[Show abstract][Hide abstract] 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.
Croatian Medical Journal 11/2008; 49(5):586-99. DOI:10.3325/cmj.2008.5.586 · 1.31 Impact Factor
[Show abstract][Hide abstract] 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.
European Journal of Vascular and Endovascular Surgery 09/2005; 30(2):137-42. DOI:10.1016/j.ejvs.2005.02.047 · 2.49 Impact Factor
[Show abstract][Hide abstract] 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.
Journal of Vascular Surgery 01/2004; 38(6):1363-7. DOI:10.1016/S0741-5214(03)01027-9 · 3.02 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Cardiovascular Surgery 07/2001; 9(3):241-8. DOI:10.1016/S0967-2109(00)00140-X
[Show abstract][Hide abstract] 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.
Journal of Vascular Surgery 06/2000; 31(5):1026-32. DOI:10.1067/mva.2000.104589 · 3.02 Impact Factor
[Show abstract][Hide abstract] 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.
Genome Research 05/2000; 10(4):473-82. · 14.63 Impact Factor
[Show abstract][Hide abstract] 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.
Journal of Vascular Research 03/2000; 37(2):73-81. DOI:10.1159/000025718 · 2.90 Impact Factor
[Show abstract][Hide abstract] 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.
Clinical and Experimental Pharmacology and Physiology 03/1998; 25(3-4):204-207. DOI:10.1111/j.1440-1681.1998.t01-17-.x · 2.37 Impact Factor
[Show abstract][Hide abstract] 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.
Clinical and Experimental Pharmacology and Physiology 01/1998; 25(3-4):204-7. · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine associations between cardiovascular parameters and genotype in 205 F2 rats of both sexes and lineages from reciprocal crosses made between rats of the New Zealand genetically hypertensive (GH) and Brown Norway (BN) rat strains.
Systolic tail blood pressure, mean arterial blood pressure, pulse rate, heart mass, body mass and relative heart mass were determined for each rat in the age range 17-19 weeks, and DNA polymorphisms were examined for the guanylyl cyclase A (GCA), angiotensin converting enzyme (ACE) and renin (REN) genes.
The phenotypic data indicated the presence of genes on the X and Y chromosomes that affected blood pressure. The GH GCA allele, in males only, and the GH ACE allele, in females only, both cosegregated with increased blood pressure. The ACE effect was confined to rats of one lineage only, namely those with GH grandfathers. A cosegregation of the GH REN allele with decreased blood pressure was also detected in females with BN grandfathers. In contrast, the GH REN allele cosegregated with a smaller heart in males only, whereas the GH ACE allele cosegregated with a larger heart both in males and in females. In males this was the consequence of a decrease in body mass with no change in absolute heart mass, whereas in females there were changes in both of these parameters.
The results show that cardiac hypertrophy and blood pressure have independent genetic determinants in the GH rat, and indicate the importance of sex in determining the phenotypic expression of genes underlying cardiovascular pathology.
Journal of Hypertension 05/1995; 13(4):397-404. DOI:10.1097/00004872-199504000-00004 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vascular smooth muscle cells cultured from spontaneously hypertensive (SHR), New Zealand genetically hypertensive (GH) rat strains and their control strains (Wistar-Kyoto (WKY) and normal Wistar (N) rats) were compared for mitogenic responses [( 3H]-thymidine incorporation) to angiotensin II (AII), fetal calf serum (FCS), and the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). SHR cells showed enhanced basal [3H]-thymidine incorporation and increased responses to all three factors. In contrast, basal and FCS-stimulated [3H]-thymidine incorporation was the same or less in GH than in N cells. However, DNA synthesis was greater in GH cells in response to AII, AII + TPA or FCS + TPA. These results suggest that vascular smooth muscle cells from both hypertensive rat strains display enhanced mitogenesis, but the enhancement occurs via different intracellular signalling pathways.
Biochemical and Biophysical Research Communications 09/1990; 170(3):1249-55. DOI:10.1016/0006-291X(90)90528-U · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Control of cell calcium handling and transport may be abnormal in hypertension. We have studied calcium efflux rates in response to angiotensin II and vasopressin in cultured vascular smooth muscle cells from New Zealand genetically hypertensive rats and normotensive control rats. Calcium efflux with both peptides was time- and concentration-dependent and was significantly greater in cells from the genetically hypertensive rats (P < 0.001, analysis of variance). In addition, mean +/- s.d. protein content (0.31 +/- 0.01 versus 0.28 +/- 0.02 mg/well, n = 48, P < 0.001) and calculated total cell calcium (3.63 +/- 0.27 versus 2.86 +/- 0.32 nmol/mg protein, n = 16, P < 0.005) were greater in genetically hypertensive rat cells. These data are consistent with the presence of abnormal cell calcium dynamics in hypertension in genetically hypertensive rats.
Journal of Hypertension 12/1988; 6(4):S234-235. DOI:10.1097/00004872-198812040-00070 · 4.72 Impact Factor