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Biomedical subjects

B Keavney

Publications and source records attributed to B Keavney.

At least 19 recordsLinked to original sources
PubMed2005

A rare variant of the leptin gene has large effects on blood pressure and carotid intima-medial thickness: a study of 1428 individuals in 248 families.

BACKGROUND: Rare mutations in the leptin (LEP) gene cause severe obesity. Common polymorphisms of LEP have been associated with obesity, but their association with cardiovascular disease has been little studied. We have examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure (BP), subclinical atherosclerosis as measured by carotid intima-medial thickness (CIMT), and body mass index (BMI) in a large family study. METHODS: Five polymorphisms spanning LEP were typed in 1428 individuals from 248 nuclear families. BP, CIMT, BMI, and plasma leptin were measured. RESULTS: The polymorphisms typed captured all common haplotypes present at LEP. There was strong association between a rare polymorphism in the 3' untranslated region of LEP (C538T) and both pulse pressure (p = 0.0001) and CIMT (p = 0.008). C/T heterozygotes had a 22% lower pulse pressure and a 17% lower CIMT than C/C homozygotes. The polymorphism accounted for 3-5% of the population variation in pulse pressure and CIMT. There was no association between any LEP polymorphism and either BMI or plasma leptin level. CONCLUSIONS: This large family study shows that the rare T allele at the C538T polymorphism of LEP substantially influences pulse pressure and CIMT, but does not appear to exert this effect through actions on plasma leptin level or BMI. This suggests that autocrine or paracrine effects in vascular tissue may be important physiological functions of leptin. This study also provides evidence that rare polymorphisms of particular genes may have substantial effects within the normal range of certain quantitative traits.

Atherosclerosis↗
PubMed2002

Electrocardiographic measures of left ventricular hypertrophy show greater heritability than echocardiographic left ventricular mass.

AIMS: To assess the heritability (i.e. relative contribution of genetic factors to the variability) of continuous measures of left ventricular hypertrophy determined by electrocardiography and echocardiography. METHODS AND RESULTS: We studied 955 members of 229 Caucasian families, ascertained through a hypertensive proband. Electrocardiographic measurements were performed manually on resting 12-lead electrocardiograms, and echocardiographic measurements were made on M-mode images. Sex-specific residuals for the left ventricular phenotypes were calculated, adjusted for age, systolic blood pressure, weight, height, waist-hip ratio, and presence of diabetes. Heritability was estimated in two ways: firstly, from familial correlations with adjustment for spouse resemblance; and secondly by using variance components methods with ascertainment correction for proband status. The heritability estimates (given as a range derived from the two methods) were higher for Sokolow-Lyon voltage (39-41%) than for echocardiographic left ventricular mass (23-29%). Electrocardiographic left ventricular mass, Cornell voltage, and Cornell product had heritability estimates of 12-18%, 19-25%, and 28-32%, respectively. CONCLUSIONS: Genetic factors may explain a substantial proportion of variability in quantitative electrocardiographic and echocardiographic measures of left ventricular hypertrophy. The greater heritability of Sokolow-Lyon voltage suggests that electrocardiographic phenotypes may be particularly important for the molecular investigation of the genetic susceptibility to cardiac hypertrophy.

Echocardiography↗
PubMed2001

Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE).

Circulating angiotensin I-converting enzyme (ACE) levels are influenced by a major quantitative trait locus (QTL) that maps to the ACE gene. Phylogenetic and measured haplotype analyses have suggested that the ACE-linked QTL lies downstream of a putative ancestral breakpoint located near to position 6435. However, strong linkage disequilibrium between markers in the 3' portion of the gene has prevented further resolution of the QTL in Caucasian subjects. We have examined 10 ACE gene polymorphisms in Afro-Caribbean families recruited in JAMAICA: Variance components analyses showed strong evidence of linkage and association to circulating ACE levels. When the linkage results were contrasted with those from a set of British Caucasian families, there was no evidence for heterogeneity between the samples. However, patterns of allelic association between the markers and circulating ACE levels differed significantly in the two data sets. In the British families, three markers [G2215A, Alu insertion/deletion and G2350A] were in complete disequilibrium with the ACE-linked QTL. In the Jamaican families, only marker G2350A showed strong but incomplete disequilibrium with the ACE-linked QTL. These results suggest that additional unobserved polymorphisms have an effect on circulating ACE levels in Jamaican families. Furthermore, our results show that a variance components approach combined with structured, quantitative comparisons between families from different ethnic groups may be a useful strategy for helping to determine which, if any, variants in a small genomic region directly influence a quantitative trait.

