Biomedical subjects

E L Harris

Publications and source records attributed to E L Harris.

At least 19 recordsLinked to original sources

PubMed2006

Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in Native Americans and whites in the Hemochromatosis and Iron Overload Screening Study.

We compared initial screening transferrin saturation (TfSat) and serum ferritin (SF) phenotypes and HFE C282Y and H63D genotypes of 645 Native American and 43,453 white Hemochromatosis and Iron Overload Screening Study participants who did not report a previous diagnosis of hemochromatosis or iron overload. Elevated measurements were defined as TfSat >50% in men and >45% in women and SF >300 ng/ml in men and >200 ng/ml in women. Mean TfSat was 31% in Native American men and 32% in white men (p = 0.0337) and 25% in Native American women and 27% in white women (p < 0.0001). Mean SF was 153 microg/l in Native American and 151 microg/l in white men (p = 0.8256); mean SF was 55 microg/l in Native American women and 63 microg/l in white women (p = 0.0015). The C282Y allele frequency was 0.0340 in Native Americans and 0.0683 in whites (p < 0.0001). The H63D allele frequency was 0.1150 in Native Americans and 0.1532 in whites (p = 0.0001). We conclude that the screening TfSat and SF phenotypes of Native Americans are similar to those of whites. The allele frequencies of HFE C282Y and H63D are significantly lower in Native Americans than in whites.

Adult↗

PubMed2005

The methylenetetrahydrofolate reductase C677T polymorphism does not associate with susceptibility to abdominal aortic aneurysm.

OBJECTIVES: To test whether the T variant of the C677T polymorphism in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) would associate with three distinct forms of vascular disease, abdominal aortic aneurysm (AAA), coronary artery disease (CAD) and peripheral vascular disease (PVD). BACKGROUND: Increases in homocysteine induce elastolytic activity in the arterial wall, a condition which may favour vascular pathogenesis including aneurysm formation. Homozygosity of the common T variant of the C677T polymorphism in the gene for MTHFR has been shown to associate with increased levels of homocysteine. Thus, this functional polymorphism may lead to an increased propensity to develop cardiovascular disease and, in particular, AAA. METHODS: An association study was conducted across 1207 subjects; 428 patients with AAA, 271 CAD patients, 226 PVD patients and 282 controls being genotyped for the C667T variants of MTHFR. RESULTS: There were no significant differences in the frequency of the MTHFR C677T variant between any of the groups examined. AAA patients who were homozygotes for the 677T allele did, however, appear to have significantly larger aneurysms than C allele carriers. CONCLUSION: This study provides no evidence that the T variant of MTHFR is associated with susceptibility to AAA, CAD or PVD. It may, however, be a contributory factor in AAA severity as indicated by aneurysm size.

Aged↗

PubMed2004

Modelling hydroenvironmental and health risk assessment parameters along the South Wales Coast.

This paper highlights the increasing concerns relating to hydroenvironmetal issues and cites recent examples of the challenges now being regularly faced by hydroenvironmetal scientists and engineers. The limitations and restrictions of both physical (or laboratory) and numerical (or computer based) hydraulic models used in the planning and management of aquatic basins are discussed. General details are given of numerical models used for flow and water quality concentration predictions in estuarine waters, with particular application to the challenges occurring along the South Wales coast. A highly accurate and non-diffusive finite difference scheme that solves the transport equation for predicting water quality indicators and suspended sediment concentration distributions is also discussed. In particular, details are outlined of the extension of the water quality indicators of faecal coliforms, as required to comply with the EU Bathing Water Directive, to predict health risk assessment, in the form of predicting the risk of gastroenteritis. Three example research projects along the South Wales coast are described; the projects involve the application of two-dimensional and three-dimensional hydroenvironmetal models to predict flow patterns and water quality indicator organism distributions in the coastal receiving waters. These studies include: (i) a curvilinear finite difference approach to modelling flows in the Bristol Channel, (ii) coastal health risk predictions in Swansea Bay using combined water quality and epidemiological models, and (iii) combined sewer overflow discharges into Cardiff Bay.

Computer Simulation↗

PubMed2001

Association of codon 72 polymorphism of p53 with lower prostate cancer risk.

BACKGROUND: A common germline polymorphism of p53 produces a protein with an Arg to Pro change at codon 72. This Pro variant has altered biochemical properties suggesting altered cancer susceptibility. METHODS: A case control study with 115 men with prostate cancer and 181 community control male subjects was conducted. Demographics, family history of cancer, and blood were obtained. Codon 72 genotypes were determined using PCR. RESULTS: The Pro/Pro genotype was associated with a markedly lower risk of prostate cancer (OR = 0.23, CI = 0.07-0.79, P = 0.012). Similar reduction in risk was observed when the analysis was limited to Caucasian subjects (86% of total). Reduction in risk remained significant in a logistic regression model after correcting for age and family history of prostate cancer (OR = 0.14, CI = 0.03-0.71, P = 0.017). CONCLUSIONS: Men with the p53 codon 72 Pro/Pro genotype appear to be at reduced risk of prostate cancer.

