PubMed Health⌕ Search

Biomedical subjects

S B Harrap

Publications and source records attributed to S B Harrap.

At least 19 recordsLinked to original sources
PubMed2005

Fine mapping of Lvm1: a quantitative trait locus controlling heart size independently of blood pressure.

We have previously reported a quantitative trait locus (QTL) on rat chromosome 2 that influences heart size independently of blood pressure (Left Ventricular Mass Locus 1; Lvm1). The recent release of the rat genome sequence allowed us to retest and refine this relatively broad QTL with a view to identifying within it candidate genes worthy of structural investigation. We sought to achieve this 'fine mapping' by increasing the marker density within the interval and undertaking a linkage analysis in a previously defined population of F2 hybrids generated from inbred spontaneously hypertensive rats (SHR) of the Okamoto strain and Fischer rat (F344) progenitors. We were able to reconfirm and resolve Lvm1 from its original width of approximately 45 to 15 cM. By reference to the ENSEBL rat genome data bank, we identified within Lvm1 27 known genes, 109 predicted genes and 7 pseudogenes. Of the known genes, candidates include potential regulators of cardiac growth, a sodium channel and calcium channel as well as the fibroblast growth factor 2 gene. Located nearby the Lvm1 locus was the gene for the angiotensin Type 1B receptor. Given the evidence that the ligand for the angiotensin Type 1B receptor-angiotensin II-is a potent cardiotroph, we also consider this gene a potential candidate. The identification of the precise allelic variant(s) within Lvm1 involved in the control of pressure-independent cardiac growth awaits further molecular studies.

Animals↗
PubMed2001

Sex, genes and blood pressure.

1. Throughout most of life, males have higher average blood pressures than females. This sexual dichotomy may be related to genetic factors including the X and Y sex chromosomes and genes that control sex steroids. Resultant physiological differences between men and women may also be relevant to the quantitative variation of blood pressure within the sexes. 2. The present overview collates our published and novel sex-related genetic data in relation to blood pressure from the Victorian Family Heart Study. These include a multipoint quantitative linkage analysis of the X chromosome and genetic association studies of single nucleotide polymorphisms (SNP) of the Y chromosome and genes encoding the androgen receptor (AR), oestrogen receptor alpha (ERalpha), 5alpha-reductase types I and II (SRD5A1 and SRD5A2) and aromatase (CYP19). 3. Systolic blood pressure (SBP) was linked (Z=3.3, genome-wide P < 0.05) to a region of the X chromosome that encompassed the AR gene and the Y chromosome was associated with diastolic blood pressure (DBP; P=0.03). In new analyses, we observed a possible association between a SNP in AR and DBP in 369 males (84.5 vs 82.1 mmHg for genotype A vs genotype B, respectively; P=0.06) and a significant association between haplotypes of the Y chromosome and AR SNP in males (P=0.01) with a difference of nearly 6 mmHg DBP between extreme groups. Associations were also observed for polymorphisms of SRD5A1 and ERalpha with DBP and SBP in males, respectively. 4. The findings indicate that genes related to sexual phenotypes may be relevant to the normal variation in blood pressure, even within the sexes. Further genetic and physiological analyses will be required to confirm these observations and to determine the mechanisms of action and the nature of any interactions.

Adolescent↗
PubMed2001

Polymorphism of the androgen receptor gene is associated with male pattern baldness.

The common heritable loss of scalp hair known as male pattern baldness or androgenetic alopecia affects up to 80% of males by age 80. A balding scalp is characterized by high levels of the potent androgen dihydrotestosterone and increased expression of the androgen receptor gene. To determine if the androgen receptor gene is associated with male pattern baldness, we compared allele frequencies of the androgen receptor gene polymorphisms (StuI restriction fragment length polymorphism and two triplet repeat polymorphisms) in cases with cosmetically significant baldness (54 young and 392 older men) and controls (107 older men) with no indication of baldness. The androgen receptor gene StuI restriction site was found in all but one (98.1%) of the 54 young bald men (p = 0.0005) and in 92.3% of older balding men (p = 0.000004) but in only 76.6% of nonbald men. The combination of shorter CAG and GGC triplet repeat lengths was also more prevalent in bald men (p = 0.03). The ubiquity of the androgen receptor gene StuI restriction site, and higher incidence of shorter triplet repeat haplotypes in bald men suggests that these markers are very close to a functional variant that is a necessary component of the polygenic determination of male pattern baldness. Functional mutation in or near the androgen receptor gene may explain the reported high levels of expression of this gene in the balding scalp.