Black People↗
PubMed2001

SNPs and snails and puppy dogs' tails: analysis of SNP haplotype data using the gamete competition model.

The gamete competition model is a likelihood version of the transmission disequilibrium test (TDT) that is inspired by conditional logistic regression and the Bradley-Terry ranking procedure. In family-based association studies, both the TDT and the gamete competition model apply directly to data on a single nucleotide polymorphism (SNP). Because any given SNP has limited polymorphism, it is tempting to collect several SNPs within a gene into a single super marker whose alleles are haplotypes. Unfortunately, this tactic wreaks havoc with the traditional TDT, which requires codominant markers (Spielman et al. 1993; Terwilliger & Ott, 1992). Eliminating phase ambiguities by assigning haplotypes to individuals before conducting the TDT may give misleading results because only the most probable haplotypes are then considered. Because pedigree implementations of the gamete competition model can accommodate dominant as well as codominant markers, they circumvent the phase problem by including all possible phases weighted by their estimated frequencies.

Germ Cells↗
PubMed2000

Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators.

BACKGROUND: The original report of a possible association between myocardial infarction and the insertion/deletion (I/D) polymorphism of the gene for the angiotensin-1-converting enzyme (ACE) indicated a risk ratio for myocardial infarction with the DD genotype of 1.34 (95% CI 1.05-1.70), and the association was claimed to be particularly strong in a retrospectively defined low-risk subgroup (3.2 [95% CI 1.7-5.9). Subsequent investigations reached varying conclusions, but all were small, and much larger studies were needed. METHODS: 4629 myocardial infarction cases and 5934 controls were compared. Cases were UK men aged 30-54 years and women aged 30-64 years recruited on presentation to hospital with confirmed myocardial infarction. Controls were aged 30-64 years with no history of cardiovascular disease, but were siblings or children of myocardial infarction survivors, or spouses of such relatives. All risk-ratio calculations allow for this relatedness of some of the controls. An updated meta-analysis of previous studies was also conducted. FINDINGS: The ACE DD genotype was found in 1359 (29.4%) of the myocardial infarction cases and in 1637 (27.6%) of the controls (risk ratio 1.10 [95% CI 1.00-1.21]). The association between myocardial infarction and the DD genotype did not seem to be stronger in the subgroup defined as low risk by previously used criteria (234 [28%] of 836 cases and 911 [28%] of 3253 controls: risk ratio 1.04 [95% CI 0.87-1.24]), or in any other subgroup. Nor was the ACE I/D genotype predictive of subsequent survival. INTERPRETATION: This study involved many more cases than any previously reported study of this question, but did not confirm the existence of any substantial association. In an updated meta-analysis of these results with those of previously published studies, the risk ratio for myocardial infarction with the DD genotype seems to lie in the range 1.0 to about 1.1. Although an increase in risk of up to about 10-15% cannot be ruled out, substantially more extreme risks can be. Moreover, there are not especially strong associations in the subgroups previously selected for emphasis. These findings illustrate the need for some studies of candidate genes to involve much larger populations than is customary, without undue emphasis on retrospectively defined subgroups.

Adult↗
PubMed2000

Genetic association studies in complex diseases.

