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R R Williams

Publications and source records attributed to R R Williams.

At least 163 records · Page 9Linked to original sources
PubMed1987

Recruitment of members of high-risk Utah pedigrees.

Cardiovascular Genetics Research Projects in Utah are designed to investigate genetic and environmental determinants of early coronary disease, stroke, and hypertension in population-based pedigrees. Early coronary disease is defined as the occurrence of documented coronary death or myocardial infarction before age 55. Detailed recruitment experience is reported for 2500 persons age 3-83 years in 98 high-risk pedigrees from three ascertainment groups: 1. Descendants of sibships with two or more stroke deaths before age 75. 2. Descendants of sibships with two or more coronary deaths before age 55. 3. First- and second-degree relatives of hypertensive and normotensive probands randomly selected from the Utah Hypertension Detection and Follow-up Program. A response rate of 94% of invited adults attending the first 4-hour clinic visit for detailed screening in 1980-1983 was achieved by multiple telephone, mail, and personal contacts and rescheduling of missed clinic appointments. For the same participants, a second screening cycle in 1983-1986 showed a 91% response of invited adults. Second visit response rates were examined within subgroups according to data collected at the first clinic visit. Below average response rates included 79% of persons with fewer than 12 years of education, 84% of current smokers, and 86% of divorced persons. Above average response rates included 93% of persons attending college and 95% of persons with total family income above $25,000. There were no differences in response according to sex or age. The average cost of recruitment was $59 per person and represented about 10% of the total budget for the High-Risk Pedigree Project.

Adolescent↗
PubMed1987

Blood pressure reactivity in adult male twins.

The purpose of the present investigation was to examine possible genetic contributions to cardiovascular reactivity by contrasting patterns of association in 82 monozygotic (MZ) and 88 dizygotic (DZ) adult male twin pairs (age range = 21 to 61 years, M = 35 years). Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded during baseline and during a mental arithmetic task (i.e., serial subtraction). The task produced significant elevations in all three cardiovascular measures (i.e., 10 mmHg SBP, 8 mmHg DBP, and 6 bpm HR, respectively). Levels of SBP and DBP reactivity were significantly correlated in MZ pairs but not in DZ pairs. Statistical tests suggest a heritability estimate of about 50% that was marginally significantly for SBP and DBP changes during the task. There was no indication of a genetic influence on HR reactivity. Resting level and static task period measures of SBP, DBP, and HR demonstrated statistically significant heritability estimates of 60% to 80%.

Adult↗
PubMed1987

Genetic studies of cation tests and hypertension.

Several tests of cation concentration and transport are being studied among members of large Utah pedigrees as part of a study of the genetic and environmental determinants of essential hypertension. Corrected urinary sodium excretion and plasma sodium concentration correlated well in spouses and siblings (r = 0.21-0.54, p less than 0.001), suggesting the effects of shared family environment (e.g., sodium intake). Intraerythrocytic sodium concentration and sodium-lithium countertransport showed no significant correlation in spouses and very significant correlations between siblings and between parents and offspring (r = 0.34-0.58, p less than 0.001), suggesting mostly genetic determination. Using maximum likelihood tests of different genetic models, both sodium-lithium countertransport and intraerythrocytic sodium showed predominantly polygenic determination (H2 = 70%) and some possible major gene determinants (H2 = 18-25%) for a total heritability of 89 to 95% for these characteristics. These data suggest both genes and shared family environment contribute to the familiality of cation tests. They also illustrate the need and utility of quantitative methods for objective analysis of pedigree data.

Adult↗
PubMed1986

Erythrocyte cation transport activities as a function of cell age.

Erythrocyte cation transport systems were evaluated on cell fractions from 17 subjects. Density centrifugation was used to separate washed red cells into fractions enriched with younger and older cells; the cell age differences in these fractions were verified by reticulocyte counts (means are 3.5% for younger cell fractions and 0.7% for older cell fractions). Red cell age has a pronounced effect on several cation transport activities. The older cell fractions had increases in lithium-potassium cotransport (p less than 0.001), the rate constant for the lithium-potassium cotransport (p less than 0.001) and cellular cation permeability. The older cells had decreases in the number of ouabain binding sites (p less than 0.001), the rate constant for sodium efflux via the sodium-potassium adenosine triphosphatase pumps (p less than 0.001) and the sodium-lithium countertransport (p less than 0.025). In subjects with markedly different cell ages, these effects should be considered when evaluating red cell cation transport activities.

