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Steven C Hunt

Publications and source records attributed to Steven C Hunt.

66 records · Page 4Linked to original sources
PubMed2002

Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript.

The ubiquitin ligase NEDD4L is a candidate gene for essential hypertension on both functional and genetic grounds. By targeting the epithelial sodium channel (ENaC) for degradation, NEDD4L is a significant determinant of sodium reabsorption in the distal nephron. Genetic linkage has been reported to a region of chromosome 18q harboring the gene, with phenotypes that include a rare orthostatic hypotension disorder, essential hypertension, and postural change in systolic blood pressure. A systematic search for genetic polymorphisms by resequencing exons and intron boundaries in 48 Caucasians yielded 38 variants. Among these, variant 13 is common, with either G (70%) or A (30%) as the last nucleotide of a putative exon 1. This mutation could affect the generation of a previously unrecognized splice isoform. In subsequent experiments, (1) we confirmed the presence of this putative isoform in both kidney and adrenals; (2) we established that variant 13-A leads to the systematic use of an alternative splice site, generating a transcript encoding a nonfunctional protein; and (3) we demonstrated differences in tissue-specific expression of the novel isoform relative to its previously reported counterpart. Variant 13-A precludes the formation of a transcript encoding a full-length Ca2+-dependent lipid-binding (C2) domain with very high evolutionary conservation among NEDD4L orthologs. A similar C2 domain in the paralogous NEDD4 gene plays a significant role in the transfer of its product to the apical membrane of epithelial cells. Differential function of NEDD4L isoforms could prove significant in blood pressure regulation through an effect on ENaC-dependent sodium reabsorption.

Alternative Splicing↗
PubMed2002

PAI-1 in human hypertension: relation to hypertensive groups.

BACKGROUND: Although the renin-angiotensin system and insulin resistance (IR) have been identified as major regulators of plasminogen activator inhibitor type-1 (PAI-1), their roles in hypertensive subjects is not clearly defined. METHODS: We examined the effect of dietary salt restriction on PAI-1 levels in 239 hypertensive subjects from three centers. Subjects were placed on a 200 and 10 mmol/day sodium diets for 1-week periods. Plasma renin activity (PRA) and PAI-1 levels were measured on the last day of both diets and fasting insulin, glucose, and aldosterone (ALDO) levels, only on the low salt diet. RESULTS: Sodium restriction increased PAI-1 levels from 32.1 +/- 2.5 ng/mL to 39.8 +/- 3.2 ng/mL (P = .009). There was a strong positive correlation between PAI-1 levels and PRA (r = 0.228, P = .0004), IR (r = 0.222, P = .001), triglycerides (r = 0.275, P < .001), and ALDO (P = .018 for linear trend). The patients were divided into low renin (low IR and ALDO levels), nonmodulators (normal PRA, high IR, and low ALDO levels), and modulators (normal PRA, intermediate IR, and normal ALDO levels) groups to assess the relative contribution of each factor to PAI-1 levels. Modulators had significantly (P = .019) higher PAI-1 levels compared to the low renin and nonmodulators who had similar PAI-1 levels. CONCLUSIONS: Plasma renin activity, IR, and ALDO all correlate with PAI-1 levels in the hypertensive subjects. However, the data suggest that ALDO may be an important factor contributing to the variability of PAI-1 levels in individual hypertensive subjects.

Adult↗
PubMed2002

Segregation analysis of HDL cholesterol in the NHLBI Family Heart Study and in Utah pedigrees.