Genetic association studies are the most frequent type of study performed in the investigation of the genetic basis of complex cardiovascular conditions. While relatively easy to perform, and having previously correctly identified genetic effects subsequently proven to be due to genetic linkage, interpretation of the results of these studies is not always straightforward. Issues such as population stratification, data-driven subgroup analysis, possible absence of linkage disequilibrium between marker and disease locus, and testing of multiple hypotheses are discussed and the likely place for association studies in a strategy involving studies of a variety of designs geared to finding genetic determinants of disease susceptibility is addressed. Journal of Human Hypertension (2000) 14, 361-367

Clinical Trials as Topic↗
PubMed2000

Measurement of blood pressure using the auscultatory and oscillometric methods in the same cuff deflation: validation and field trial of the A&D TM2421 monitor.

We have evaluated under laboratory validation conditions and in an extensive field trial the behaviour of an ambulatory monitoring device that is capable of recording both by the Korotkoff-sound and oscillometric methods in a single cuff deflation (TM2421: A&D Co, Tokyo, Japan). The effects of subject age and blood pressure (BP) level on the accuracy and field reliability of the two methods implemented in the device have been determined. In the validation phase, automatic BP measurements were compared with readings by two trained observers in 96 subjects, and the results compared with the AAMI criteria for automatic BP monitors. In the field trial phase, the performances of Korotkoff-sound and oscillometric methods over a 24-h period of ambulatory BP monitoring were compared in 515 subjects, with analysis of the agreement between the two methods in patients where both provided satisfactory recordings. In the validation phase, the Korotkoff-sound method gave satisfactory results for both systolic and diastolic BP, but the oscillometric technique narrowly failed to meet the AAMI criteria for the measurement of either systolic or diastolic BP. In the field trial, the K-sound method failed to record BP accurately in 12% of subjects whereas the oscillometric method was successful in all of these. Where both methods provided technically adequate records, agreement between mean values for each method was close. In 18% of patients, the availability of the oscillometric measurement as a 'back-up' method for the K-sound method significantly improved the number of available measurements in the monitoring period, which should result in improved accuracy and reproducibility of the ambulatory mean values.

Adult↗
PubMed1998

Measured haplotype analysis of the angiotensin-I converting enzyme gene.

Linkage and segregation analysis have shown that circulating angiotensin-I converting enzyme (ACE) levels are influenced by a major quantitative trait locus that maps within or close to the ACE gene. The D variant of a 287 bp insertion/deletion (I/D) polymorphism in intron 16 of the gene is associated with high ACE levels and may also be related to increased risk of cardiovascular disease. Multiple variants that are in linkage disequilibrium with the I/D polymorphism have been described, but it is unknown if any of these are directly implicated, alone or in combination with as yet undiscovered variants, in the determination of ACE levels. An analysis of 10 polymorphisms spanning 26 kb of the ACE gene revealed a limited number of haplotypes in Caucasian British families due to strong linkage disequilibrium operating over this small chromosomal region. A haplotype tree (cladogram) was constructed with three main branches (clades A-C) which account for 90% of the observed haplotypes. Clade C is most likely derived from clades A and B following an ancestral recombination event. This evolutionary information was then used to direct a series of nested, measured haplotype analyses that excluded upstream sequences, including the ACE promoter, from harbouring the major ACE-linked variant that explains 36% of the total trait variability. Residual familial correlations were highly significant, suggesting the influence of additional unlinked genes. Our results demonstrate that a combined cladistic/measured haplotype analysis of polymorphisms within a gene provides a powerful means to localize variants that directly influence a quantitative trait.

England↗
PubMed1998

Evaluation of the angiotensinogen locus in human essential hypertension: a European study.

Different family and case-control studies support genetic linkage and association at the human angiotensinogen (AGT) locus with essential hypertension. To extend these previous observations, a European collaborative study of nine centers was set up to create a large resource of affected sibling pairs. The AGT locus was studied using a highly polymorphic dinucleotide repeat in the 3'-flanking region of the gene in 350 European families, comprising 630 affected sibling pairs. Statistical analyses using two different methods did not show any evidence for linkage either in the whole panel or in family subsets selected for severity or early onset of disease. Although several arguments from association studies suggest a role of the AGT gene in essential hypertension, this large family study did not replicate the initial linkage reported in smaller studies. Our results highlight the difficulty of identifying susceptibility genes by linkage analysis in complex diseases.

