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S B Harrap

Publications and source records attributed to S B Harrap.

At least 37 records · Page 2Linked to original sources
PubMed1999

Mutational analysis of the high affinity immunoglobulin E receptor beta subunit gene in asthma.

BACKGROUND: The gene for the beta subunit of the high affinity receptor for immunoglobulin E (FcepsilonRI-beta) on chromosome 11q13 is linked with clinical asthma and certain mutations have been identified. A study was undertaken to identify DNA variation in the FcepsilonRI-beta gene in a population sample in which linkage between 11q13 and asthma was explained by bronchial hyperreactivity (BHR) but not atopy. METHODS: DNA samples from 71 subjects with asthma, atopy, or BHR were analysed. The complete coding region, some of the introns, and some of the 5' untranscribed region of the FcepsilonRI-beta gene were sequenced. RESULTS: In the subjects studied there were no deviations from the published sequence in any of the seven coding exons of the FcepsilonRI-beta gene. In particular, the three previously reported mutations (Ile181, Leu183, Glu237) were not detected. Two new polymorphisms were discovered, one at position 243 in the 5' untranscribed region and one at position 4390 in intron III. Neither of these variants showed significant association with asthma, atopy, or BHR. CONCLUSIONS: These results suggest that, in the population studied, linkage of asthma and BHR to 11q13 is not explained by mutations in the FcepsilonRI-beta gene. Other mutations in the non-coding region of this gene or in adjacent genes must explain the linkage findings in this study.

Asthma↗
PubMed1999

Linkage analysis of glucocorticoid and beta2-adrenergic receptor genes with blood pressure and body mass index.

Glucocorticoids and catecholamines exert important effects on cardiovascular physiology and metabolism. Variants of the glucocorticoid receptor gene (GRL) and the beta2-adrenergic receptor gene (ADRB2) have been associated with high blood pressure and obesity. These genes are close on human chromosome 5q31-5q32, and we undertook a linkage analysis of this region in 264 families from the general population in relation to systolic and diastolic blood pressure, body mass index, weight, height, and pulse rate. All family members were genotyped at four microsatellite loci (D5S207, D5S210, D5S519, and D5S119) located on chromosome 5q31-5q33.3. Using quantitative identity-by-descent sibling pair linkage analysis, we found that at no loci was genetic similarity associated with phenotypic similarity for systolic and diastolic blood pressure, body mass index, weight, height, or pulse rate. Although it is not possible to exclude the influence of specific combinations of certain GRL and ADRB2 polymorphisms, the absence of significant linkage in our population argues against a role for GRL or ADRB2 in physiological variation of blood pressure and body mass index.

Adult↗
PubMed1999

Long-term effects of angiotensin-converting enzyme inhibition on renal medullary neutral lipid in spontaneously hypertensive rats.

Short-term treatment of young spontaneously hypertensive rats (SHR) with angiotensin-converting enzyme (ACE) inhibitors reduces systolic blood pressure. Renal medullary neutral lipids (RMNLs) have vasodilator properties that may explain the effects of ACE inhibition. We measured RMNL levels of SHR treated between 6 and 10 weeks of age with (1) vehicle, (2) ramipril 1 mg. kg-1. d-1, (3) the bradykinin B2 receptor antagonist icatibant 0.5 mg. kg-1. d-1, or (4) icatibant 0.5 mg. kg-1. d-1 plus ramipril 1 mg. kg-1. d-1. RMNLs were quantified by oil red O fluorescence at 10 and 20 weeks of age. Systolic blood pressure (BP) was measured by tail-cuff plethysmography. Ramipril reduced BP at 10 weeks of age and increased RMNLs compared with controls (0.99+/-0.07% versus 0.56+/-0. 06%, P<0.01). Icatibant alone had no significant effect on RMNLs (0.55+/-0.04%) but attenuated the increase in RMNLs by ramipril (0. 81+/-0.05%). In control SHR, the increase in BP between 10 and 20 weeks of age was associated with a significant increase in RMNLs (0.79+/-0.09%). SHR that had received ramipril had significantly lower BP than controls at 20 weeks of age, but RMNL was not significantly different (0.92+/-0.10%). Therefore, in young SHR, ACE inhibition increases RMNLs and reduces blood pressure, an effect that appears to depend on bradykinin. The changes in RMNLs at the age of 10 weeks paralleled long-term BP effects and may be involved in setting the BP track in SHR.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Insulin gene polymorphism and premature male pattern baldness in the general population.

