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R R Williams

Publications and source records attributed to R R Williams.

At least 37 records · Page 2Linked to original sources
PubMed1999

Primordial prevention of cardiovascular disease through applied genetics.

Primordial prevention might be considered prevention of the development of disease at its earliest stages or early intervention on risk factors to eliminate increased risk in the first place. In this review we consider how knowledge of genetic causes of early cardiovascular disease can lead to directed screening and better treatment of high risk individuals. While gene therapy would be the most "primordial" approach to prevention of some diseases such as familial hypercholesterolemia, its practical application remains on the horizon. Nevertheless, there is much we can do now to prevent early deaths in genetically high risk patients. Here we consider epidemiology as the parent discipline for applied genetics and as integral to primordial prevention. With new knowledge of special susceptibility and new understanding of the interaction of genetics and exposures, prevention of individual high-risk in the first place is realizable. We summarize here the known and candidate genes influencing atherosclerosis, hypertension, and thrombosis; their diagnosis; and some useful preventive approaches. MEDPED, an international scheme for detection of risk in medical pedigrees, is described, along with the cost and social implications of its application as a preventive strategy.

Cardiovascular Diseases↗
PubMed1999

A novel LDLR mutation, H190Y, in a Utah kindred with familial hypercholesterolemia.

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein (LDL) cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications together with diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon-intron boundaries of the LDL receptor gene (LDLR). Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 631, causing substitution of tyrosine for histidine at codon 190 in exon 4 of the LDLR gene. The mutant allele-specific amplification method was used to examine 12 members of the family recruited for the diagnosis. This method helped to unequivocally diagnose 7 individuals as heterozygous for this particular LDLR mutation, while excluding the remaining 5 individuals from carrier status with FH.

Adult↗
PubMed1999

Enhanced blood pressure response to mild sodium reduction in subjects with the 235T variant of the angiotensinogen gene.

The relationship of high salt intake to elevated blood pressure levels has been demonstrated in most populations by cross-sectional, longitudinal, physiological, and clinical intervention studies. Variation within the angiotensinogen gene has been implicated in the genetic control of blood pressure levels and has been suggested to contribute to increased salt sensitivity. A total of 86 hypertensive men and women who had never been treated and who had participated in a 6-month randomized, placebo-controlled, clinical trial of low-sodium mineral salt (19% reduction in urinary sodium versus 12% increase in placebo group) were genotyped at the angiotensinogen M235T locus to test the hypothesis that the 235T allele is associated with a significant blood pressure response to a sodium reduction intervention whereas the 235M allele is not. After adjustment for gender and baseline blood pressure, persons with the TT and MT genotypes showed significant systolic blood pressure reductions on mineral salt compared with control subjects (P = .02 and P = .001, respectively) but not persons with the MM genotype (P = .10). Net adjusted diastolic blood pressure reductions also showed greater significance for persons with the TT and MT genotypes than for persons with the MM genotype (P = .08, P = .01, and P = .83, respectively). The net adjusted systolic and diastolic blood pressure reduction was -8.6/-3.9 mm Hg for persons with the TT genotype, -9.0/-5.2 mm Hg for the MT genotype, and -5.3/-1.0 mm Hg for the MM genotype. We conclude that the 235T allele of the angiotensinogen gene is associated with greater blood pressure decreases than the 235M allele after a sodium reduction intervention. The angiotensinogen gene accounts for some of the interindividual variation of the blood pressure response to sodium reduction.

Aged↗
PubMed1999

Evidence for a major gene accounting for mild elevation in LDL cholesterol: the NHLBI Family Heart Study.

Studies of rare Mendelian disorders of low density lipoprotein cholesterol (LDL-C) metabolism have identified specific genetic mutations in the LDL receptor and apolipoprotein B. Although these rare mutations account for a small proportion of LDL-C variation, twin and adoption studies indicate that at least 50% of the overall LDL-C observed variation is genetically determined. In a heterogeneous sample of 3227 subjects from the NHLBI Family Heart Study collected from four US centres, we find evidence for a common major gene accounting for mild elevations (1.25 standard deviations) in LDL-C. The analysis favored a recessive model with a frequency of 0.52 for the gene influencing elevated LDL-C, phenotypic means of 113 mg/dl for the normal genotypes and 146 mg/dl for the abnormal genotype, and a significant polygenic heritability. This statistically-inferred major gene accounted for 24% of the variation in LDL-C, with polygenes accounting for another 28% of the variation. Using parameters for major gene transmission estimated in the segregation analysis, LDL-C showed no linkage to the LDL receptor gene (LDLR), nor to the apolipoprotein E gene (APOE), nor to the cholesterol 7alpha-hydroxylase gene (CYP7A1), indicating the major gene effect influencing mild elevation in LDL-C is not explained by any of these candidate loci.

