reported, we performed haplotype-based haplotype relative risk (HHRR) and transmission disequilibrium (TDT) in 97 family trios with schizophrenia from SW China. We found no evidence for an excess of longer CAG repeats in the patients, and the ETDT test was not significant for either allele-wise (P = 0.31) or genotype-wise analysis (P = 0.18). However, there was a deficit of transmission of the (CAG)20 repeat allele to affected offspring when this allele was considered individually by TDT (P = 0.012; not corrected for multiple testing). These data do not support a role for larger alleles at the hKCa3 locus in psychosis in Chinese subjects.

Adolescent↗
PubMed1998

A transmission/disequilibrium study of the DRB1*04 gene locus on chromosome 6p21.3 with schizophrenia.

Patients with schizophrenia rarely develop rheumatoid arthritis, an autoimmune disease that exhibits genetic association with the HLA DRB1*04 gene. We previously investigated the hypothesis that schizophrenia is negatively associated with DRB1*04, and found that only half the expected number of schizophrenic patients had this gene when compared with controls. We now report the results of DRB1*04 genotyping in pedigrees multiply affected with schizophrenia. Polymerase chain reaction amplification and sequence-specific oligonucleotide probes were used to determine the DRB1 genotypes of the 187 members of 23 pedigrees multiply affected with RDC schizophrenia. DQA1, DQB1 and DPB1 genotypes were similarly determined. We analysed data using the extended transmission/disequilibrium test and found a trend for the preferential non-transmission of DRB1*04 alleles from heterozygous parents to their schizophrenic offspring (16 of 23 alleles not transmitted, chi 2 = 3.5, p = 0.06). We found no evidence for a gene of major effect using GENEHUNTER for parametric and non-parametric linkage analysis. The results from this small sample need to be interpreted with caution, but they are in keeping with previous reports and suggest that HLA DRB1*04 alleles may be associated with a reduced risk of schizophrenia.

Alleles↗
PubMed1998

The surgical treatment of low back pain.

If nonoperative management fails to relieve a clearly identifiable and surgically treatable cause of lumbar pain, then surgery may be beneficial. Certain "red flags" indicate the need for urgent or emergent surgical intervention. Low back pain is associated with several degenerative conditions in the lumbar spine, including degenerative disc disease, spinal stenosis, spondylolisthesis, degenerative scoliosis, facet joint syndrome, and disc herniation.

Diskectomy↗
PubMed1997

The effect of empiric and prophylactic treatment with fluconazole on yeast isolates in a surgical trauma intensive care unit.

OBJECTIVE: To assess the effect of aggressive antifungal prophylaxis and empiric antifungal therapy using fluconazole on the mycotic microbiology and associated infectious complications in a surgical intensive care unit. DESIGN: Retrospective review of a cohort of critically ill surgical patients treated during an 11-month period. SETTING: Surgical intensive care unit, university hospital, state-designated level I trauma center. PATIENTS: All patients treated with fluconazole during the study. MAIN OUTCOME MEASURES: Positive fungal cultures obtained after commencement of antifungal prophylaxis or antifungal treatment with fluconazole. Overall and infectious mortality rates for patients with positive cultures were also measured. RESULTS: Of 72 surgical patients who were treated with fluconazole; 16 (22%) had secondary mycoses. Fourteen (88%) of these patients were receiving fluconazole as antifungal prophylaxis or as empiric treatment of suspected but unproved infection. The predominant organisms isolated from these 16 patients were Candida glabrata (41%) and Candida parapsilosis (41%). Overall mortality for this group was 44%, and infectious mortality was 38%. The infectious mortality rate was significantly higher than the rate found in patients who were successfully treated with fluconazole for primary mycoses, and who did not have secondary infections with resistant organisms (mortality, 9%; P < .01, chi 2). CONCLUSIONS: Emergence of resistant species after treatment with fluconazole does occur in surgical patients, and suggests that the development of a secondary fungal infection with a resistant organism may be associated with a poor prognosis.

Antifungal Agents↗
PubMed1997

Regional distribution of cystic fibrosis-linked DNA haplotypes in Brazil: multicenter study.

The restriction fragment length polymorphism (RFLP) haplotypes of cystic fibrosis (CF) alleles vary between populations. To determine the distribution of two RFLPs (XV-2C and KM-19) that are tightly linked to the CF locus, we analyzed a white sample from five different states of Brazil. The haplotypes of 314 CF- and 237 non-CF-bearing chromosomes were uniformly distributed over the five states. The XV-2C allele and haplotype frequencies and the degree of linkage disequilibrium were determined. These were similar to values previously reported in southern European countries but different from results reported for northern and central Europe and North America. In contrast, although KM-19 allele frequencies differed between Brazilian states and European and North American countries, these frequencies were similar to values reported in black Americans. A significant proportion of Brazilian CF-bearing chromosomes had less common haplotypes, suggesting a heterogeneous distribution of CF gene mutations among Brazilians. Further studies are needed to identify the mutations affecting the Brazilian CF patients with various haplotypes.