Insulin is found in hair follicles and may play a role in the regulation of androgen metabolism and the hair growth cycle, which are relevant to the loss of scalp hair known as male pattern baldness. An excess of dihydrotestosterone on balding scalp indicates that the condition is androgen dependent. Premature male pattern baldness may be the male phenotype of familial polycystic ovary syndrome, a condition characterized by high levels of androgens and insulin that has been linked to insulin gene polymorphism. Therefore, we studied possible associations between relevant insulin gene polymorphisms and premature male pattern baldness in the general community. We examined the distribution of three dimorphic restriction fragment length polymorphisms: HphI, PstI and FokI in cases consisting of 56 men aged 18-30 years with significant baldness, and in 107 control men aged 50 years or more with no indication of baldness. No significant differences between cases and controls in allele, genotype or haplotype frequencies were identified. We conclude that, in the general population, the insulin gene is not associated with premature male pattern baldness.

Adolescent↗
PubMed1999

Discrepancies between echocardiographic measurements of left ventricular mass in a healthy adult population.

Increased left ventricular (LV) mass is associated with increased cardiovascular morbidity and mortality. LV mass is commonly estimated from echocardiography according to the Penn or ASE (American Society of Echocardiography) conventions. No formal statistical test of agreement between these methods has been published. Therefore we compared M-mode echocardiographic LV mass estimates by the Penn and ASE methods in a normal adult population. M-mode echocardiographic tracings were obtained in 169 healthy volunteers and used to calculate LV mass using the Penn and ASE methods. Median values of the estimates were similar [Penn, 126 g (interquartile range 96-170 g); ASE, 129 g (105-164 g); P=0.08] and were highly intercorrelated (r=0.98, P<0.0001). However, the Bland-Altman analysis of agreement revealed significant inconsistencies between Penn and ASE LV mass values. The difference between Penn and ASE values was correlated significantly with heart size (P<0.0001), such that, for small hearts, the Penn LV mass was lower than the ASE LV mass; in contrast, for large hearts, Penn estimates were greater than ASE values. In the upper 5% of the LV mass distribution, the median value for the Penn LV mass index was 132.4 g/m(2), compared with 116.5 g/m(2) for ASE values (2P=0.017). Thus the two most common methods of echocardiographic estimation of LV mass differ significantly at the upper and lower ends of the heart size distribution. These results have important implications for both cardiac research and clinical evaluation.

Adult↗
PubMed1998

Genetic analysis of male pattern baldness and the 5alpha-reductase genes.

Genetic predisposition and androgen dependence are important characteristics of the common patterned loss of scalp hair known as male pattern baldness. The involvement of the 5alpha-reductase enzyme in male pattern baldness has been postulated due to its role in the metabolism of testosterone to dihydrotestosterone. There are two known isozymes of 5alpha-reductase. Type I has been predominantly localized to the skin and scalp. Type II, also present on the scalp, is the target of finasteride, a promising treatment for male pattern baldness. We conducted genetic association studies of the 5alpha-reductase enzyme genes (SRD5A1 on chromosome 5 and SRD5A2 on chromosome 2) using dimorphic intragenic restriction fragment length polymorphisms. From a population survey of 828 healthy families comprising 3000 individuals, we identified 58 young bald men (aged 18-30 y) and 114 older nonbald men (aged 50-70 y) for a case control comparison. No significant differences were found between cases and controls in allele, genotype, or haplotype frequencies for restriction fragment length polymorphisms of either gene. These findings suggest that the genes encoding the two 5alpha-reductase isoenzymes are not associated with male pattern baldness. Finally, no clear inheritance pattern of male pattern baldness was observed. The relatively strong concordance for baldness between fathers and sons in this study was not consistent with a simple Mendelian autosomal dominant inheritance. A polygenic etiology should be considered.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1998

Cosegregation of spontaneously hypertensive rat renin gene with elevated blood pressure in an F2 generation.

