Biomedical subjects

S C Hunt

Publications and source records attributed to S C Hunt.

At least 91 records · Page 5Linked to original sources

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

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

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

Non-modulation as an intermediate phenotype in essential hypertension.

Non-modulation is a trait characterized by abnormal angiotensin-mediated control of aldosterone release and the renal blood supply. To determine whether non-modulation defines a specific subgroup of the hypertensive population and its utility as an intermediate phenotype, we have studied the distribution of this quantitative trait, whether its features are reproducible on repeated testing, and whether there is concordance of its multiple features. Essential hypertensive patients (224) and normotensive subjects (119) received an infusion of angiotensin II (Ang II) at 3 ng.kg-1.min-1 for 30-45 minutes. p-Aminohippurate (PAH) clearance was assessed as an index of renal plasma flow while the subjects were on a 200 meq sodium diet; plasma aldosterone levels were measured while the subjects were on a 10 meq sodium diet. In 54 subjects, diuretic-induced volume depletion superimposed on a low salt diet was substituted for the Ang II infusion. The results of each study were submitted to maximum likelihood analysis to assess bimodality. In response to both diuretic-induced volume depletion (p < 0.000023) and Ang II infusion (p < 0.0009), aldosterone responses were bimodally distributed in the essential hypertensive but not in the normotensive subjects, suggesting that this trait identifies a discrete subgroup. In the 59 subjects who had both an adrenal and renal study, 50 (85%) were concordant. Finally, in 27 subjects studied two to six times over a span of 1-60 months, the intraclass correlations of the adrenal, PAH, or both responses were highly significant (p values between 0.001 and 0.00007), indicating high reproducibility of results on repeated testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

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

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↗

PubMed1991

Time-varying limits for single blood pressures and heart rates of group-synchronized healthy women.

The circadian waveform in blood pressure (BP) and heart rate (HR) was explored in young adult women. Clinically healthy nurses, 18-25 years of age, volunteered for this study. Each was to provide measurements of systolic, mean arterial, and diasolic BP and HR at 15-min intervals over 48 h by using an ambulatory monitor ABPM-630 (Colin Medical, Komaki, Japan). The data consist of several sets of values. One set consists of a series from each of 44 student nurses, monitored in November, 1987. A second set stems from 50 nurses studied in June, 1988. Another set is composed of data from 56 nurses monitored between May and September, 1989. The nurses were all on a diurnal activity/nocturnal rest schedule. Reference limits were computed as 90% prediction limits specified by circadian stage. Data in intervals of 1 h, displaced by 30 min were used for the computation of these limits. Examination of chronodesms, i.e., time-specified limits of acceptability, revealed that the limits were very rugged. Similar features were found for all sets of data, such as peaks after arising, around noon, and in the evening. The features may perhaps be related to a physiologic response rather than representing purely random variation.

Adolescent↗

PubMed1991

Different plasma ionized calcium correlations with blood pressure in high and low renin normotensive adults in Utah.

Plasma ionized calcium levels have been shown to be lower than normotensive control levels in hypertensive patients with low plasma renin activity and higher than control levels in hypertensive patients with high renin activity; they did not differ between high and low plasma renin activity groups of normotensive controls. To see if ionized calcium may have different relationships with blood pressure across renin categories in normotensive individuals, plasma ionized calcium was measured on 875 healthy individuals, ages 3 to 83, who had never been diagnosed as having hypertension. Blood pressures were measured in the sitting, standing, and supine positions, along with pressures measured during two stress maneuvers: isometric handgrip and a 50 degrees tilt from a supine position. There was no linear correlation of blood pressure with plasma ionized calcium in the entire sample of youths or adults. However, after dividing the adults into tertiles based on plasma renin activity, there were significant inverse correlations between ionized calcium and systolic and diastolic blood pressure in the low renin group (r = -0.16 to -0.25, P less than or equal to .05), while the systolic blood pressure correlations were significantly positive in the high renin group (r = 0.14 to 0.22, P less than or equal to .05). Adults with normal renin levels did not have any significant correlations of plasma ionized calcium with blood pressure. These confounding effects of renin were greater for systolic than for diastolic blood pressure. These correlations within renin tertiles occurred even though there were no differences in mean blood pressure, plasma ionized calcium, total plasma protein and plasma sodium across renin categories.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

A prospective study of sodium-lithium countertransport and hypertension in Utah.

A 7-year prospective study of a cohort of 1,458 normotensive adults from Utah pedigrees, screened from 1980 to 1985, was done to determine whether baseline levels of sodium-lithium countertransport were associated with an increased risk of future hypertension. Subsequent new hypertension (n = 39) was ascertained in 1989 from detailed follow-up medical questionnaires (67% response). Previous segregation analyses on a subset of these pedigree members who responded (n = 342) using family relationships in addition to countertransport levels have shown statistically inferred major gene segregation of sodium-lithium countertransport levels. In the normotensive adults inferred by segregation analysis to carry the recessive major gene for high sodium-lithium countertransport, new-onset hypertension occurred in 18.8% (3 of 16) compared with 3.7% (12 of 326) in the low sodium-lithium countertransport genotype group (relative risk, 4.6 [1.6, 13.9]; p = 0.03). However, an elevated baseline sodium-lithium countertransport level without genotype information from segregation analysis did not increase the risk of future hypertension in the complete cohort of adult pedigree members (relative risk, 1.02 [0.85, 1.22]). Adjustment for other risk factors reduced the relative risk to 0.90 (0.72, 1.11). We conclude that the presence of a major gene for sodium-lithium countertransport or another closely linked gene, rather than the actual level of sodium-lithium countertransport, may increase the risk of hypertension onset. High sodium-lithium countertransport levels do not increase the risk of future hypertension for individuals in whom only polygenic and environmental effects determine sodium-lithium countertransport level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Exclusion of the Na(+)-H+ antiporter as a candidate gene in human essential hypertension.

