Eugenie L. Harris

Children's Hospital of Wisconsin, Madison, Wisconsin, United States

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Publications (28)84.18 Total impact

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    ABSTRACT: To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background. Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics. Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (beta=-1.25-/+0.17), whereas BN.GH2 (beta=0.66-/+0.09) and BN.GH18 (beta=0.71-/+0.07) had significantly decreased responses to ANGII from those observed in the BN (beta=0.88-/+0.08). The failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome background-dependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.
    Full-text · Article · Nov 2008 · Croatian Medical Journal
  • Eugenie L Harris · Ross Barnard

    No preview · Article · Dec 2006 · Journal of Hypertension
  • Eugenie L Harris · Ross Barnard

    No preview · Article · Jul 2006 · Journal of Hypertension
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    G T Jones · E L Harris · L V Phillips · A M van Rij
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    ABSTRACT: 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). 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. 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. 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. 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.
    Full-text · Article · Sep 2005 · European Journal of Vascular and Endovascular Surgery
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    ABSTRACT: Matrix metalloproteinase-9 (MMP-9) is a potent endopeptidase with activity against both collagens and elastin. Expression of MMP-9 is elevated in vascular disease, and in particular within aneurysm tissues. This study tested the hypothesis that the functionally more active T allele of the MMP9 C-1562T polymorphism may be overrepresented in patients with abdominal aortic aneurysm (AAA) compared with control subjects and patients with atherosclerotic peripheral vascular disease (PVD). Seven hundred eighty-nine unrelated persons (AAA, n = 414; control subjects, n = 203; PVD, n = 172) were genotyped for the common C-1562T functional promoter polymorphism of the MMP9 gene. Genotypes containing the T allele of this polymorphism were significantly more common in patients with AAA compared with both control subjects and patients with PVD (adjusted odds ratio, 2.41 and 2.94, respectively). The greatest shift between groups was observed in male patients, with a difference of 20.6% in CT/TT genotypes. and 12.1% in T allele frequency between patients with AAA compared with patients with PVD. This study provides further evidence to support the role of MMP-9 in the pathogenesis of AAA, and indicates that the MMP9 C-1562T functional polymorphism may represent a genetic component contributing to susceptibility to this vascular disease.
    Full-text · Article · Jan 2004 · Journal of Vascular Surgery

  • No preview · Article · Jan 2002 · ANZ Journal of Surgery
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    ABSTRACT: A putative 1079A->T mutation in the {alpha}1 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.
    Preview · Article · Oct 2001 · Hypertension
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    ABSTRACT: 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.
    No preview · Article · Aug 2001 · Physiological Genomics
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    ABSTRACT: To investigate the familial incidence and phenotypic characteristics of patients with abdominal aortic aneurysms (AAA) in the Otago region of New Zealand. 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. 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. 19.4% of patients operated on in the Otago area for AAA had a familial component to their aneurysm.
    No preview · Article · Jul 2001 · Cardiovascular Surgery
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    ABSTRACT: 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. 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. 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). 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.
    Full-text · Article · Jun 2000 · Journal of Vascular Surgery
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    ABSTRACT: 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.
    Full-text · Article · May 2000 · Genome Research
  • Gregory T. Jones · Eugenie L. Harris · Howard J. Jacob · A M van Rij
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    ABSTRACT: In this study, phenotypic expression of spontaneous elastic laminae defects within the rat abdominal aorta was examined. Lesions in Brown Norway (BN) rats were compared with those of New Zealand genetically hypertensive (GH) rats. BN and GH rats were cross-bred to determine the phenotypic expression of these lesions in successive F(1) and F(2) generations. Lesions were assessed by distribution, number and a semiquantitative index of severity. All BN aortae contained numerous elastic tissue defects. In comparison, GH aortae contained only occasional elastic tissue lesions. F(1) aortae contained lesions in numbers similar to those of the parental BN strain; however, F(1) lesions were of significantly greater severity. Within the F(2) generation, a wide range in both lesion numbers and severity indices was observed, with approximately a quarter of animals having lesion numbers analogous to the GH parental strain. In conclusion, this study indicates that the spontaneous elastic tissue lesions observed within BN rats are consistent with an autosomal dominant, possibly single gene, effect. Moreover, epistatic effects, derived from the GH strain, may influence the severity of these lesions. The gene(s) responsible may be important in the development of conditions such as arteriosclerosis and aneurysms in humans.
    No preview · Article · Mar 2000 · Journal of Vascular Research
  • J. I. Rossaak · A. M. van Rij · G. T. Jones · E. L. Harris

    No preview · Article · Jan 2000
  • J. I. Rossaak · E. L. Harris · G. T. Jones · A. M. van Rij

    No preview · Article · Jan 2000 · ANZ Journal of Surgery
  • Eugenie L Harris · Murray R Grigor · Caryn M Thompson
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    ABSTRACT: 1. The association of the Tnfα locus with several cardiovascular phenotypes and body mass has been studied in the F2 generation of a reciprocal cross between rats of the New Zealand genetically hypertensive (GH) and the normotensive Brown Norway (BN) strains. In the total F2 population the GH allele of Tnfα cosegregated with increased intra-arterial blood pressure (BP) in a recessive manner. A similar but weaker effect was observed for tail BP. 2. An association between genotype and body mass in females with GH grandfathers was also detected. 3. An association between genotype and pulse rate was observed for females. 4. This work supports other evidence pointing to an association of a gene (or genes) on rat chromosome 20 with hypertension.
    No preview · Article · Mar 1998 · Clinical and Experimental Pharmacology and Physiology
  • E L Harris · M R Grigor · C M Thompson
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    ABSTRACT: 1. The association of the Tnfalpha locus with several cardiovascular phenotypes and body mass has been studied in the F2 generation of a reciprocal cross between rats of the New Zealand genetically hypertensive (GH) and the normotensive Brown Norway (BN) strains. In the total F2 population the GH allele of Tnfalpha cosegregated with increased intra-arterial blood pressure (BP) in a recessive manner. A similar but weaker effect was observed for tail BP. 2. An association between genotype and body mass in females with GH grandfathers was also detected. 3. An association between genotype and pulse rate was observed for females. 4. This work supports other evidence pointing to an association of a gene (or genes) on rat chromosome 20 with hypertension.
    No preview · Article · Jan 1998 · Clinical and Experimental Pharmacology and Physiology

  • No preview · Article · Jan 1998 · Proceedings of the University of Otago Medical School

  • No preview · Article · Jan 1998

  • No preview · Article · Nov 1997 · Mammalian Genome

  • No preview · Article · Sep 1997 · Mammalian Genome

Publication Stats

514 Citations
84.18 Total Impact Points

Institutions

  • 2008
    • Children's Hospital of Wisconsin
      Madison, Wisconsin, United States
  • 1977-2005
    • University of Otago
      • • Department of Surgery
      • • Department of Biochemistry
      • • Department of Pharmacology and Toxicology
      Taieri, Otago, New Zealand