OBJECTIVE: To investigate the role of the renin gene in the hypertension of the spontaneously hypertensive rat (SHR) of the Okamoto strain. METHODS: We determined whether the SHR renin allele was cosegregated with high blood pressure in 137 F2 rats derived from inbred SHR and Wistar-Kyoto rats. Systolic blood pressure in conscious rats was measured by the tail-cuff method, whereas mean arterial pressure was determined from an indwelling catheter in the left carotid artery. Renin genotypes of F2 rats were determined using a SHR-specific Bg/II restriction fragment length polymorphism that we have previously described. RESULTS: The SHR renin allele was cosegregated significantly with higher systolic blood pressure in male F2 rats aged 8-24 weeks and in females aged 12-24 weeks. The greatest differences in blood pressure between SHR renin allele homozygotes and Wistar-Kyoto rat renin allele homozygotes were 35 mmHg for males and 17 mmHg for females aged 24 weeks. The SHR renin allele was also associated with a higher mean arterial pressure in rats aged 24 weeks and cosegregated with higher body weight of male F2 rats aged 12-24 weeks but not with that of the females. In contrast to the relationship with blood pressure, the SHR renin allele was segregated with lower plasma renin concentrations in rats aged 24 weeks. CONCLUSION: These results are consistent with the SHR renin gene being one of the loci determining high blood pressure in rats of this strain, possibly through action at some extra-renal site subserving control of blood pressure.

Animals↗
PubMed1998

Persistent reduction in renal nerve growth factor mRNA after perindopril treatment of young spontaneously hypertensive rats.

Nerve growth factor (NGF) determines sympathetic innervation of target tissues, and NGF levels are increased in young spontaneously hypertensive rats (SHR). Angiotensin can affect NGF levels, and the persistent reduction in blood pressure after brief angiotensin-converting enzyme inhibition in young SHR may involve long-term changes in NGF and sympathetic innervation. We measured the relative abundance of renal NGF mRNA by reverse transcription-polymerase chain reaction in SHR during and after treatment from 6 to 10 weeks of age with vehicle, perindopril (3 mg/kg per day), the bradykinin B2 antagonist Hoe 140 (0.5 mg/kg per day), both perindopril and Hoe 140, or angiotensin II (Ang II; 200 ng/kg per minute). Glomerular filtration rates were estimated at 10 and 20 weeks of age. At 10 weeks of age, Ang II caused a significant (P<.01) increase and perindopril caused a significant (P<.01) decrease in renal NGF mRNA levels. Blockade of the bradykinin B2 receptor during perindopril treatment attenuated (P<.05) the reduction in NGF mRNA levels. Renal NGF mRNA (P=.005) and blood pressure (P<.001) remained significantly lower than control 10 weeks after perindopril treatment was stopped. The partial reduction in blood pressure at 20 weeks of age in rats that had received perindopril and Hoe 140 was not associated with any difference in renal NGF mRNA. Perindopril-induced long-term reduction in renal NGF mRNA levels may decrease sympathetic innervation and thereby contribute to the long-term posttreatment blood pressure reduction.

Aging↗
PubMed1998

Independent genetic susceptibility to cardiac hypertrophy in inherited hypertension.

Cardiac hypertrophy is a common but not inevitable complication of hypertension. Variation in heart size in hypertensives may reflect independent genetic susceptibility to cardiac hypertrophy. Using an experimental genetic model, we determined the location of quantitative trait loci responsible for cardiac hypertrophy and/or hypertension. We studied 182 F2 male animals derived from a cross of the spontaneously hypertensive rat and normotensive Donryu rats. Direct mean arterial pressure (MAP) and left ventricular (LV) mass were measured at 20 weeks of age, and DNA was obtained for linkage analysis. The estimated heritability of MAP was 62% and for LV mass expressed per unit of body weight (relative LV mass) was 76%. We used 185 polymorphic markers, with an average intermarker distance of 12.3 centimorgans for a genome-wide scan in a representative subgroup of 46 animals to identify preliminary quantitative trait loci, which were then mapped in all 182 male F2 rats. Two loci showed logarithm of the odds scores of > 4.0. One on chromosome 2, Lvm-1, was linked to relative LV mass but showed no evidence of linkage to MAP. Another locus on chromosome 1, Map-1, was linked to MAP. In the same region, a locus Lvm-2 was linked with relative LV mass. These data indicate the existence of a genetic locus on chromosome 2 of the spontaneously hypertensive rat that affects relative LV mass independently of blood pressure.