We investigated the genetic determination of high-density-lipoprotein cholesterol (HDL-C) levels in the NHLBI Family Heart Study by segregation analysis. Included was a total of 3755 subjects from 560 randomly selected nuclear families and 522 families selected due to a high family risk of coronary heart disease (CHD). In the whole dataset, there was no evidence for an allele at a major gene locus responsible for HDL-C levels lower than the population mean or even for significant bimodality for low levels of HDL-C. However, we observed evidence for a recessive allele that was associated with higher HDL-C levels than average. This evidence for a recessive major gene was independent of triglyceride concentrations and was most strongly observed in families recruited for CHD. The environmental model was rejected (P=0.0027) while the codominant and recessive models were not rejected (P=0.085 and P=0.133, respectively). The dominant model was also rejected (P<0.0001). In the recessive segregation model, the means of those inferred to be homozygous for the high HDL-C allele and those without the high HDL-C allele were separated by about 25 mg/dl HDL-C (73.9+/-1.99 vs 48.2+/-0.36 mg/dl). Because these results were unexpected, segregation was tested in a separate sample of 2013 individuals in 85 large pedigrees ascertained for early heart disease deaths, early stroke deaths, and early hypertension in Utah. Similar evidence for an allele at a major gene locus for high HDL-C was found. In summary, we did not find evidence for an allele at a major gene locus associated with low HDL-C levels segregating in pedigrees recruited for the NHLBI Family Heart Study, or in pedigrees ascertained in Utah for early CHD or related phenotypes. Instead we found some evidence for the segregation of an allele associated with high HDL-C. d

Alleles↗
PubMed2002

A genome scan for loci influencing anti-atherogenic serum bilirubin levels.

Epidemiological studies have shown an association of decreased serum bilirubin levels with coronary artery disease. Two segregation analyses in large pedigrees have suggested a major gene responsible for high bilirubin levels occurring in about 12% of the population. Based on a recessive model from a previous segregation analysis, we performed a genome scan using 587 markers genotyped in 862 individuals from 48 Utah pedigrees to detect loci linked to high bilirubin levels. As a complementary approach, non-parametric linkage (NPL) analysis was performed. These two methods identified four regions showing evidence for linkage. The first region is on chromosome 2q34-37 with multipoint LOD and NPL scores of 3.01 and 3.22, respectively, for marker D2S1363. This region contains a previously described gene, uridine diphosphate glycosyltransferase 1, which has been associated with high bilirubin levels. A polymorphism in the promoter of this gene was recently shown to be responsible for Gilbert syndrome which is associated with mild hyperbilirubinemia. The other regions were found on chromosomes 9q21, 10q25-26, and 18q12 with maximum NPL scores of 2.39, 1.55, and 2.79, respectively. Furthermore, we investigated in these pedigrees the association between bilirubin levels and coronary artery disease. One-hundred and sixty-one male and 41 female subjects had already suffered a coronary artery disease event. Male patients showed significantly lower bilirubin concentrations than age-matched controls. This association, however, was not observed in females. These results provide evidence that loci influencing bilirubin variation exist on chromosomes 2q34-37, 9q21, 10q25-26, and 18q12 and confirms the association of low bilirubin levels with coronary artery disease in males.

Adult↗
PubMed2002

Linkage of creatinine clearance to chromosome 10 in Utah pedigrees replicates a locus for end-stage renal disease in humans and renal failure in the fawn-hooded rat.

BACKGROUND: Renal failure is an important health concern for persons with hypertension and diabetes. In the fawn-hooded rat, a renal failure locus, Rf-1, has been identified on rat chromosome 1. A study of African American sibpairs with end-stage renal disease (ESRD) replicated this finding on the orthologous region in humans, chromosome 10, with a maximum logarithm of odds (LOD) score of 3.4. An important question is whether this region can be detected in healthy subjects prior to onset of ESRD by examining creatinine clearance as an indicator of early renal damage. METHODS: We analyzed 49 Utah Caucasian pedigrees and performed quantitative nonparametric linkage analysis using 21 markers spanning chromosome 10. Pedigree members (mean age of 40 +/- 17) were examined up to three different times over 10 years, with creatinine clearance measured at each exam. For examination 1, three overnight, timed, 12-hour urine samples were obtained and averaged. One 12-hour sample was obtained for examinations 2 and 3. RESULTS: Heritabilities of creatinine clearance were 0.33 (N = 1360), 0.36 (N = 1196), and 0.53 (N = 718) for the three examinations, respectively. The nonparametric LOD score for examination 1 was 1.4 at marker D10S677 (approximately 117 cM). The LOD score at examination 2, an average of 21/2 years later, was 1.8 at marker D10S1239 (approximately 123 cM) and 1.9 at marker D10S1425 (approximately 137 cM). The LOD score at examination 3, an average of 10 years from baseline, was 2.1 at marker D10S2470 (approximately 113 cM). Thus, there is consistent evidence of linkage to this region from three different examinations spanning a period of 10 years. CONCLUSIONS: These linkage results confirm the ESRD linkage and the rat renal failure linkage to this region even though the LOD score is somewhat weaker, probably due to the less severe phenotype that was analyzed. It also suggests that there may be a locus on chromosome 10 that leads to reduced renal function that can be detected while subjects are still healthy. Identification of the responsible gene may help in predicting renal disease progression in susceptible patients.