The primary abnormalities that contribute to the pathogenesis of human essential hypertension are unknown. The known genetic contribution to this disorder suggests the possible use of genetic linkage analysis to test whether specific candidate genes contribute to the pathogenesis of either essential hypertension or intermediate phenotypes. Among such phenotypes, elevated erythrocyte Na(+)-Li+ countertransport (SLC) is the best known, supporting major gene inheritance by pedigree analysis. Striking similarities between SLC and Na(+)-H+ exchange suggest that mutations at the Na(+)-H+ antiporter gene locus (APNH) might result in elevated SLC and contribute to the subsequent pathogenesis of hypertension. We have tested these hypotheses by genetic linkage analysis, with APNH as a candidate gene. By determining genotypes at APNH and flanking loci in pedigrees that support major gene segregation of elevated SLC, we have excluded linkage of APNH and the major SLC locus with a LOD score of -5.91, an odds ratio of almost 1,000,000:1 against linkage. In the analysis of 93 hypertensive sibling pairs, we have further demonstrated that APNH explains none of the variance in SLC in hypertensive individuals (r2 = 6 x 10(-7), p greater than 0.99). Finally, we have directly tested for linkage of APNH to genes predisposing toward hypertension by linkage in hypertensive sibling pairs. Mean allele sharing at APNH is not greater than expected from random assortment in hypertensive siblings (0.92 versus 1.0, p greater than 0.80), and the upper 95% confidence limit of this value (1.04) indicates that mutations at APNH rarely if ever contribute to the pathogenesis of hypertension in this population.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiporters↗

PubMed1991

Genetic traits related to hypertension and electrolyte metabolism.

The genetic and cultural heritability and intercorrelation of traits related to hypertension have been carried out in 98 Utah pedigrees (2,500 person) and 58 sibships with two or more hypertensive persons (131 hypertensive persons). Although none of these traits has been established as a marker for "sodium-sensitive hypertension," many of them are related at least indirectly to both electrolyte metabolism and risk of hypertension. Significant recessive monogenic effects and high total heritability (52-84%) were found for urinary kallikrein, high fat pattern index, intraerythrocytic sodium, Na-Li countertransport, and ouabain binding sites. Familial correlations more strongly attributable to shared environment than to genetic effects were found for Na,K-ATPase pump activity, intraerythrocytic magnesium, plasma digoxin-like factor, plasma renin activity, and plasma sodium concentration. All anthropometric variables tested showed highly significant genetic heritability with low and insignificant shared family environmental effects. Several of the genetically determined cellular cation tests also correlated with other genetic traits including plasma lipids, anthropometric measurements, and other cellular cation tests. Among hypertensive individuals with familial dyslipidemic hypertension, plasma insulin levels correlated with obesity and lipid abnormalities and with several cellular cation flux tests associated with hypertension.

Adolescent↗

PubMed1991

Predictors of an increased risk of future hypertension in Utah. A screening analysis.

A prospective study on 1,482 adult members of 98 Utah pedigrees was carried out to determine which variables may be associated with an increased risk of hypertension incidence. After an average of 7 years of follow-up, 40 individuals had been placed on antihypertensive medications to lower blood pressure. Baseline study variables included anthropometrics, clinical chemistry measurements of blood and urine, socioeconomic and lifestyle variables, and detailed erythrocyte ion transport and concentration measurements. Age (relative risk of 4.28 for a 2 SD difference, p less than 0.0001) and baseline systolic and diastolic blood pressures (relative risks of 3.55 and 3.52, respectively, both p less than 0.0001) had the strongest associations with hypertension incidence. Controlling for age and baseline blood pressure, the following age- and sex-adjusted variables were associated with an increased risk of future hypertension (relative risks for a 2 SD difference, all p less than 0.10): family history of hypertension (2.35); height (1.97); body mass index (2.31); abdominal girth (2.66); subscapular, suprailiac, and triceps skinfold thicknesses (2.79, 2.52, and 2.28, respectively); percent ideal body weight (2.63); log triglyceride concentration (2.02); plasma uric acid (2.16); inorganic phosphate (0.50); and passive erythrocyte sodium permeability (1.59). The final model,which included all of the age- and sex-adjusted variables (p less than 0.10) in a backward elimination logistic regression analysis, consisted of age (4.78), systolic blood pressure (2.91), subscapular skinfold thickness (2.21), height (1.92), uric acid (2.06), inorganic phosphate (0.50), and family history of hypertension (1.82). None of the ion transport or concentration measurements ws associated with an increased risk of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