Adolescent↗
PubMed1996

A gene at 6p? Schizophrenia.

Schizophrenia often exhibits familial clustering; this is suggestive of heritable factors, but the whereabouts of responsible gene(s) has remained elusive. Recent research suggests that a region of chromosome 6p may hold some of the answers.

Chromosome Mapping↗
PubMed1995

Systematic search for major genes in schizophrenia: methodological issues and results from chromosome 12.

We describe a method of systematically searching for major genes in disorders of unknown mode of inheritance, using linkage analysis. Our method is designed to minimize the probability of missing linkage due to inadequate exploration of data. We illustrate this method with the results of a search for a locus for schizophrenia on chromosome 12 using 22 highly polymorphic markers in 23 high density pedigrees. The markers span approximately 85-90% of the chromosome and are on average 9.35 cM apart. We have analysed the data using the most plausible current genetic models and allowing for the presence of genetic heterogeneity. None of the markers was supportive of linkage and the distribution of the heterogeneity statistics was in accordance with the null hypothesis.

Chromosomes, Human, Pair 12↗
PubMed1995

Linkage studies of bipolar disorder in the region of the Darier's disease gene on chromosome 12q23-24.1.

We have recently described a family in which there is cosegregation of major affective disorder with Darier's disease and have mapped this autosomal dominant skin disorder to 12q23-q24.1. This has provided an interesting candidate region for genetic studies of bipolar disorder. We have studied the segregation of seven markers spanning the Darier's disease locus in 45 bipolar disorder pedigrees and found modest evidence in support of linkage under heterogeneity for 5 of these markers. Nonparametric analyses were suggestive of linkage with a marker at the gene encoding a secretory form of phospholipase A2. Our sample has relatively low power to detect linkage under heterogeneity and independent researchers should examine markers from this region in further samples of bipolar pedigrees.

Alleles↗
PubMed1995

Genetic association between alleles of pancreatic phospholipase A2 gene and bipolar affective disorder.

Chromosome 12q is a region of interest for the genetics of bipolar affective disorder because of reports of apparent cosegregation between this disorder and Darier's disease in a small number of families. Findings from a recent linkage study suggest that this chromosomal region may contain a susceptibility gene for bipolar affective disorder. We have found evidence of an allelic association between bipolar disorder and a marker at the pancreatic phospholipase A2 gene (PLA2A) in this region (p < or = 0.01). These results are consistent with the linkage study, and warrant additional investigations.

Alleles↗
PubMed1995

Cytochrome P4502D6 genotype does not determine response to clozapine.

1. The atypical antipsychotic drug clozapine, used in the treatment of resistant schizophrenia, is metabolized partly by the hepatic cytochrome P450 enzyme CYP2D6. Two phenotypes with respect to the activity of the enzyme are recognized (extensive metabolisers (EM) and poor metabolisers (PM)), resulting from allelic variation in the gene, CYP2D6. 2. Genotype was determined in 123 schizophrenic patients currently being treated with clozapine, in order to determine if EM or PM status influences response to this drug. Patients were divided into responders and non-responders using the Global Assessment Scale, and genotyped for the A and B poor metaboliser mutations by digesting PCR products with HpaII or BstNI. 3. Fifty-nine patients were heterozygous for allele B and for allele A. Eight patients were determined as poor metabolisers since they were homozygous either for A and B. Poor metabolisers were equally distributed between responders and nonresponders and no correlation between CYP2D6 alleles and response to clozapine was found. 4. The results are consistent with recent findings showing that CYP1A2, rather than CYP2D6, is the major enzyme responsible for the metabolism of clozapine.

Alleles↗
PubMed1995

An association study of a neurotrophin-3 (NT-3) gene polymorphism with schizophrenia.

Since abnormalities of brain development play a role in the aetiology of schizophrenia, growth factors, known to play a role in neurodevelopment, such as neurotrophin-3 (NT-3), are therefore candidate genes for this disorder. The A3/147 bp allele of a dinucleotide repeat polymorphism in the promoter region of the NT-3 gene has been reported as occurring more frequently in a sample of Japanese schizophrenics compared to controls. We have determined the frequency of alleles of this polymorphism in 175 Caucasian schizophrenic patients and 147 control subjects. The patient and control samples showed no significant deviation from Hardy-Weinberg equilibrium and, in a test of allalleles, the patients and controls did not differ significantly in allele frequencies. However, the male schizophrenics were more likely than male controls to have the A3/147 bp allele (P = 0.029).

Alleles↗