Adenocarcinoma↗

PubMed2001

Identification of two susceptibility loci for vascular fragility in the Brown Norway rat.

A trait of vascular fragility, characterized by the formation of abrupt defects within the elastic laminae of the abdominal aorta, has been identified in Brown Norway (BN) rats. These lesions are greatly exacerbated in F(1) rats from a BN x New Zealand genetically hypertensive (GH) intercross, implying that the genetic background provided by the GH rat influences lesion severity. The F(2) progeny of the BN x GH intercross were used to identify susceptibility loci for the lesions as well as exacerbating loci. Two major quantitative trait loci (QTLs) for number of internal elastic lamina lesions were identified on rat chromosomes 5 and 10, with the maximum "log of the odds ratio" (LOD) scores at D5Rat119 (LOD 5.0) and at D10Mit2 (LOD 4.5), respectively, together contributing 33.5% to the genetic variance. Further analysis revealed that the chromosome 10 locus exhibits a dominant mode of inheritance, with BN alleles being associated with increased lesion number (P < 0.0002) compared with GH homozygotes. This locus was in epistasis to a modifier locus on rat chromosome 2 at D2Mit14 (LOD score 2.12). A second major locus was identified on chromosome 5, exhibiting a semidominant mode of inheritance, again with the BN allele being significantly associated with increased lesion number (P < 0.0001). Furthermore, a locus influencing lesion severity was identified on chromosome 3 wherein GH alleles associated with increased severity. This is the first study to identify susceptibility loci for vascular elastic tissue fragility.

Animals↗

PubMed2001

Familial abdominal aortic aneurysms in the Otago region of New Zealand.

PURPOSE: To investigate the familial incidence and phenotypic characteristics of patients with abdominal aortic aneurysms (AAA) in the Otago region of New Zealand. METHODOLOGY: A retrospective audit based pilot study and a prospective study of patients having abdominal aortic aneurysm repair from September 1988 to September 1999 was performed. RESULTS: 248 probands were enrolled, of which 19.4% had one or more first degree relative affected. The age at diagnosis of the familial (70.2) and non-familial (70.5) patients was similar. The proportion of females was increased in the familial subgroup. Hypercholesterolaemia was the only phenotypic feature to differentiate familial from non-familial patients and was associated with an earlier age of presentation. In the familial families, brothers were the most common relative affected and 77% of the families had two patients with AAA. CONCLUSION: 19.4% of patients operated on in the Otago area for AAA had a familial component to their aneurysm.

Age Distribution↗

PubMed2001

Neither the New Zealand genetically hypertensive strain nor Dahl salt-sensitive strain has an A1079T transversion in the alpha1 isoform of the Na(+),K(+)-ATPase gene.

A putative 1079A-->T mutation in the alpha1 isoform of the Na(+), K(+)-ATPase (Atp1a1) gene of the Dahl salt-sensitive rat inbred by John Rapp (SS/Jr) strain was projected to cause a conformation change in the membrane hydrophobic region of the protein product, possibly resulting in hypertension. The existence of the mutation was challenged, but the challenge was apparently rebutted. The New Zealand genetically hypertensive (GH) rat is known to have a blood pressure quantitative trait locus on chromosome 2 containing the gene for the ATPase. Thus, we sought to determine whether the GH rat carried the 1079A-->T transversion. We chose a method, first nucleotide change analysis, that can detect point mutations in a mixed population of polymerase chain reaction (PCR) products, even in the presence of PCR bias, and confirmed our analysis by restriction enzyme digestion of PCR products. To ensure the validity of our analyses, we used site-directed mutagenesis to create positive controls containing the mutation. Surprisingly, we found that neither the GH nor the SS/Jr strain had the A1079T transversion. Indeed, the transversion was not found in any strain tested. As an incidental observation, we have sequenced the intron preceding the exon containing the putative A1079T transversion. Within this intron, a single-base C/T polymorphism was observed at base 132. Our results definitively eliminate the putative A1079T transversion in Atp1a1 as a causative factor underlying hypertension in the GH, spontaneously hypertensive, and SS/Jr rat strains and indicate that alternative candidate genes in the region defined by the chromosome 2 hypertension quantitative trait locus should be examined.

Adenosine Triphosphate↗

PubMed2000

Association of the 4G/5G polymorphism in the promoter region of plasminogen activator inhibitor-1 with abdominal aortic aneurysms.

