Biomedical subjects

R R Williams

Publications and source records attributed to R R Williams.

At least 55 records · Page 3Linked to original sources

PubMed1998

Molecular genetic diagnosis of a family with hypercholesterolemia by a mismatched PCR-RFLP method for genotyping single base substitution of the LDL receptor gene.

Plasma lipid and lipoprotein levels reflect in part the influence of relevant genetic loci. Defects at some of these loci account for specific types of dyslipoproteinemia occurring with regularity among family members. In the course of familial investigations of coronary artery disease, we identified an family in which several members were affected with elevated low density lipoprotein (LDL) cholesterol levels. To study the genetic defects responsible for plasma lipoprotein abnormality in this pedigree, we developed a simple method for genotyping a single base substitution that does not affect a restriction recognition enzyme site in exon 10 of the LDL receptor gene. Using our mismatched PCR method, this G- > A substitution at nucleotide 1413 could be genotyped in the form of a biallelic restriction fragment length polymorphism (RFLP) after digestion with restriction enzyme Hpa II. Linkage analysis using this molecular method demonstrated that the defect at the LDL receptor locus is responsible for elevated LDL cholesterol phenotype observed in this family by segregation of defective alleles at the LDL receptor locus with the disease (peak decimal logarithm of odds score > 3.0).

Adolescent↗

PubMed1998

Familial hypercholesterolemia kindred in Utah with novel C54S mutations of the LDL receptor gene.

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 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 T-to-A transversion at nucleotide position 223, causing substitution of Ser for Cys at codon 54 in exon 3 of the receptor gene. This amino acid replacement would disrupt one of the disulfide bonds necessary for maintenance of the secondary structure of the repeat at the N-terminal of the receptor, prevent correct folding of the receptor, and result in defective intracellular transport of the receptor.

Adult↗

PubMed1998

Fibrinogen, plasminogen activator inhibitor-1, and carotid intima-media wall thickness in the NHLBI Family Heart Study.

Several studies have linked higher plasma fibrinogen and plasminogen activator inhibitor (PAI-1) concentrations with increased risk of cardiovascular disease. We studied whether members of families with increased occurrence of coronary heart disease (CHD) have increased levels of fibrinogen and PAI-1 and whether subclinical carotid atherosclerosis is associated with these two hemostatic factors. Contrary to our hypothesis, fibrinogen and PAI-1 antigen levels were not different between high CHD risk families versus random families. Adjusted for age and family type, fibrinogen and PAI-1 were both associated positively with carotid intima-media thickness assessed by B-mode ultrasound. However, adjustment for lifestyle and medical covariates essentially eliminated these associations. These data suggest 1) elevated fibrinogen and PAI-1 do not explain clustering of CHD in families and 2) fibrinogen and PAI-1 may partly mediate the effects of other risk factors on carotid atherosclerosis, though the data are also consistent with them playing no causal role.

Aged↗

PubMed1998

Modeling disease incidence rates in families.

We apply an extended Cox model to study latent genes and measured environmental exposures simultaneously as risk factors for disease. Using this method, we assume Mendelian transmission of the genes and either dominant or recessive gene action. We compared the results from this model with those obtained under a model that includes the environmental variables and a family risk score. We demonstrate the method in samples of 1,433 Caucasian families (N = 6,791) and 206 African-American families (N = 771) from the National Heart, Lung, and Blood Institute Family Heart Study. In Caucasians, we found evidence suggesting that having ever smoked increased the risk of coronary heart disease only in individuals who carry a genetic susceptibility. We also noted that in both Caucasian and African-American families, the relative risk of coronary heart disease for ever-treated vs never-treated for high serum total cholesterol increased after including an unobserved susceptibility genotype in the model. This finding implied that there may be genes influencing coronary heart disease independent of those that influence total cholesterol. Such findings were not evident when genetic risk was summarized by the family history score. We also discuss the extension of the model to address the etiology of complex diseases.

Age of Onset↗

PubMed1997

Euphenic prevention of coronary artery disease.

