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R R Williams

Publications and source records attributed to R R Williams.

At least 91 records · Page 5Linked to original sources
PubMed1993

Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah.

The genetic and environmental determinants of hypertension, lipid abnormalities, and coronary artery disease (CAD) have been studied for 15 years in Utah in population-based multigenerational pedigrees (2500 subjects among 98 pedigrees), twin pairs (74 monozygous and 78 dizygous), hypertensive siblings (131 sibships), siblings with CAD before age 55 (45 sibships), and anecdotally ascertained pedigrees with type II diabetes (271 subjects among 16 pedigrees), lipoprotein lipase deficiency (106 subjects in a single pedigree), and familial hypercholesterolemia (502 heterozygotes among 50 pedigrees). Estimates of heritability ranged from 20 to 75% for blood pressures and blood lipids. A strong positive family history predicts a future occurrence of hypertension (relative risk [RR] = 3.8) and CAD (RR = 12.7). Segregating single-gene effects were found for several 'intermediate phenotypes' associated with hypertension (erythrocyte sodium-lithium countertransport, intraerythrocytic sodium, a relative fat pattern, total urinary kallikrein excretion, and fasting insulin levels). Strong single-gene effects in segregation analysis were also found for low-density lipoprotein (LDL) cholesterol, lipoprotein (a) (Lp[a]), low high-density lipoprotein (HDL) cholesterol, and high apolipoprotein (apo) B. Deoxyribonucleic acid (DNA) markers of lipid abnormalities or hypertension have included LDL-receptor defects, lipoprotein lipase deficiency, high Lp(a), familial defective apo B, decreased quantitative levels of apo B, apo E phenotype, angiotensinogen, and 'glucocorticoid remediable aldosteronism (GRA) hypertension.' Also tested in Utah studies, but not found to be DNA markers for hypertension, were the genetic loci for the structural genes for renin and angiotensin-converting enzyme, and the sodium antiport system. In addition, important gene-gene interactions (LDL receptor with apo E2) and gene-environment interactions (kallikrein with potassium intake) were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1993

Response to antituberculous chemotherapy after splenectomy.

A case of a 17-year-old Indian male with disseminated tuberculosis is reported. While on chemotherapy, he was detected to have splenic abscesses. The patient remained unresponsive to antituberculous drugs until a splenectomy was performed.

Abscess↗
PubMed1993

A gene-environment interaction between inferred kallikrein genotype and potassium.

Urinary kallikrein excretion has been shown statistically to be partially determined by a major gene in large Utah pedigrees with the use of segregation analysis. A previous twin analysis of environmental factors influencing urinary kallikrein level showed that urinary potassium twin differences were strongly related to differences in urinary kallikrein. The present study uses 769 individuals in 58 Utah pedigrees to analyze the association of urinary potassium with urinary kallikrein within statistically inferred kallikrein genotypes. Fitting genotype-specific curves relating urinary kallikrein level to 12-hour urinary potassium amount within a major gene, polygene, and common environment model, we showed a significant statistical urinary potassium interaction with the inferred major gene for kallikrein (P = .0002). The heterozygotes (with a frequency of 50%) had a significant association between urinary kallikrein and potassium (slope, 0.51 +/- 0.04 SD), whereas there was no association with potassium in the low homozygotes, suggesting a genetic defect involving the kallikrein response to potassium. The model predicted that an increase in urinary potassium excretion of 0.8 SD above the mean in these pedigrees would be associated with high kallikrein levels in the heterozygotes similar to the high homozygotes. A decrease of 1.3 SD in urinary potassium excretion in heterozygous individuals was associated with kallikrein levels similar to the homozygous individuals with low kallikrein. Because in the steady state urinary potassium represents dietary potassium intake, this study suggests that an increase in dietary potassium intake in 50% of these pedigree members, estimated to be heterozygous at the kallikrein locus, would be associated with an increase in an underlying genetically determined low kallikrein level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Management of residual squamous intraepithelial lesions of the cervix after conization.

From January 1985 to October 1992, 158 conizations of the cervix were performed for squamous intraepithelial lesions (SIL) of the cervix. Thirty-one (20.4%) of these cases had disease extending to the margins of resection. The majority (60.7%) had spontaneous resolution of disease. Conservative follow-up aided by the body's own immune system may allow an even greater percentage to resolve spontaneously. Smoking presents an added factor for persistent as well as recurrent disease.

Adolescent↗
PubMed1993

Environmental determinants of urinary kallikrein excretion.