Animals↗
PubMed1998

Human alpha-adducin gene, blood pressure, and sodium metabolism.

The adducin genes contribute significantly to population variation in rat blood pressure and cell membrane sodium transport. The 460Trp mutation of the human alpha-adducin gene has been associated with hypertension, in particular hypertension sensitive to sodium restriction. We studied the relationship between the 460Trp mutation and population variation in blood pressure and sodium metabolism. From 603 Scottish families, we selected 151 offspring and 224 parents with blood pressures in either the upper (high) or bottom (low) 30% of the population distribution and measured the 460Trp mutation using allele-specific hybridization. In offspring, we also measured exchangeable sodium, plasma volume, and total body water. Plasma levels of components of the renin-angiotensin system, atrial natriuretic peptide, and cellular sodium and transmembrane sodium efflux were also estimated. The overall frequency of the 460Trp mutation was 27.1%. In offspring and parent groups, we found no difference in the genotype or allele frequencies of the 460Trp mutation between subjects with high or low blood pressure. There was no overall association between the alpha-adducin genotypes and blood pressure variation. In offspring, the 460Trp mutation was not associated with any significant differences in body fluid volumes or exchangeable sodium; levels of plasma renin, angiotensin II, aldosterone, or atrial natriuretic peptide; intracellular sodium; or ouabain-sensitive transmembrane sodium efflux. These findings suggest that in our Scottish population, the alpha-adducin 460Trp polymorphism is not related to blood pressure and does not affect whole body or cellular sodium metabolism.

Adolescent↗
PubMed1998

Nerve growth factor gene locus explains elevated renal nerve growth factor mRNA in young spontaneously hypertensive rats.

Nerve growth factor (NGF) controls the growth of sympathetic nerves and is increased in young spontaneously hypertensive rats (SHR). The NGF gene has been linked genetically with hypertension in the SHR strain and may explain high NGF mRNA levels. To test for genetic linkage between the NGF gene and its expression in vivo, we examined renal NGF mRNA levels in male SHR, control Donryu rats (DRY), and F2 rats derived from SHR and DRY at ages 2, 4, 10, and 20 weeks. Tail-cuff blood pressure was measured at 4, 10, and 20 weeks of age. NGF mRNA levels in SHR (NGF genotype: SS) were higher than those in DRY (NGF genotype: DD) at 2, 4, and 10 weeks of age (P<0.0001) but the same at 20 weeks of age. In the F2 generation, the S allele was associated with significantly (P=0.01) higher renal NGF mRNA levels at 2 weeks of age. Mean NGF mRNA levels fell (P=0.01) with age in F2 rats, and the difference between SS and DD genotype F2 rats diminished at older ages and was not significant. In F2 rats there was a positive correlation between the number of NGF S alleles inherited and tail-cuff pressure (P<0.007). Our findings indicate that the NGF locus is an important regulator of NGF mRNA levels. It is likely that mutations in or near the NGF gene explain in part high early NGF gene expression in SHR.

Animals↗
PubMed1998

The new asthma genetics and its implications for public health.

OBJECTIVE: To review the genetics of asthma from a public health perspective. DATA SOURCES: Studies of asthma genetics published between 1990 and 1997 were reviewed. STUDY SELECTION: Studies based on random population sampling were preferred. Both linkage and association studies were included, as were genome scans. Studies needed to report results for asthma or the related traits of atopy and bronchial hyperreactivity (BHR). DATA EXTRACTION: The chromosomal locations linked to or candidate genes associated with asthmatic traits were tabulated. DATA SYNTHESIS: A clear majority of studies relied on clinical ascertainment or highly inbred populations. Although there is no consensus about the definition of asthma, phenotypic characterisation of subjects is more complete in recent studies. The high affinity IgE receptor gene on chromosome 11q and a cluster of cytokine genes on chromosome 5q are linked both to atopy and BHR. The T cell receptor gene on chromosome 14q is linked to specific IgE responses, and a region on chromosome 12q is linked both to total IgE levels and asthma. Genome scans have identified other regions of interest on chromosomes 2q, 4, 5p, 6, 7, 11p, 13, 16, 17, 19q, and 21q. CONCLUSIONS: Asthma is a complex polygenic disorder with marked gene-environment interactions. However, it is proving tractable to powerful new genetic approaches arising from the human genome project. At the present state of knowledge, population screening for the asthma genes so far identified cannot be justified. Gene therapy for asthma is an even more remote prospect.