Adult↗
PubMed2001

Significant population variation in adult male height associated with the Y chromosome and the aromatase gene.

The determination of human adult height is dependent on both environmental and genetic factors. Rare causes of abnormal stature have been identified, including mutations in the gene encoding aromatase (CYP19) and regions on the Y chromosome. However, the possible role of these loci in the genetic control of normal adult height is unknown. We have performed an association study using common biallelic polymorphisms within CYP19 and the Y chromosome to determine whether these loci are associated with variation in height in 413 adult males and 335 females drawn at random from a large population sample. An association between CYP19 and height was found (difference, 2.0 cm; 95% confidence interval, 0.16-3.8; P = 0.003), but this was more evident in men (difference, 2.3 cm; 95% confidence interval, 0.38-4.4; P = 0.05) than women (difference, 0.2 cm; 95% confidence interval, -2.1 to 1.6; P = 0.94). An association was also found with the Y chromosome (P = 0.009; difference of 1.9 cm; 95% confidence interval, 0.5-3.4). Additionally, when men were grouped according to haplotypes of the CYP19 and Y chromosome polymorphisms, a difference of 4.2 cm (95% confidence interval, 0.67-7.3) was detected (P = 0.004). These results suggest that in men, genetic variation in CYP19 and on the Y chromosome are involved in determining normal adult height, and that these loci may interact in an additive fashion.

Adolescent↗
PubMed2001

Male pattern baldness is not associated with established cardiovascular risk factors in the general population.

A number of studies have shown an association between male pattern baldness (MPB) and cardiovascular disease. Few of these studies, however, have examined whether MPB is a novel risk factor, or is associated with abnormalities of established coronary risk factors. We have therefore performed an analysis of MPB and cardiovascular risk factors in the general population. A total of 1219 male participants aged 18-70 years from the Victorian Family Heart Study were surveyed using a validated questionnaire for degree and pattern of baldness. Carefully standardized measures of height, weight, blood pressure, pulse rate, total and high-density lipoprotein cholesterol, and plasma fibrinogen were made. Subjects were grouped according to the degree and pattern of baldness as: no baldness, frontal baldness and vertex baldness. Bald men were older than non-bald men (P < 0.0001). Age was also associated with increased levels of coronary risk factors (P < 0.0001). When multiple regression was used to adjust for age differences, the levels of coronary risk factors were not significantly different between the bald and non-bald groups. The lack of association between baldness and established coronary risk factors implies that baldness may predispose to coronary heart disease through novel mechanisms yet to be defined.

Adolescent↗
PubMed2001

Physiological relationships between central vascular haemodynamics and left ventricular structure.

Left ventricular hypertrophy is an independent cardiovascular risk factor. In hypertensives, the pattern of hypertrophy is influenced by central haemodynamic characteristics. Central haemodynamics may also determine physiological differences in left ventricular structure and predispose to particular responses of the left ventricle to pathological increases in load. M-mode echocardiography was used to measure left ventricular diastolic dimension and to estimate left ventricular mass index, relative wall thickness and stroke volume in 159 healthy volunteers aged between 19 and 74 years. Tonometric sphygmography was used to estimate augmentation index, central end-systolic and mean arterial blood pressure. Effective arterial elastance was calculated as the ratio of end-systolic pressure to stroke volume. Left ventricular mass index and relative wall thickness were adjusted for variation in age, sex and blood pressure before analyses. Left ventricular diastolic dimension exhibited significant inverse correlations with both effective arterial elastance (r=-0.72, P<0.0001) and augmentation index (r=-0.23, P=0.004). Adjusted left ventricular mass index was inversely correlated with effective arterial elastance (r=-0.35, P<0.0001), but no correlation was observed between left ventricular mass index and augmentation index (r=0.04). Adjusted relative wall thickness correlated with increasing effective arterial elastance (r=0.32, P<0.0001) and augmentation index (r=0.18, P=0.02). Relative wall thickness (r=0.34, P<0.0001), but not left ventricular mass index, correlated with age. Higher elastance and augmentation correlates with relatively smaller left ventricular cavity size but larger relative wall thickness. Age-related changes in left ventricular afterload may affect relative wall thickness more significantly than left ventricular mass index and may contribute to a particular change in left ventricular geometry with age.