Decreased urinary kallikrein excretion has been shown to be related to hypertension. Kallikrein levels also have been shown to be determined primarily by genes, with 51% of the total variance being due to a single gene. However, there exists strong spouse-spouse correlation, indicating that common environment plays a significant role. This study used 69 pairs of monozygous twins to investigate possible dietary, biochemical, and anthropometric determinants of kallikrein that could result in this high spouse correlation. Urinary sodium and potassium excretion differences were significantly related to kallikrein differences, with urinary potassium having the strongest relationship (r = 0.46, P = .0001). Urinary pH (r = 0.23, P = .03) and systolic blood pressure (r = -0.25, P = .03) differences were associated with urinary kallikrein excretion differences independently of urinary potassium. Information on nutrients was obtained from a dietary food frequency questionnaire that ascertains usual intake over the last 5 years. Kallikrein differences between monozygous twins were not explained by differences in nutrient intake as measured by this questionnaire. Therefore, urinary potassium and pH probably represent the more acute effects of recent dietary sodium and potassium intake on urinary kallikrein levels. Urinary potassium, pH, and systolic blood pressure differences explained 34% of the difference in kallikrein levels between monozygous twins. The significant difference in systolic blood pressure between twins, even after controlling for electrolyte excretion differences suggests an additional unmeasured environmental variable that is associated with decreased kallikrein excretion and elevated blood pressure.

Adult↗
PubMed1992

Molecular basis of human hypertension: role of angiotensinogen.

Essential hypertension is a common human disease believed to result from the interplay of multiple genetic and environmental determinants. In genetic studies of two large panels of hypertensive sibships from widely separated geographical areas, we obtained evidence of genetic linkage between the angiotensinogen gene (AGT) and hypertension, demonstrated association of AGT molecular variants with the disease, and found significant differences in plasma concentrations of angiotensinogen among hypertensive subjects with different AGT genotypes. The corroboration and replication afforded by these results support the interpretation that molecular variants of AGT constitute inherited predispositions to essential hypertension in humans.

Adult↗
PubMed1992

Coronary risk factors and the severity of angiographic coronary artery disease in members of high-risk pedigrees.

Affected members of early coronary pedigrees in Utah are at markedly increased risk for the development of clinical coronary heart disease (CHD). The relationship between the presence of coronary risk factors and the severity of angiographic coronary artery disease (CAD) in 53 members of high-risk Utah pedigrees was examined. Mean angiographic severity scores were higher in familial hypercholesterolemia or familial low high-density lipoprotein cholesterol (HDL-C) pedigrees than in type III hyperlipidemia or familial combined hyperlipidemia pedigrees. One sibling pair with hyperhomocyst(e)inemia had the highest mean angiographic severity scores. Clinical CHD (p less than 0.0001), increasing low-density lipoprotein cholesterol (LDL-C) (p = 0.0107), and decreasing HDL-C (p = 0.0068) were significant predictors of angiographic CAD severity. There appeared to be an interaction between gender and body mass index but not between gender and serum lipids in the prediction of angiographic CAD severity. Results of the present study in members of high-risk Utah pedigrees are consistent with results from other angiographic studies in non-high-risk persons. Of particular interest is the suggested independent predictive value of low HDL-C for angiographic CAD severity in members of high-risk pedigrees.

Coronary Angiography↗
PubMed1992

Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension.

The angiotensin converting enzyme (ACE) is a key component of the renin angiotensin system that contributes to the regulation of blood pressure (BP). Recent demonstration of linkage between the ACE locus and elevated BP in a rat model of hypertension has further emphasized ACE as a candidate gene in human hypertension. We report the localization of the ACE gene on the genetic map of chromosome 17, and identify an extremely polymorphic marker at the human growth hormone (hGH) locus which shows no recombination with ACE. We have found no evidence to support linkage between the ACE locus and hypertension, which suggests that mutations at the ACE locus do not commonly contribute to the pathogenesis of hypertension in our test population.

Base Sequence↗
PubMed1992

Performance of an aquatic multispecies system in evaluating the effects of a model microbial pest control agent on nontarget organisms.

A recirculating multispecies test system was developed in conjunction with a study of the fate and persistence of a model microbial pest control agent on non-target marine and freshwater organisms. The basic unit of the system was a 113-I glass aquarium with vertical biological filters in the center of the aquarium, such that two compartments were formed. This allowed the sequestration of predator and prey species within the same system. Organisms from six phyletic groups were subjected to a genetically altered strain of Pseudomonas putida for 15-29 d in either artificial seawater or fresh water. The system was able to maintain the animals for these periods with a minimum of maintenance. Additionally, the system design lent itself to disinfection, dismantling, and rebuilding between experiments with a minimum of labor, and has potential for longer-term studies.