The purpose of this feasibility study was to incorporate the primary prevention of coronary artery disease (CAD) into periconception care. The first task was the preconceptional screening for CAD. The family and case histories and risk status of prospective mothers and fathers were obtained. Serum total cholesterol was measured in 3,530 female and 3,127 male participants. The mean serum nonfasting cholesterol was 192 +/- 40 mg/dl in women and 204 +/- 49 mg/dl in men. The levels of total cholesterol exceeded the upper limit of desirable total cholesterol (200 mg/dl) in 37% of women and in 49% of men. Only 7% of women and 5% of men had previous knowledge about their high total cholesterol. The second task was risk assessment for CAD in prospective parents and their planned baby and the identification of couples at high risk. The third step was the education of couples at high risk: how to reduce risk factors and how to enhance protective factors. Three months later, the short-term follow-up study indicated a 49 mg/dl (18%) and 43 mg/dl (16%) (range 250 to 300) reduction in total cholesterol in female and male participants, respectively, mainly due to an education program including change in diet, cessation of smoking, and so forth. The long-term follow-up will include both parents and children 3 years after the birth. Periconception care is appropriate for both a general and selective approach to population screening for total cholesterol and for primary prevention of CAD.

Adult↗

PubMed1997

Segregation analysis of cardiovascular reactivity to laboratory stressors.

To better understand the contribution of major gene influences to individual differences in cardiovascular reactivity, we performed a segregation analysis on blood pressure responses to two laboratory tasks, mental arithmetic and bicycle exercise. The study population consisted of 1,451 adults (age > or = 18 years) who were members of 81 Utah pedigrees. Only 864 members performed the bicycle task because persons age 60 years or older or with heart disease were excluded. Blood pressure reactivity to mental arithmetic was defined as change from resting values, and reactivity to the bicycle task was defined as the difference between maximum blood pressure during exercise and resting values adjusted for the individual's workload. Complex segregation analysis and likelihood procedures were used to test for a major gene effect controlling blood pressure reactivity to each task. Two modifiers of the penetrance, age and sex, were considered parameters in these models. We found that diastolic blood pressure (DBP) but not systolic blood pressure reactivities to the mental arithmetic and bicycle exercise tasks were controlled by major gene effects. The best-fitting model, however, differed for the two tasks. For DBP reactivity to mental arithmetic, a major codominant model with gene frequency 0.10 was the best-fitting model; for the bicycle task, the best-fitting model was a mixed recessive model with gene frequency 0.21. Sex differences in DBP reactivity were significant in both tasks: the effect of age was significant only for the mental arithmetic task. These results suggest a significant genetic component for DBP reactivity to laboratory stressors.

Adult↗

PubMed1997

Absence of a pharmacokinetic interaction between intravenous theophylline and orally administered levofloxacin.

A randomized, placebo-controlled, two-way crossover study in 16 healthy men was performed to determine the effect of orally administered levofloxacin at steady-state conditions, given at 500 mg every 12 hours, on the pharmacokinetics of theophylline given as a single 4.5-mg/kg intravenous infusion. Participants were assigned randomly to receive theophylline with levofloxacin in one study period and theophylline with placebo in the other period. Fourteen individuals completed the study. Mean (+/-SD) values for theophylline pharmacokinetic parameters for the levofloxacin and placebo treatments, respectively, were peak plasma concentrations (Cmax) of 11.4 (1.8) micrograms/mL and 10.7 (1.3) micrograms/mL; areas under the concentration time curve from time 0 extrapolated to infinity (AUCzero-infinity) of 124 (32) micrograms.hr/mL and 126 (30) micrograms.hr/mL; volumes of distribution at steady state (Vdss) 31.7 (3.5) L and 32.0 (3.9) L; clearances (Cl) of 48.6 (11.6) mL/min and 47.4 (10.3) mL/min; and half-lives (t1/2) of 8.1 (1.9) hours and 8.2 (1.8) hours. There were no statistically significant differences between treatments for any of these parameters. There was no pharmacokinetic interaction between levofloxacin administered orally at steady-state conditions and intravenously administered theophylline.

Adult↗

PubMed1997

Multicenter, randomized study comparing levofloxacin and ciprofloxacin for uncomplicated skin and skin structure infections.