Adult↗
PubMed2000

Familial patterns of covariation for cardiovascular risk factors in adults: The Victorian Family Heart Study.

The Victorian Family Heart Study was established to address the causes of familial patterns in cardiovascular risk factors. From 1990 to 1996, a representative population sample of 783 adult families (2,959 individuals), each comprising both parents (40-70 years) and at least one natural adult offspring (18-30 years), was recruited in Melbourne, Australia. Included in both generations were 461 monozygotic and dizygotic twins as pairs or singletons. A multivariate normal model was used for pedigree analysis of height, weight, body mass index, diastolic and systolic blood pressure, pulse rate, and total and high density lipoprotein cholesterol. All traits showed evidence for additive genetic variation, explaining from 55% (height) to 26% (pulse) of age- and sex-adjusted variance. An effect persisting into adulthood of shared family environment during cohabitation explained from 39% (body mass index) to 13% (systolic blood pressure) of variance (not nominally significant for diastolic blood pressure). These shared environmental effects were strongest within twin pairs, less so for sibling pairs, and least for parent-offspring pairs (in which an effect was not observed for weight, diastolic and systolic blood pressure, and total cholesterol). On a background of genetic influences, there are periods in early life during which the family environment cements long-term correlations between adult relatives in cardiovascular risk factors.

Adult↗
PubMed2000

Increased left ventricular mass is not associated with impaired left ventricular diastolic filling in normal individuals.

BACKGROUND: Hypertensive left ventricular (LV) hypertrophy has been associated with diastolic dysfunction. However, the underlying physiological relationship between LV size and diastolic function remains to be clarified. The aim of this study was to evaluate the relationship between several measures of diastolic filling and LV mass in a population sample. METHODS: We used M-mode and Doppler echocardiography to compare left ventricular mass index (LVMI) and wall thickness with five measures of ventricular diastolic filling (ratio of the peak early mitral inflow velocity to the peak atrial mitral inflow velocity, deceleration time of early mitral inflow, isovolumetric relaxation time, ratio of the peak pulmonary venous systolic to diastolic flow and difference between the durations of the pulmonary venous and mitral inflow atrial waves) in 159 healthy volunteers. RESULTS: LVMI was significantly (P< 0.0001) greater in men (81.3 g/m2, interquartile range: 67-94) than women (59.7 g/m2, interquartile range: 49-74), but no gender differences were observed in diastolic filling. Higher age, blood pressure and heart rate showed significant correlation with diminished diastolic filling. However, no measure of diastolic filling correlated with LVMI or wall thickness in either univariate or multiple regression analyses that adjusted for relevant covariates. CONCLUSIONS: LVMI does not explain physiological differences in diastolic filling. The significant decline in diastolic filling with age reflects changes in the quality rather than the quantity of myocardial tissue.

Adult↗
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↗
PubMed2000

Glomerular hyperfiltration, high renin, and low- extracellular volume in high blood pressure.

Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (P<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (P<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.

Adolescent↗
PubMed2000

Association of the human Y chromosome with high blood pressure in the general population.

Genetic variation in the Y chromosome has significant effects on male blood pressure in experimental animals, but the effects in humans are unknown. We examined the relationship between blood pressure and a polymorphic HINdIII restriction site in the nonrecombining region of the Y chromosome in 409 randomly selected men from the general population. Carefully standardized measures of systolic and diastolic blood pressures were made. The HINdIII restriction site was significantly more common (43.2%) in men in the lowest decile of the diastolic blood pressure distribution than men in the highest decile (15.9%, P=0.007). No significant difference in genotype frequency was observed between the lowest and highest deciles for systolic pressure (32.4% versus 27.8%, P=0.66). In the entire group, men with the HIN:dIII restriction site had significantly lower diastolic blood pressures (81.2 mm Hg, SD:8.3, versus 83.2 mm Hg, SD:8.7, P=0.03). No significant differences in systolic blood pressure (130.6 mm Hg, SD:14.7, versus 128.3 mm Hg, SD:13.6) were observed in relation to genotypes. Our results indicate that genetic variation in the human Y chromosome is associated with high blood pressure and contributes significantly to the quantitative variation of male diastolic blood pressure in the general population.