Adult↗
PubMed2002

Genome scans for blood pressure and hypertension: the National Heart, Lung, and Blood Institute Family Heart Study.

This study presents genome scans for hypertension and blood pressures from 2959 individuals in 500 white families from the National Heart, Lung, and Blood Institute Family Heart Study. Genome scans were performed with different methods of handling the 27% of individuals taking antihypertensive medications. Variance components LOD scores were estimated by assigning medicated hypertensive individuals (1) to have a blood pressure of 140/90; (2) to be missing; and (3) to have a randomly assigned systolic blood pressure between 140 and 160 (N[150,5] distribution) and diastolic blood pressure between 90 and 100 mm Hg (N[95,2.5] distribution). There were 5 regions with heterogeneity LOD scores > or =2.0 for hypertension (unadjusted for multiple models): 2.8 on chromosome 1 (192 cM), 2.6 on chromosome 7 (58 cM), 2.0 on chromosome 7 (127 cM), 2.4 on chromosome 12 (83 cM), and 2.4 on chromosome 15 (103 cM). Diastolic blood pressure had no LOD scores > or =2.0. Only chromosome 6 showed linkage for systolic blood pressure, with a LOD score of 3.3 at 88.7 cM from the initial randomization. Multiple randomizations of medicated subjects' systolic blood pressures yielded a mean LOD score of 2.8+/-0.4, whereas setting medicated systolic blood pressures to 140 mm Hg yielded a LOD score of 3.3. Excluding the medicated individuals or using their treated blood pressures reduced the LOD scores to 0.8 and 1.3, respectively, indicating the importance of including the extremes of quantitative trait distributions in linkage analyses. These results overlap other published scans, particularly regions on chromosomes 1 and 6, which have been implicated in familial combined hyperlipidemia.

Adult↗
PubMed2002

Influence of apolipoprotein E, smoking, and alcohol intake on carotid atherosclerosis: National Heart, Lung, and Blood Institute Family Heart Study.

BACKGROUND AND PURPOSE: Apolipoprotein E (apoE) isoforms and lifestyle factors play an important role in the development of coronary heart disease. The association of apoE and carotid atherosclerosis remains controversial. METHODS: We investigated the relation of apoE, cigarette smoking, alcohol drinking, and their interaction with carotid atherosclerosis on 544 individuals free of coronary heart disease in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Atherosclerotic lesions of the carotid arteries were detected through high-resolution ultrasound. RESULTS: Subjects in the apoE4 group had lower blood pressure, lower high-density lipoprotein cholesterol, and higher low-density lipoprotein cholesterol. In a multivariate logistic regression model, apoE isoforms and alcohol consumption were not significantly associated with the prevalence odds of carotid atherosclerosis (P=0.94 and 0.98, respectively, for trend). In contrast, compared with those who never smoked, the prevalence odds ratios for carotid atherosclerosis were 1.7 [95% confidence interval (CI),1.1 to 2.7], 2.8 (95% CI, 1.2 to 6.2), and 1.9 (95% CI, 0.7 to 5.5) for former smokers, current smokers of 1 to 20 cigarettes per day, and current smokers of >20 cigarettes day, respectively (P=0.0018 for trend). We did not find evidence of an interaction between apoE and alcohol consumption. Our data suggested a synergistic effect between the apoE allele epsilon(4) and smoking on carotid atherosclerosis: odds ratios were 1.7 (95% CI, 0.8 to 3.6) for smoking alone, 1.0 (95% CI, 0.6 to 1.8) for epsilon4 alone, and 3.7 (95% CI, 1.1 to 3.6) for the joint presence of the apoE allele epsilon4 and smoking. CONCLUSIONS: Smoking but not alcohol consumption or ApoE is associated with an increased odds of carotid atherosclerosis. Our data suggest a synergistic effect between the apoE allele epsilon4 and smoking on carotid atherosclerosis.