Asthma↗
PubMed1997

Abnormal epinephrine release in young adults with high personal and high parental blood pressures.

BACKGROUND: Increased activity of the sympathetic nervous system has been proposed as a cause of high blood pressure (BP) and may be related to diet and body weight. To determine the role of these factors in predisposition to high BP, we studied 100 young adults with high or low BP from families in which both parents had either high or low BP. METHODS AND RESULTS: Plasma catecholamine, glucose, and insulin levels were measured before and after an oral glucose load. There was a significant correlation between fasting plasma norepinephrine and mean arterial pressure (P=.001). Subjects with high BP, irrespective of parental BP, were heavier (P=.003) and fatter (P=.002) and had a greater rise in plasma insulin (P=.003) following glucose than those with low BP. Offspring with high BP whose parents also had high BP showed an unexpected rise in plasma epinephrine (P=.004) following glucose. This adrenal medullary response was not the result of high parental or high personal BP alone as it was not seen in offspring with low BP whose parents had high BP or in offspring with high BP whose parents had low BP. CONCLUSIONS: Irrespective of family history, high BP is associated with increased body weight and hyperinsulinemia and reflects personal environment and behavior. However, abnormal epinephrine release is characteristic of the combination of genetic, environmental, and behavioral factors that is associated with high personal BP and a familial predisposition to high BP.

Adolescent↗
PubMed1997

Linkage analysis of bronchial hyperreactivity and atopy with chromosome 11q13.

There are two key clinical features of asthma: allergy and bronchial hyperreactivity (BHR). Some pedigree studies of atopy have indicated linkage with the high affinity IgE receptor (Fc epsilon RI-beta) gene on chromosome 11q13, but others failed to confirm this linkage. We examined the genetic linkage of three polymorphic microsatellite markers to atopy and BHR in 120 affected sibling pairs recruited from the general community. We found no linkage to atopy at any of the three 11q13 loci studied. Our findings also do not favour linkage between BHR and loci approximately 8-9 cM either side of the Fc epsilon RI-beta gene.

Adult↗
PubMed1997

Absence of genetic linkage of chromosome 5q31 with asthma and atopy in the general population.

BACKGROUND: Clinical asthma is associated with increased serum total immunoglobulin E (IgE), atopy (skin prick test positivity to common aeroallergens), and bronchial hyperreactivity (BHR) to non-specific stimuli (positive methacholine challenge test). A region on chromosome 5q31-33 has been linked with increased total serum IgE and BHR. A study of the genetic linkage of this region with clinical asthma and atopy was therefore undertaken. METHODS: A polymorphic microsatellite marker in chromosome 5q31 (D5S399) was studied in 119 sibling pairs recruited from the general population who shared asthma, atopy, and/or BHR. Based on our population distribution of 13 different alleles, it was expected that by chance alone sibling pairs would share on average 1.24 alleles and that a significant excess would indicate genetic linkage. RESULTS: No evidence of linkage was found in 45 siblings concordant for asthma (shared alleles = 1.09, p = 0.95), in 103 sibling pairs with atopy (shared alleles = 1.18, p = 0.82), in 51 sibling pairs with BHR (shared alleles = 1.22, p = 0.62), or in 68 sibling pairs who shared atopy in the absence of BHR (shared alleles = 1.22, p = 0.61). A slight non-significant excess of shared alleles (1.44, p = 0.11) was observed in siblings who shared BHR without atopy. CONCLUSIONS: No evidence of genetic linkage of chromosome 5q31 with either clinical asthma or atopy was therefore detected in the population studied. Linkage between chromosome 5q and BHR needs further investigation.

Adult↗