Adolescent↗
PubMed1986

Evidence that men with familial hypercholesterolemia can avoid early coronary death. An analysis of 77 gene carriers in four Utah pedigrees.

To study the genetic influence on serum cholesterol levels and early coronary heart disease, 1,134 individuals were screened from 18 Utah pedigrees. In most pedigrees, serum cholesterol appeared to be a purely polygenic trait, with 54% heritability. In four pedigrees with dominant familial hypercholesterolemia, male heterozygotes had a mean serum cholesterol level of 352 mg/dL, myocardial infarction at an average age of 42 years, and coronary death at an average age of 45 years. An informative pedigree structure allowed the identification of four ancestral males born before 1880 who carried this lethal gene and survived to ages 62, 68, 72, and 81 years. This suggests that some healthy life-style factors protected these men against the expression of a gene that has led to coronary disease by age 45 years in all of their heterozygous great-grandsons. One heterozygote showed a drop in serum cholesterol level from 426 to 248 mg/dL, with strict adherence to a low-fat diet without drugs. These observations should help encourage physicians to try harder to identify and help such individuals.

Adult↗
PubMed1986

A re-examination of major locus hypotheses for high density lipoprotein cholesterol level using 2,170 persons screened in 55 Utah pedigrees.

A dominant major locus (allele frequency of .0025 +/- .0014), resulting in low levels of high density lipoprotein cholesterol (HDL-C), was revealed by likelihood analysis on 2,170 persons in 55 Utah pedigrees. This allele was expressed through HDL-C levels ranging from 20 to 30 mg/dl in seven persons in two pedigrees. Early coronary heart disease was associated with the allele in one pedigree, but not in the other. In the pedigree without associated heart disease, HDL subfractions HDL2 and HDL3 were both low in individuals with the low HDL-C allele. No other major locus determining either high or low levels of HDL-C was identified in our sample. Polygenic heritability as part of the mixed model was estimated as .561 +/- .035.

Adolescent↗
PubMed1986

Testing for familial aggregation of a dichotomous trait.

Familial aggregation of a disease is usually tested using a chi square statistic on a sample of pairs of related individuals. Standard sampling designs often produce dependent observations (multiple pairs from the same family), possibly inflating the numerical value of the statistic over the value independent observations would produce. This article presents a derivation of the chi square statistic for familial aggregation, allowing for dependency because of the inclusion of the same and related persons in multiple pairs. For intraclass aggregation, the standard chi square statistic is appropriate. For interclass aggregation, an adjustment to the standard chi square statistic is needed; the adjustment depends on the disease frequency and the intraclass aggregation within each class.

Analysis of Variance↗
PubMed1986

A comparison of positive family history definitions for defining risk of future disease.

The relative risk of developing future coronary heart disease (CHD) or hypertension between positive and negative family history families is compared for different definitions of a positive family history when applied to life-table data for 94,292 persons. Having two or more first degree relatives with CHD identifies 8% of the population with relative risks of 3.3-5.9 for CHD before age 50. A quantitative family history score (FHS) compares the family's age and sex specific disease incidence to that expected in the general population and predicts future disease incidence in unaffected family members slightly better (relative risks = 3.4-6.9 for CHD before age 50). Using only one affected relative, even if affected at an early age (less than 55 years old) does not discriminate low and high risk families as well (relative risks = 1.4-3.9 for CHD before age 50). Similar results were obtained for family history of hypertension. There is an increase in future disease incidence for all ages with increasing FHS values (p less than 0.0001), which can be used as a continuous or categorical variable in analysis where family history is associated with a particular variable under study. These results provide a rational basis for choosing and applying specific definitions of a positive family history of coronary disease or hypertension in clinical, epidemiologic and genetic studies.

Adult↗
PubMed1986

Associations of three erythrocyte cation transport systems with plasma lipids in Utah subjects.