Animals↗
PubMed1992

Risk factors for cardiovascular disease predict the development of diabetes among Utah families.

In 1989, we sent a medical follow-up questionnaire to 2,728 members of 98 Utah families originally screened from 1980 to 1983 in the Cardiovascular Genetics Research Clinic. The response rate was 69.9%. Of 1,134 nondiabetic individuals initially age 18 or older who returned the questionnaire, 10 were found to be newly diagnosed with diabetes. The incidence of diabetes was higher among individuals who were found at baseline to have central obesity, lipid abnormalities, especially increased triglyceride levels, and hypertension. Family histories of coronary heart disease and diabetes were not related to the development of diabetes. Our findings that cardiovascular disease risk factors predict the development of diabetes in this relatively young, Caucasian population are consistent with the results of studies from several different populations.

Adult↗
PubMed1992

Fasting insulin and left ventricular mass in hypertensives and normotensive controls.

The mechanism by which increased left ventricular (LV) mass leads to increased coronary heart disease morbidity and mortality is unknown. We evaluated the relation between fasting insulin and echocardiographic LV mass in hypertensives off medication and normotensive controls, controlling the analyses for blood pressure (BP) and body mass index (BMI). Fasting insulin (p = 0.0217) was the most significant predictor of LV mass in hypertensives, while BMI (p = 0.0265) and diastolic BP (p = 0.0159) were the only significant predictors of LV mass in controls. The relation between fasting insulin and LV mass was not confounded by obesity in hypertensives, but obesity and fasting insulin may interact to predict LV mass.

Adult↗
PubMed1992

Major gene effect for insulin levels in familial NIDDM pedigrees.

Insulin resistance and hyperinsulinemia are familial traits that may precede and predict the onset of non-insulin-dependent diabetes mellitus (NIDDM). In some populations, the distribution of fasting insulin levels and measures of in vivo insulin action suggest the effects of a single major gene. We previously noted hyperinsulinemia among unaffected members of 16 large white pedigrees ascertained through two or more NIDDM siblings. To examine the hypothesis that insulin levels are determined by a single major genetic locus, we used segregation analysis to examine fasting insulin levels in 206 family members and 65 spouses who had normal glucose tolerance tests by World Health Organization criteria. Segregation analysis supported a major locus determining fasting insulin levels and segregating as an autosomal recessive allele with a frequency of 0.25. Thus, homozygotes represented 6.25% of the population, and homozygosity for the hyperinsulinemia allele elevated the mean fasting insulin level from 70.3 to 211.1 pM (11.7-35.2 microU/ml). The analysis apportioned the variance in fasting insulin as 33.1% due to the major autosomal locus, 11.4% due to polygenic inheritance, and 55.5% due to unmeasured effects. Homozygotes for the recessive allele had higher 1-h insulin levels than all others (911.7 vs. 427.2 pM [152.0 vs. 71.2 microU/ml]). We also found evidence for a major locus determining 1-h-stimulated insulin levels, with codominant inheritance as the most likely pattern in inheritance. The causal relationship between these findings and NIDDM has not been determined, and segregation of direct measures of insulin action remains to be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Dyslipidemias among normoglycemic members of familial NIDDM pedigrees.

OBJECTIVE: To examine the hypothesis that hyperinsulinemia among relatives of NIDDM probands will increase the prevalence of DLPs, we measured insulin levels and examined the frequency of DLPs among NIDDM pedigree members. RESEARCH DESIGN AND METHODS: We performed 2-h 75-g OGTTs and measured lipid and insulin levels of 287 family members and 86 spouses from 16 large Utah pedigrees ascertained for greater than or equal to 2 siblings with NIDDM. RESULTS: One-hour insulin levels were higher among 206 family members with NGT than among 65 NGT spouses (483.3 vs. 361.7 pM, P = 0.05). Among the NGT family members, 32% had cholesterol levels at or above the age- and sex-specific 90th percentile level defined by the LRC studies, 33% had HDL levels less than or equal to 10th percentile, and 20% had triglyceride levels greater than or equal to 90th percentile. DLP (any of the three abnormalities) was found among 58% of NGT family members, which was significantly higher than the expected 27% (P less than 0.00001) and the prevalence among spouses of 45% (P less than 0.05). By NCEP criteria for hyperlipidemia, 40% of family members met criteria for diet and/or pharmacological therapy. CONCLUSIONS: Normoglycemic members of NIDDM pedigrees have a high prevalence of DLPs, which approaches the prevalence in patients with NIDDM. Our data suggest that members of NIDDM pedigrees should be screened carefully for lipid abnormalities.