Adult↗
PubMed2002

Low-renin hypertension, altered sodium homeostasis, and an alpha-adducin polymorphism.

Defining the genetic basis of common forms of human essential hypertension is most informative when correlated with physiological mechanisms that underlie blood pressure regulation. A polymorphism of the alpha-adducin gene as been associated with elevated blood pressure in the rat, but previous studies of the 460Trp polymorphism of the human alpha-adducin gene have not clearly identified an association with hypertension. In this study, the frequency of the 460Trp allele was 19% and 9 of 279 subjects (3.2%) were homozygous for the 460Trp allele. The systolic blood pressure response to changes in dietary sodium was significantly greater in subjects homozygous for the 460Trp allele (25 +/- 4 mm Hg) compared with subjects heterozygous for 460Trp (12 +/- 2 mm Hg) or homozygous for the 460Gly allele (14 +/- 1 mm Hg). Intracellular erythrocyte sodium content, sodium-lithium countertransport, and renal fractional excretion of sodium were significantly decreased in subjects homozygous for the 460Trp polymorphism (P<0.05). There was a significant association between homozygosity for the 460Trp allele and low-renin hypertension. Subjects heterozygous for the 460Trp allele did not have increased salt-sensitivity or an increased frequency of low-renin hypertension. Therefore, this study demonstrates a common genetic basis for altered cellular sodium homeostasis, impaired renal sodium handling, and salt-sensitivity of systolic blood pressure in individuals homozygous for the 460Trp polymorphism of the alpha-adducin gene. Homozygosity for this alpha-adducin allele may be an important determinant for approximately 10% of individuals with low-renin hypertension.

Adolescent↗
PubMed2002

Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity.

Kallikrein is synthesized in the distal tubules and produces kinins, which are involved in the regulation of vascular tone in the kidney. Urinary kallikrein activity has been reported to be partly inherited and to be reduced in essential hypertension. In a systematic search for molecular variants of the human kallikrein gene, nine single-nucleotide polymorphisms were identified. Five of those polymorphisms, including two nonsynonymous substitutions in exon 3, i.e., Arg53His (allelic frequency in Caucasian subjects, 0.03) and Gln121Glu (allelic frequency, 0.33), were studied in a normotensive group and two independent hypertensive groups for which 24-h urinary kallikrein activity had been measured. A significant decrease in urinary kallikrein activity was observed for the subjects who were heterozygous for the Arg53His polymorphism, compared with the other subjects. This finding was consistent in the two hypertensive groups and was observed with several kallikrein enzymatic assays. The Gln121Glu polymorphism and the other polymorphisms were not associated with changes in urinary kallikrein activity. None of the polymorphisms was associated with hypertension. Recombinant kallikrein variants were synthesized and enzymatically characterized, using native kininogen and kininogen-derived synthetic peptide substrates. No important effect was observed after Gln121 mutation, but there was a major decrease in enzyme activity when Arg53 was replaced by histidine. A model of kallikrein derived from crystallographic data suggested that Arg53 can affect substrate binding. The identification of a subset of subjects with genetically reduced kallikrein activity as a result of an amino acid mutation could facilitate analysis of the role of the kallikrein-kinin system in renal and vascular diseases.

Alleles↗
PubMedDate not supplied

Genetics of hypertension.

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Calmodulin-Binding Proteins↗