Adult↗
PubMed1999

No linkage of the lipoprotein lipase locus to hypertension in Caucasians.

OBJECTIVE: A previous study has shown significant linkage of five markers near the lipoprotein lipase locus to systolic blood pressure, but not to diastolic blood pressure, in nondiabetic members of 48 Taiwanese families selected for noninsulin-dependent diabetes. However, lipoprotein lipase markers did not appear strongly linked to systolic blood pressure in a study of Mexican-Americans using a variety of selection schemes. The objective of the current study was to test whether markers near the lipoprotein lipase gene were linked to hypertension in Caucasians. DESIGN: To test for linkage of genetic markers in or near the lipoprotein lipase gene to hypertension in Caucasians, two sets of Caucasian hypertensive sibships were genotyped. The samples included 261 sibships (431 effective sibpairs) from four field centers of the National Heart, Lung and Blood Institute Family Heart Study and 211 sibships (282 effective sibpairs) from the Health Family Tree database in Utah. RESULTS: Two highly polymorphic markers in or near the lipoprotein lipase gene showed no evidence of excess allele sharing in either set of hypertensive sibships. Combining the two datasets resulted in 653 and 713 effective sibpairs for the two markers, sharing 0.495 +/- 0.30 and 0.486 +/- 0.28 alleles identical by descent compared to an expected sharing of 0.50. Multipoint analysis of the two loci also did not show linkage (P = 0.95). CONCLUSIONS: We conclude that the lipoprotein lipase locus and nearby regions do not appear to be linked to hypertension in Caucasians.

Alleles↗
PubMed1999

Pharmacokinetics and safety of high-dose and extended-interval regimens of levofloxacin in human immunodeficiency virus-infected patients.

The pharmacokinetics of levofloxacin, administered in high doses and with extended dosing intervals, was studied in human immunodeficiency virus (HIV)-infected patients. Thirty patients received either 750 mg of the drug or a placebo once daily for 14 days, followed by 750 mg or 1,000 mg of the drug or a placebo three times weekly for an additional 14 days. Levofloxacin disposition was characterized by rapid oral absorption, with peak concentrations occurring approximately 1.5 h after dosing and elimination half-lives from 7.2 to 9.4 h. The overall incidence of any adverse effect was 70% (1,000 mg) to 95% (750 mg) for levofloxacin-treated patients and 71% for those taking the placebo. Levofloxacin pharmacokinetic parameters for HIV-infected patients were consistent with those observed in studies of healthy volunteers.

Administration, Oral↗
PubMed1999

Familial hypercholesterolemia in Utah kindred with novel 2412-6 Ins G mutations in exon 17 of the LDL receptor gene.

Familial hypercholesterolemia (FH) is a monogenic disorder associated with primary hypercholesterolemia. FH is characterized by autosomal co-dominant inheritance with strikingly elevated LDL-cholesterol, the presence of xanthoma and premature atherosclerosis. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To determine the genetic etiology of the lipoprotein abnormalities, we screened DNA samples from the family for mutations in all 18 exons and the exon- intron boundaries of the low-density lipoprotein receptor (LDLR) gene. Novel point mutations were identified in the proband: a one-base insertion of G to a five-G stretch at nucleotides 2412-6 (codons 783-785), causing a frameshift in exon 17 of the LDL receptor gene. The direct sequencing method was used to examine six members of the family recruited for the diagnosis. This method helped to unequivocally diagnose the five individuals as heterozygous for this particular LDL receptor mutation. This method also helped us to diagnose with FH, or to exclude from carrier status, three children between ages 6 and 11.

Child↗
PubMed1999

Familial hypercholesterolemia in Utah kindred with novel R103W mutations in exon 4 of the LDL receptor gene.

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein cholesterol levels early in childhood and very early coronary disease in both men and women. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon- intron boundaries of the low-density lipoprotein (LDL) receptor gene. Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 369, causing substitution of Tryptophan for Arginine at codon 103 in exon 4 of the LDL receptor gene. The SSCP method was used to examine seven members of the family recruited for the diagnosis. This method helped to unequivocally diagnose only the proband as heterozygous for this particular LDL receptor mutation while excluding the remaining six individuals from carrier status with FH.

Adolescent↗
PubMed1999

Evidence for a third genetic locus causing familial hypercholesterolemia. A non-LDLR, non-APOB kindred.