To investigate the pathophysiology of essential hypertension, detailed biochemical and clinical variables were collected and analyzed for 2091 Utah subjects aged 3 to 83 years. Three different measurements of erythrocyte cation transport were obtained: Na+-Li+ countertransport, Li+-K+ cotransport, and furosemide-insensitive Li+ efflux into MgCl2. Total plasma cholesterol, triglycerides, and high density lipoprotein cholesterol levels were obtained from fasting subjects. Levels of high density lipoprotein subfractions 2 and 3 were also obtained from 350 subjects. Standardized data collection also included blood pressure, height, weight, and presence or absence of a diagnosis or treatment of essential hypertension. In univariate analyses of all 1420 adults, each of the three transport systems showed the same significant correlations with triglyceride levels (r = 0.33-0.35, p less than 0.0001), high density lipoprotein concentration (r = -0.19 to -0.21, p less than 0.001), and weight (r = 0.22-0.28, p less than 0.0001). In multivariate regression analyses, values for each transport system were significantly higher in hypertensive subjects; values for triglycerides, high density lipoprotein, and usually, the high density lipoprotein subfractions continued to have strong significant independent associations with all three transport systems; and weight remained significantly related only to Na+-Li+ countertransport. In separate logistic regressions, plasma triglyceride levels (positively, p less than 0.001) and high density lipoprotein subfraction 3 levels (inversely, p less than 0.03) were associated with hypertension itself. In multivariate analyses among 671 children, high density lipoprotein and high density lipoprotein subfraction 3 levels showed significant (p less than 0.05) inverse correlations with Na+-Li+ countertransport and furosemide-insensitive Li+ efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Factor analysis suggesting contrasting determinants for different blood pressure measurements.

A multiple regression analysis was performed on statistically independent factors derived from blood pressure measurements and possible predictive variables in 618 Utah adults. Nine blood pressure factors obtained in a previous study composed the dependent variables; 35 anthropometric, questionnaire, and biochemical variables were reduced by factor analysis to 10 factors and used as independent variables. Body size and obesity had significant independent effects on different types of blood pressure: body size correlated most highly with systolic blood pressure, while obesity correlated most highly with sitting diastolic blood pressure measurements. Smoking did not correlate with sitting blood pressure but did show a significant positive correlation (after controlling for obesity) with tilt and supine diastolic pressure. Alcohol consumption correlated positively with sitting diastolic pressure when the effects of body size and obesity were controlled. No correlations were found between urinary potassium or sodium excretion and any blood pressure factors, but a significant positive correlation was seen between plasma sodium concentration and several different types of diastolic blood pressure measurements. Psychological stress showed a significant independent positive correlation with systolic blood pressure measurements that was strongest in adults over 35 years of age. The multiple correlation values for the multiple regression equations ranged from 0.19 to 0.52.

Adolescent↗
PubMed1986

Innovative blood pressure measurements yield information not reflected by sitting measurements.

A study of 873 healthy adults and children from Utah kindreds was performed to identify redundant and unique information contained in multiple diverse blood pressure determinations. Systolic blood pressure, fourth-phase and fifth-phase diastolic blood pressures, and simultaneous heart rates were measured in subjects sitting, standing, supine, and tilting, during half-maximal handgrip exercise, and just before blood drawing. A correlation matrix of 57 blood pressure and pulse variables in 618 healthy adults was analyzed. Factor analysis of the correlation matrix showed that all systolic blood pressures loaded as a single factor, accounting for 44% of the total variance of the observed variables. All heart rates also loaded together as a single factor. Diastolic blood pressures showed much more heterogeneity of information distributed among five separate factors. The same basic factors were found in young adults (age, 18-35 years) and older adults (age, 36 + years). Children under 12 years of age showed very different factor patterns, and youths 12 to 17 years of age showed patterns intermediate between those of adults and children. In light of recent clinical trials, better definitions are being sought for hypertension. Information from blood pressures other than sitting determinations may improve the definition of hypertension or better predict which patients have the highest risk of hypertension and its cardiovascular complications.

Adolescent↗
PubMed1986

The evolution of an effective P & T Committee: advice from the chairman.

In an exclusive Hospital Formulary interview, Dr. Roger Williams, Chairman of the University Hospitals P & T Committee, identifies factors that have contributed to the success of their P & T Committee. Policies for evaluating drugs for formulary inclusion, the use and availability of nonformulary drugs, and efforts in improving adverse drug reaction reporting by clinicians are a few of the topics discussed. Dr. Williams' committee supports the concept of a closed, rather rigid formulary, but contends that mechanisms must be available for easy acquisition of nonformulary drugs. Dr. Williams also comments on the clinical benefits derived from participation on a P & T Committee.