PURPOSE: A familial component has previously been identified in 11% to 20% of patients with abdominal aortic aneurysms (AAAs). The genetic basis of familial AAA remains elusive, however. Matrix metalloproteinases have been implicated in aneurysm development; and plasmin, a serine protease, activates metalloproteinases. Plasminogen activator inhibitor-1 (PAI-1) regulates plasmin activation through the tissue plasminogen activators. A polymorphism within the promoter area of PAI-1 has been described that modifies PAI-1 expression and consequently plasminogen activation. The 4G homozygous variant is associated with increased PAI-1 expression and consequently reduced plasmin activity and therefore may be selected against in-familial AAA. The purpose of this study was to investigate the incidence of the 4G/5G insertion/deletion polymorphism in the promoter area of the PAI-1 gene in a population with AAA. METHODS: Patients seen at a tertiary referral center for repair of abdominal aortic aneurysms were recruited. DNA was extracted from blood. Primers were designed to amplify a 99 (5G)-base pair (bp) and a 98 (4G)-bp fragment bracketing the polymorphism. The 5' primer was mutated to allow a restriction endonuclease to cleave the 5G polymorphism into a 77-bp and a 22-bp fragment. Samples were run on agarose gels and stained with ethidium bromide. RESULTS: One hundred ninety patients with AAAs, including 39 patients with strong family histories and 163 controls were examined. The frequency of the 4G:5G alleles in the AAA population and in the control population was 0.6:0.4. However, 26% of patients with familial AAA were homozygous 5G compared with 13% of the control population. The 4G-allele frequency was 0.47 in the familial AAAs, compared with 0.62 in the nonfamilial patients (P =.02) and 0.61 in the control population (P =.03). CONCLUSION: The selection against the 4G4G genotype in the familial AAA population may indicate a role for PAI in the development of AAA in this population.

Aged↗

PubMed2000

XPD polymorphisms: effects on DNA repair proficiency.

XPD codes for a DNA helicase involved in transcription and nucleotide excision repair. Rare XPD mutations diminish nucleotide excision repair resulting in hypersensitivity to UV light and increased risk of skin cancer. Several polymorphisms in this gene have been identified but their impact on DNA repair is not known. We compared XPD genotypes at codons 312 and 751 with DNA repair proficiency in 31 women. XPD genotypes were measured by PCR-RFLP. DNA repair proficiency was assessed using a cytogenetic assay that detects X-ray induced chromatid aberrations (breaks and gaps). Chromatid aberrations were scored per 100 metaphase cells following incubation at 37 degrees C (1.5 h after irradiation) to allow for repair of DNA damage. Individuals with the Lys/Lys codon 751 XPD genotype had a higher number of chromatid aberrations (132/100 metaphase cells) than those having a 751Gln allele (34/100 metaphase cells). Individuals having greater than 60 chromatid breaks plus gaps were categorized as having sub-optimal repair. Possessing a Lys/Lys751 genotype increased the risk of sub-optimal DNA repair (odds ratio = 7.2, 95% confidence interval = 1.01-87.7). The Asp312Asn XPD polymorphism did not appear to affect DNA repair proficiency. These results suggest that the Lys751 (common) allele may alter the XPD protein product resulting in sub-optimal repair of X-ray-induced DNA damage.

Breast Neoplasms↗

PubMed2000

New target regions for human hypertension via comparative genomics.

Models of human disease have long been used to understand the basic pathophysiology of disease and to facilitate the discovery of new therapeutics. However, as long as models have been used there have been debates about the utility of these models and their ability to mimic clinical disease at the phenotypic level. The application of genetic studies to both humans and model systems allows for a new paradigm, whereby a novel comparative genomics strategy combined with phenotypic correlates can be used to bridge between clinical relevance and model utility. This study presents a comparative genomic map for "candidate hypertension loci in humans" based on translating QTLs between rat and human, predicting 26 chromosomal regions in the human genome that are very likely to harbor hypertension genes. The predictive power appears robust, as several of these regions have also been implicated in mouse, suggesting that these regions represent primary targets for the development of SNPs for linkage disequilibrium testing in humans and/or provide a means to select specific models for additional functional studies and the development of new therapeutics.

Animals↗

PubMed1999

Black-white differences in risk of developing retinopathy among individuals with type 2 diabetes.

OBJECTIVE: To assess racial differences in risk of developing retinopathy among individuals with type 2 diabetes, after taking into account differences in the distribution of risk factors for retinopathy. RESEARCH DESIGN AND METHODS: The participants were 105 individuals with type 2 diabetes, aged 40-69 years, who had no evidence of retinopathy at the time of a diabetic eye disease screening project. After an average of 4 years of follow-up, the subjects were reevaluated using nonmydriatic funds photography. RESULTS: Retinopathy occurred more often among black than white participants (50 vs. 19%). This difference could not be explained by differences in risk factors for retinopathy or potential confounders (odds ratio [95% CI] 2.96 [1.00-8.78] after adjustment for level of glycosylated hemoglobin, systolic blood pressure, type of diabetes treatment, and sex). CONCLUSIONS: These results are consistent with the concept that racial differences in risk of developing retinopathy exist among individuals with type 2 diabetes and that these differences may be caused by differential (genetic) susceptibility to the adverse effects of increased levels of blood glucose and/or blood pressure. Discovery of the etiology of this differential susceptibility would allows us to identify and target secondary prevention efforts to individuals with type 2 diabetes who are at increased risk of retinopathy.