Age Factors↗
PubMed2000

Cardiovascular disease: genes and public health.

INTRODUCTION: The advances in molecular biology hold great promise for complex conditions such as cardiovascular disease. Early accurate diagnosis and new preventive and treatment strategies are among the potential benefits of genetic understanding. Many genes and mutations have been discovered that contribute to rare Mendelian forms of cardiovascular disease. However, there has been little tangible success in defining specific mutations that explain the more common forms of cardiovascular disease. Of the numerous genes tested, inconsistent results are a recurring theme. METHODS: This review addresses broader issues that touch on the clinical and epidemiological context in which the genetics of cardiovascular disease might develop. How do genes and environment interact in cardiovascular disease? What characteristics of a marker might make it useful? How will genetic understanding be used? What is the place of physiology in molecular biology? Is the future of genetics in patient management or public health? RESULTS: It is concluded that individuals and communities are unlikely to accept widespread DNA screening, and less likely to tolerate genetic manipulation. Genetic complexity will make the identification of specific mutations an expensive and potentially thankless task. CONCLUSIONS: Genetics may reveal new pathophysiological mechanisms against which simple, safe and effective public health measures can bring benefit to the greatest number.

Cardiovascular Diseases↗
PubMed1999

Genetic linkage of beta and gamma subunits of epithelial sodium channel to systolic blood pressure.

BACKGROUND: Mutations in the genes on chromosome 16p12 that encode the beta and gamma subunits of the epithelial sodium channel (SCNNIB and SCNNIG, respectively) have been linked with rare sodium-dependent forms of low and high blood pressure. Other DNA variants in or around these genes may contribute to variation in blood pressure and the risk of coronary heart disease and stroke. METHODS: We studied 286 white families from the general population in Victoria, Australia. Each family comprised both parents and two natural children. All participants were genotyped at chromosome 16p12 by use of four highly polymorphic microsatellite markers. Quantitative phenotype measurements were correlated with genotype in identity-by-descent sibling-pair linkage analyses. FINDINGS: We found significant linkage between systolic blood pressure and chromosome 16p12 after parametric analyses (p=0.0003) and non-parametric analyses (p=0.001). The mean difference in systolic blood pressure between siblings identical-by-descent at these loci was half as large (7.1 mm Hg) as the difference between siblings non-identical at these loci (14.0 mm Hg, p=0.001). No linkage between chromosome 16p12 and diastolic blood pressure or body-mass index was observed. INTERPRETATION: Chromosome 16p12 and the SCNNIB and SCNNIG genes are implicated in the physiological variation of systolic blood pressure. Our findings are important in explaining individual cardiovascular risk within the general population.

Adolescent↗
PubMed1999

Linkage analysis of endothelial nitric oxide synthase gene with human blood pressure.

OBJECTIVE: Endothelial nitric oxide exerts important effects on the regulation of vascular tone and structure. Variants of the endothelial nitric oxide synthase gene (eNOS) have been associated with hypertension and myocardial infarction, although some reports have shown negative linkage with hypertension. To examine whether the region encoding the eNOS gene is linked with physiological blood pressure variation, we undertook a linkage analysis of this region in the general population. DESIGN: In healthy volunteer families, we used two independent quantitative linkage analyses to examine the relationship between genotypes and phenotypes, with both parametric and non-parametric and single-locus and multi-point methods. METHODS: We selected 260 families comprising mother and father (aged 40-70 years) and two natural offspring (aged 18-30 years) from the Victorian Family Heart Study. After standardized measurement of clinical data and extraction of DNA, all family members were genotyped at five microsatellite loci including the CA repeat in the eNOS gene by a PCR method. The quantitative linkage analyses were conducted according to two different analysis programs, the Genetic Analysis System (GAS) and the MAPMAKER/SIBS. RESULTS: With both linkage analyses, we found no linkage between any of the loci on chromosome 7q35-36 and the phenotypes systolic and diastolic blood pressure, mean arterial pressure, pulse pressure, pulse rate, weight, height and body mass index. CONCLUSION: Based on these results, we conclude that in this population the eNOS gene is not linked to the physiological variation of blood pressure and other related phenotypes.

Adult↗