Adult↗
PubMed1997

Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10.

Hypertension is a significant risk factor for heart attack and stroke and represents a major public health burden because of its high prevalence (e.g. 15-20% of the European and American populations). Although blood pressure is known to have a strong genetic determination, the genes responsible for susceptibility to essential hypertension are mostly unknown. Loci involved in blood pressure regulation have been found by linkage in experimental hereditary hypertensive rat strains, but their relationship to human hypertension has not been extensively investigated. One of the principal blood pressure loci has been mapped to rat chromosome 10 and we have undertaken an investigation of the homologous region on human chromosome 17 in familial essential hypertension. Affected sib-pair analysis and parametric analysis with ascertainment correction gave significant evidence of linkage ( P <0.0001 in some analyses) near two closely linked microsatellite markers, D17S183 and D17S934, that reside 18 cM proximal to the ACE locus in the homology region. Our results indicate that chromosome 17q could contain a susceptibility locus for human hypertension and show that comparative mapping may be a useful approach for identification of such loci in humans.

Animals↗
PubMed1996

Prediction of patient responses to antihypertensive drugs using genetic polymorphisms: investigation of renin-angiotensin system genes.

OBJECTIVE: To investigate whether the M235T polymorphism of the angiotensinogen (AGT) gene and the insertion/deletion (I/D) polymorphism of the angiotensin-1 converting enzyme (ACE) gene predict blood pressure response to different antihypertensive agents. DESIGN: Sixty-three patients with untreated essential hypertension were randomly assigned in a placebo-controlled crossover comparison to atenolol 50 mg once daily, lisinopril 10 mg once daily and nifedipine SR 20 mg twice daily, and the effect on blood pressure was assessed by ambulatory blood pressure monitoring (ABPM). In a further 44 patients, placebo-controlled ABPM data were available after treatment with a single agent (atenolol 50 mg once daily in 16 cases and lisinopril 10mg once daily in 28 cases). The change in systolic and diastolic blood pressure achieved by each agent was analysed for association with genotypes at the AGT and ACE gene loci. METHODS: Polymerase chain reaction (PCR) amplification of genomic DNA from each individual was used to identify the I/D polymorphism of the ACE gene. The M235T polymorphism of the AGT gene was detected by Tth111I digestion of PCR product. RESULTS: There was no significant association between response to any drug and either the AGT M235T or ACE I/D polymorphisms. CONCLUSIONS: The large variability between individuals in the observed blood pressure response to these agents cannot be attributed to the polymorphisms analysed at the ACE and AGT loci.

Alleles↗
PubMed1996

Normal coronary angiograms: financial victory from the brink of clinical defeat?

OBJECTIVE: To examine the hypothesis that, in patients undergoing coronary angiography for suspected ischaemic heart disease, a normal angiographic result is associated with a fall in consumption of health care resources following the angiogram. DESIGN: Retrospective cost-benefit analysis comparing the 12 month periods before and after coronary angiography. SETTING: Tertiary cardiac referral centre. SUBJECTS: 69 consecutive patients investigated in the financial year 1991-92 whose angiograms were normal. MAIN OUTCOME MEASURES: Drug and hospital admission costs in the 12 month periods before and after angiography; urgent and elective consultations with general practitioner in that time. RESULTS: The mean cost of care per patient in the year before investigation was 656.89 pounds. A highly significant fall in all indices of resource consumption was observed in the year following investigation, the mean resulting difference in the cost of care being 35.15 pounds per month. The cost of coronary angiography would, if this fall were maintained, be recouped in a mean time of 18 months. CONCLUSIONS: Patients suspected on clinical grounds to have coronary atherosclerosis who are found at angiography to have normal coronary arteries are heavy consumers of health care resources. Early investigation for these patients is safe and has beneficial resource consequences in the medium term.

Coronary Angiography↗