Adult↗
PubMed1992

Familial dyslipidaemic hypertension and other multiple metabolic syndromes.

Data from several different studies are reviewed suggesting that a subset of hypertension is associated with metabolic abnormalities involving lipids, insulin, and often obesity, all aggregating strongly in families. Persons with 'familial dyslipidaemic hypertension (FDH)' have an especially high risk of early coronary disease. The clinical and biochemical features of FDH are compared with Reaven's Syndrome X, familial combined hyperlipidaemia, dense LDL subfractions, diabetes, impaired glucose tolerance, central and general obesity, pre-diabetes, pre-hypertension, and heterozygous lipoprotein lipase deficiency. Some contribution from major gene effects is suggested in specific subsets reported in several different genetic studies reviewed in this report. It seems likely that multiple metabolic abnormalities are genetically heterogeneous. The data also suggest significant contributions from environmental factors such as diet and physical activity.

Coronary Disease↗
PubMed1992

Evidence for gene-environmental interactions in Utah families with hypertension, dyslipidaemia and early coronary heart disease.

1. Among 45,258 Utah families surveyed, about 4% have a strong aggregation of early coronary disease. In detailed clinical evaluation, about 21% of such high risk coronary families were found to have familial dyslipidaemic hypertension (FDH) and about 3% were found to have heterozygous familial hypercholesterolaemia (hFH). 2. Common and potentially modifiable environmental factors seem to play an important role in these high risk families. Non-genetic obesity promotes the expression of FDH. A high fat diet promotes the expression of FH. Cigarette smoking promotes earlier death in all coronary prone families. 3. Practical approaches are suggested for helping coronary prone pedigrees by applying our understanding of genetic and environmental factors that promote earlier coronary disease onset.

Adult↗
PubMed1992

Two apolipoprotein B gene defects in a kindred with hypobetalipoproteinemia, one of which results in a truncated variant, apoB-61, in VLDL and LDL.

We report the presence of two distinct defects of the gene for apolipoprotein B, one resulting in a new truncated variant, apoB-61, in a kindred with familial hypobetalipoproteinemia (FHB). The proband (age 33) and a sister (age 36) are both compound heterozygotes with total cholesterol levels of 39 mg/dl and 50 mg/dl, and apoB levels of 1 mg/dl and 2 mg/dl in plasma, respectively. Both appear to be asymptomatic. The apoB-61 mutation, present in a total of five individuals and inherited from the proband's father, is a 37 bp deletion in exon 26 starting with nucleotide 8525. This results in an apoB of 2784 amino acids with 12 novel carboxy-terminal residues. The apoB-61 is present to a considerable degree, relative to apoB-100, in the proband's very low (VLDL) and low density (LDL) lipoprotein fractions. Both lipoprotein fractions have abnormal particle size distribution by electron microscopy. The LDL contain cuboidal particles. Total cholesterol, LDL cholesterol, and apoB levels in the family display three phenotypic patterns: normal, low, and extremely low. ApoB haplotyping indicates the presence of another defective apoB allele in a total of seven individuals. This allele leads to low levels of apoB-100. The second apoB gene-linked defect occurring together with the apoB-61 mutation explains the 3-phenotype pattern. The severe hypocholesterolemia seen in the proband and a sister result from the genetic compound state involving both alleles. This study shows that severe hypolipidemia in an individual heterozygous for a truncation in apoB is likely to involve a second genomic defect.

Adult↗
PubMed1992

Prevention of familial cardiovascular disease by screening for family history and lipids in youths.

We analyzed medical family history information from 51,053 families of high school students in Utah and Texas and cholesterol measurements from 853 youths and 1618 adults in Utah families with cardiovascular disease (CVD) to assess the utility of different approaches to risk-factor evaluation for youths. The major question addressed was in which youths should blood cholesterol be tested? Applying National Cholesterol Education Program recommendations suggested that 36% in Utah and 38% in Texas be tested. Heterozygous familial hypercholesterolemia (hFH) is the best documented and most serious cholesterol disorder readily diagnosed in youths. In Utah families ascertained for CVD in adults, blood cholesterol levels among youths were significantly bimodal with hFH present in 84% of youths in the upper cholesterol mode. Blood cholesterol levels in adults from the same families were less bimodal with hFH present in 38% of adults in the upper mode. More overlap existed between high and normal modes in adults than in youths. Data from this study suggest that family histories and cholesterol concentrations obtained from high school students may meet the needs of cholesterol screening, education, and follow-up in a controlled and cost-effective setting.

Adolescent↗