Monogenically inherited hypercholesterolemia is most commonly caused by mutations at the low density lipoprotein receptor (LDLR) locus causing familial hypercholesterolemia (FH) or at the apolipoprotein B (APOB) locus causing the disorder familial defective apoB (FDB). Probands from 47 kindreds with a strict clinical diagnosis of FH were selected from the Cardiovascular Genetics Research Lipid Clinic, Utah, for molecular genetic analysis. Using a combination of single-strand conformation polymorphism (SSCP) and direct sequencing, 12 different LDLR gene mutations were found in 16 of the probands. Three of the probands were carriers of the APOB R3500Q mutation. In five of the remaining 28 pedigrees where no mutation had been detected, samples from enough relatives were available to examine co-segregation with the LDLR region using the microsatellite marker D19S221, which is within 1 Mb centromeric of the LDLR locus, and D19S394, sited within 150 kb telomeric of the LDLR locus. In four of the families there was strong evidence for co-segregation between the LDLR locus and the phenotype of hypercholesterolemia, but in one large family with 18 living affected members and clear-cut bimodal hypercholesterolemia, there were numerous exclusions of co-segregation. Using length polymorphic markers within and outside the APOB gene, linkage of phenotype in this family to the APOB region was similarly excluded. In this large family, the degree of hypercholesterolemia, prevalence of tendon xanthomata, and occurrence of early coronary disease were indistinguishable from the other families studied. In summary, the data provide unequivocal evidence that a third locus can be etiological for monogenic familial hypercholesterolemia and should be reinvigorating to research in this field.

Adolescent↗
PubMed1998

Levofloxacin does not alter cyclosporine disposition.

Certain fluoroquinolones have been shown to elevate the serum concentrations of the immunosuppressant cyclosporine. It is thus important to investigate the potential interaction between levofloxacin, a new fluoroquinolone antimicrobial agent, and the pharmacokinetics of cyclosporine. Twelve healthy subjects (6 men, 6 women) were enrolled in and completed a placebo-controlled, randomized, double-blind, two-phase crossover study. Subjects were given a single oral 10-mg/kg dose of cyclosporine solution during multiple-dose twice-daily oral treatment with placebo or 500 mg of levofloxacin. Blood cyclosporine concentrations were measured for 48 hours after each cyclosporine dose for pharmacokinetic evaluation. Cyclosporine pharmacokinetic parameters were comparable and not significantly different in the absence and presence of levofloxacin. Results of this study suggest that a clinically important pharmacokinetic interaction between levofloxacin and cyclosporine is unlikely to occur during concurrent therapy.

Adult↗
PubMed1998

Lipoprotein(a) interactions with lipid and non-lipid risk factors in patients with early onset coronary artery disease: results from the NHLBI Family Heart Study.

BACKGROUND: A positive interaction between high plasma lipoprotein(a) [Lp(a)] and unfavorable plasma lipid levels has been reported to result in very high risk for premature coronary artery disease (CAD). We further examined this issue for men and women with early onset CAD. We also examined potential interactions between Lp(a) and non-lipid risk factors. METHODS AND RESULTS: In 338 men and women with early onset CAD (most with a positive family history of early CAD) and 480 general population controls, we measured Lp(a), lipids and other risk factors. In univariate analysis, relative odds for CAD was 1.7 (P = 0.002) for plasma Lp(a) >50 mg/dl. Elevated Lp(a) level was found to interact with adjusted plasma total/high density lipoprotein (HDL) cholesterol such that when Lp(a) was over 50 mg/dl and adjusted plasma total/HDL cholesterol >5.8, relative odds for CAD were 8.0-9.6 (P<0.0001) in multiple logistic regression. Non-lipid risk factors were generally found to multiply the risk associated with Lp(a) (as predicted by logistic regression) without evidence for interaction. CONCLUSIONS: We find evidence that Lp(a) does interact positively with adjusted plasma total/HDL cholesterol ratio. Aggressive risk factor intervention, especially for lipids, in those with elevated Lp(a) therefore appears indicated.

Adult↗
PubMed1998

Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers.

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0-24) following a single 750-mg dose were 7.1 microg/ml and 71.3 microg x h/ml, respectively, compared to 8.6 microg/ml and 90.7 microg x h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0-24 values were 8.9 microg/ml and 95.4 microg x h/ml, respectively; corresponding values at steady state were 11.8 microg/ml and 118 microg x h/ml. These Cmax and AUC0-24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CL[R]) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CL(R) following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.

Adolescent↗
PubMed1998

Segregation analysis of plasminogen activator inhibitor-1 and fibrinogen levels in the NHLBI family heart study.