Formularies, Hospital as Topic↗
PubMed1986

A DNA probe for the LDL receptor gene is tightly linked to hypercholesterolemia in a pedigree with early coronary disease.

A large, multigenerational family with dominantly inherited hypercholesterolemia was analyzed for genetic linkage between blood levels of low-density lipoprotein (LDL) cholesterol and the locus for the LDL receptor. A genetic marker was identified by restriction fragment length polymorphism (RFLP) in a cloned segment of the LDL receptor gene. We found no exceptions to segregation of the high-LDL cholesterol phenotype with a unique allele at the LDL receptor locus in this pedigree; tight linkage was indicated by a maximum lod score of 7.52 at theta = 0. Knowledge of the LDL receptor genotype will enable investigators to study variability of phenotypic expression in response to environmental influences or to different genetic determinants.

Cholesterol, LDL↗
PubMed1986

The genetic determination of plasma apolipoprotein A-I levels measured by radioimmunoassay: a study of high-risk pedigrees.

Apolipoprotein A-I (apo A-I) is the major protein component of the high-density lipoprotein (HDL) found in all primates. Using radioimmunoassay, we measured plasma apo A-I levels in 97 individuals from 23 pedigrees ascertained through cases of hypertension or early coronary artery disease (CAD). Using complex segregation analysis, we found that a genetic model with both a single locus with a major effect and polygenic loci gave the best explanation for the distribution of apo A-I levels in these pedigrees. There was no evidence for a major locus effect on HDL cholesterol in these pedigrees. This is the first study to show evidence of a major effect of a single genetic locus on the quantitative variation of plasma apo A-I in a sample of pedigrees enriched for individuals at risk for CAD.

Apolipoprotein A-I↗
PubMed1986

Identification and relative weight of cardiovascular risk factors.

Basic concepts of epidemiology are presented with an update on the more than 270 factors that the authors have found suggested as contributors to cardiovascular disease risk. A comprehensive classification scheme and public health and clinical implications are discussed. Based on predictions from prospective and intervention studies, up to 90 per cent of coronary heart disease could be prevented by optimization of known cardiovascular risk factors.

Adolescent↗
PubMed1986

Evidence for environmental familiality of kallikrein excretion in Utah kindreds.

In investigating the role of urinary kallikrein in the pathophysiology of hypertension, we measured 12-hour kallikrein excretion in 1,100 persons in 68 Utah kindreds. The kallikrein excretion was statistically adjusted to account for variations in body size and urine output. Adjusted kallikrein excretion was greater in youths than in adults and correlated with potassium excretion and sodium excretion in persons with normal blood pressure. It was decreased in normotensive subjects with strong family histories of stroke and hypertension, but was not significantly different in adults with hypertension. Adjusted kallikrein excretion was correlated between pairs of siblings, parent-offspring pairs and spouses. Our results indicate that kallikrein excretion is a familial variable, with the familiality due more to shared environmental than genetic factors.

Adolescent↗
PubMed1986

Coronary disease and risk factors in close relatives of Utah women with early coronary death.

Familial aggregation of coronary heart disease (CHD) and specific major risk factors were determined among 639 first-degree relatives of 73 women with confirmed coronary death before age 55. They were compared with 1,151 persons in 141 control families. Of women with early coronary death, 62% had first-degree relatives with early coronary disease compared with 12% of affected control family members. In the proband families, coronary incidence rates were 2.7 times the control population rates for women (P<.001) and 1.6 times the control population rates for men (P<.05). An excess incidence of coronary disease was observed for ages 45 to 74 in both men and women.Smoking, hypertension, diagnosed hyperlipidemia and diabetes were all two to three times more common in the female probands with early coronary death than in healthy controls. Hypertension was more common in all proband relatives (both sexes with and without coronary disease). Smoking was more common among female relatives of probands when compared with the controls. These data suggest that early coronary disease in women is often familial and associated with smoking and hypertension. The familial aggregation seems to be stronger in female relatives of female probands with early CHD than in male relatives. Genetic factors or shared family life-style or both likely account for these observations.

Adult↗