Adult↗

PubMed1998

Segregation analysis of Parkinson disease.

Parkinson disease (PD) is a prevalent movement disorder of unknown cause whose incidence rises with increasing age. Nearly 20% of PD is familial, a small subset of which exhibits autosomal dominant transmission. However, in most families, the inheritance is not clear. To determine the most likely mode of inheritance of PD, we performed complex segregation analyses using kindreds of 136 PD patients randomly ascertained from a clinic population. The hypotheses of a nontransmissible environmental factor, no major gene or type (sporadic), and all Mendelian inheritance (dominant, recessive, additive, decreasing) were rejected (P <0.001). Familial clustering of PD in this data set is best explained by a rare familial factor which a) is transmitted in a nonMendelian fashion, and b) influences the age at onset of PD. If confirmed, our results have immediate implications in gene-mapping studies which often search for genes that behave in a Mendelian fashion that affect susceptibility rather than age at onset and long term implications in understanding the pathogenesis of PD.

Adolescent↗

PubMed1998

Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia.

The efficacy of allografting in acute lymphoblastic leukemia (ALL) is heavily influenced by remission status at the time of transplant. Using polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis, we have investigated retrospectively the impact of submicroscopic leukemia on outcome in 64 patients receiving allogeneic bone marrow transplantation (BMT) for childhood ALL. Remission BM specimens were taken 6 to 81 days (median, 23) before transplant. All patients received similar conditioning therapy; 50 received grafts from unrelated donors and 14 from related donors. Nineteen patients were transplanted in first complete remission (CR1) and 45 in second or subsequent CR. MRD was analyzed by PCR of Ig or T-cell receptor delta or gamma rearrangements, electrophoresis, and allele-specific oligoprobing. Samples were rated high-level positive (clonal band evident after electrophoresis; sensitivity 10(-2) to 10(-3)), low-level positive (MRD detected only after oligoprobing; sensitivity 10(-3) to 10(-5)), or negative. Excluding 8 patients transplanted in CR2 for isolated extramedullary relapse (all MRD-), MRD was detected at high level in 12 patients, low level in 11, and was undetectable in 33. Two-year event-free survival for these groups was 0%, 36%, and 73%, respectively (P <.001). Follow-up in patients remaining in continuing remission is 20 to 96 months (median, 35). These results suggest that MRD analysis could be used routinely in this setting. This would allow identification of patients with resistant leukemia (who may benefit from innovative BMT protocols) and of those with more responsive disease (who may be candidates for randomized trials of BMT versus modern intensive relapse chemotherapy).

Adolescent↗

PubMed1998

Minimal residual disease status as a predictor of relapse after allogeneic bone marrow transplantation for children with acute lymphoblastic leukaemia.

We have analysed the behaviour of minimal residual disease (MRD) after allogeneic bone marrow transplantation (allo-BMT) in 71 children with acute lymphoblastic leukaemia (ALL). The method relied on PCR of IgH, TCRdelta and/or TCRgamma gene rearrangements followed by electrophoretic size resolution and allele-specific oligoprobing. Patients were similarly conditioned; 55 received marrow from unrelated donors and 16 from related donors. MRD was assessed at various time-points up to 24 months after BMT. Three children were not evaluable due to transplant-related mortality. MRD was detected in 28/32 patients (88%) who relapsed post-BMT; 16 were positive at all times and 12 were initially negative but became positive at a median of 3 months (range 1.5-11) prior to relapse. In contrast, only eight of 36 (22%) patients who remained in continuing complete remission (CCR) (median follow-up 43 months, range 20-94) showed MRD at any time after BMT (P<0.0001). In these eight patients MRD was found up to 9 months after transplant and at low levels (0.01-0.001%). All eight (median follow-up 39 months, range 24-87) had at least two MRD-negative samples tested subsequently and five of the eight had evidence of grade I-II acute graft-versus-host disease (GvHD), raising the possibility of a graft-versus-leukaemia effect. In general, any evidence of MRD after allo-BMT is a poor prognostic sign. However, if immunotherapy were to be targeted towards patients with evidence of persisting MRD after BMT, the method described would expose only a small proportion of patients to unnecessary additional toxicity.

Adolescent↗

PubMed1997