Elevated plasminogen activator inhibitor-1 (PAI-1) and fibrinogen concentrations are risk factors for coronary heart disease. We investigated environmental, familial, and genetic influences on PAI-1 antigen and fibrinogen concentrations in 2029 adults from 512 randomly ascertained families in 4 US communities. We used maximum-likelihood segregation analysis to fit several genetic and nongenetic modes of inheritance to the data to determine whether mendelian inheritance of a major gene could best explain the familial distributions of these 2 hemostatic factors. Age- and gender-adjusted familial correlations for PAI-1 antigen level averaged 0.16 in first-degree relatives (95% CI=0.11 to 0.21); the spouse correlation was positive but not statistically significant (r=0.10, 95% CI=-0.02 to 0.23). Complex segregation analysis indicated a major gene associated with higher PAI-1 concentrations in 65% of individuals from these families. Demographic, anthropometric, lifestyle, and metabolic characteristics together explained 37% to 47% of the variation in PAI-1 antigen levels, and the inferred major gene explained an additional 17% of the variance. Positive and statistically significant age- and gender-adjusted familial correlations in first-degree relatives indicated a possible heritable component influencing plasma fibrinogen concentration (r=0. 17, 95% CI=0.13 to 0.22); however, segregation analysis did not provide statistical evidence of a major gene controlling fibrinogen level. These family data suggest that there are modest familial and genetic effects on the concentration of PAI-1.

Adult↗
PubMed1998

Increased urinary free cortisol: a potential intermediate phenotype of essential hypertension.

We evaluated urinary cortisol excretion as a potential intermediate phenotype of essential hypertension in 153 white patients with essential hypertension and 18 normotensive white control subjects. Analyses were controlled for dietary sodium and gender to adjust for potential confounding effects of these variables on cortisol excretion. Urinary cortisol excretion measured on both high- and low-salt diets was significantly related to hypertension by repeated measures ANCOVA (P=.02). Additional determinants of urinary free cortisol included dietary sodium intake and gender; cortisol excretion was significantly higher in men (P=.0006) and during a high-sodium diet (P=.0001). Maximum likelihood analysis showed urinary cortisol to have a bimodal distribution on both 200-mmol (P<.01) and 10-mmol (P<.002) sodium diets in hypertensive subjects. On the low-salt diet, the mean urinary cortisol in normotensive subjects (108.7+/-44.7 nmol/d) was similar to the mean of hypertensive subjects in the low mode (127.2+/-43.0 nmol/d). The high mode comprised 31.2% of the hypertensive population and had a mean urinary cortisol of 224.3+/-93.8 nmol/d. Subjects with the highest urinary free cortisol showed the least sensitivity of blood pressure to dietary sodium loading (P<.05). These data suggest that there is an association between salt-resistant hypertension and high urine cortisol levels. This association may have a genetic basis.

Adult↗
PubMed1998

Angiotensinogen genotype, sodium reduction, weight loss, and prevention of hypertension: trials of hypertension prevention, phase II.

The angiotensinogen gene has been linked to essential hypertension and increased blood pressure. A functional variant believed to be responsible for hypertension susceptibility occurs at position -6 in the promoter region of the gene in which an A for G base pair substitution is associated with higher angiotensinogen levels. To test whether an allele within the angiotensinogen gene is related to subsequent incidence of hypertension and blood pressure response to sustained sodium reduction, 1509 white male and female subjects participating in phase II of the Trials of Hypertension Prevention were genotyped at the angiotensinogen locus. Participants had diastolic blood pressures between 83 and 89 mm Hg and were randomized in a 2x2 factorial design to sodium reduction, weight loss, combined intervention, or usual care groups. Persons in the usual care group with the AA genotype at nucleotide position -6 had a higher 3-year incidence rate of hypertension (44.6%) compared with those with the GG genotype (31.5%), with a relative risk of 1.4 (95% confidence interval [0.87, 2.34], test for trend across all 3 genotypes, P=0.10). In contrast, the incidence of hypertension was significantly lower after sodium reduction for persons with the AA genotype (relative risk=0.57 [0.34, 0.98] versus usual care) but not for persons with the GG genotype (relative risk=1.2 [0.79, 1.81], test for trend P=0.02). Decreases of diastolic blood pressure at 36 months in the sodium reduction group versus usual care showed a significant trend across all 3 genotypes (P=0.01), with greater net blood pressure reduction in those with the AA genotype (-2.2 mm Hg) than those with the GG genotype (+1.1 mm Hg). A similar trend across the 3 genotypes for net systolic blood pressure reduction (-2.7 for AA versus -0.2 mm Hg for GG) was not significant (P=0.17). Trends across genotypes for the effects of weight loss on hypertension incidence and decreases in blood pressure were similar to those for sodium reduction. We conclude that the angiotensinogen genotype may affect blood pressure response to sodium or weight reduction and the development of hypertension.

Adult↗