BACKGROUND: The fluoroquinolone, levofloxacin, is active against most common pathogens in skin and skin structure infections. METHODS: The efficacy, tolerability, and safety of levofloxacin and ciprofloxacin were compared in a randomized, open-label, multicenter trial of patients with uncomplicated skin and skin structure infections. Of 469 patients treated, 231 received levofloxacin (500 mg qd) and 238 were given ciprofloxacin (500 mg bid). RESULTS: Overall clinical success rates (cured plus improved) for levofloxacin and ciprofloxacin were 98% and 94%, respectively (95% confidence interval [CI], -7.7, 0.7). Overall microbiologic eradication rates by patient were 98% in the levofloxacin group and 89% in the ciprofloxacin group (95% CI, -14.5, -2.7), whereas eradication rates by pathogen were 98% and 90%, respectively (95% CI, -12.6, -3.7). The eradication rate for Staphylococcus aureus was 100% in the levofloxacin group and 87% in the ciprofloxacin group (95% CI, -20.2, -5.1). Treatment-emergent adverse events were comparable, with drug-related adverse events reported in 6% of levofloxacin patients and 5% of ciprofloxacin patients. CONCLUSIONS: Levofloxacin is as effective and safe as ciprofloxacin in the treatment of uncomplicated skin and skin structure infections.

Administration, Oral↗

PubMed1997

Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses.

The pharmacokinetics of once-daily oral levofloxacin (study A) or intravenous levofloxacin (study B) in 40 healthy male volunteers were investigated in two separate randomized, double-blind, parallel-design, placebo-controlled studies. Levofloxacin at 500 mg or placebo was administered orally or intravenously as a single dose on day 1; daily oral or intravenous dosing resumed on days 4 to 10. In a third study (study C), the comparability of the bioavailabilities of two oral and one intravenous levofloxacin formulations were investigated with 24 healthy male subjects in an open-label, randomized, three-way crossover study. Levofloxacin at 500 mg as a single tablet or an intravenous infusion was administered on day 1; following a 1-week washout period, subjects received the second regimen (i.e., the other oral formulation or the intravenous infusion); the third and final regimen was administered following a 1-week washout period. The concentrations of drug in plasma and urine were measured by validated high-pressure liquid chromatography methods. Pharmacokinetic parameters were estimated by noncompartmental methods. In both study A (oral levofloxacin) and study B (intravenous levofloxacin), steady state was attained within 48 h after the start of the multiple dosing on day 4. Levofloxacin pharmacokinetics were linear and predictable for the single and multiple 500-mg, once-daily oral and intravenous dosing regimens, and the values of the pharmacokinetic parameters for the oral and intravenous administrations were similar. Study C indicated that levofloxacin was rapidly and completely absorbed from the oral tablets, with mean times to the maximum concentration of drug in serum of approximately 1.5 h and mean absolute bioavailability of > or =99%. These results support the interchangeability of the oral and intravenous routes of levofloxacin administration.

Administration, Oral↗

PubMed1997

Absence of age and gender effects on the pharmacokinetics of a single 500-milligram oral dose of levofloxacin in healthy subjects.

The influence of age and gender on the pharmacokinetics of levofloxacin in healthy subjects receiving a single oral 500-mg dose of levofloxacin was investigated in this parallel design study. Six young males (aged 18 to 40 years), six elderly males (aged > or = 65 years), six young females (aged 18 to 40 years), and six elderly females (aged > or = 65 years) were enrolled and completed the study. The study reveals that the bioavailability (rate and extent) of levofloxacin was not affected by either age or gender. In both age (young and elderly) and gender (male and female) groups of subjects, peak concentrations in plasma were reached at approximately 1.5 h after dosing; renal clearance of levofloxacin accounted for approximately 77% of total body clearance, and approximately 76% of the administered dose was recovered unchanged in urine over the 36 h of collection. The apparent differences in the calculated pharmacokinetic parameters for levofloxacin between the age groups (young versus elderly) and between the gender groups (males versus females) could be explained by differences in renal function among the subjects. A single dose of 500 mg of levofloxacin administered orally to both young and old, male and female healthy subjects was found to be safe and well tolerated. As the differences in levofloxacin kinetics between the young and the elderly or the males and the females are limited and are mainly related to the renal function of the subjects, dose adjustment based on age or gender alone is not necessary.

Administration, Oral↗

PubMed1997

Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine.

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.

Adult↗

PubMed1997

A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia.

Five hundred ninety patients were enrolled in a prospective, multicenter, randomized trial comparing the efficacy and safety of 7 to 14 days of levofloxacin treatment with that of ceftriaxone and/or cefuroxime axetil in the management of community-acquired pneumonia in adults. Patients received either intravenous and/or oral levofloxacin (500 mg once daily) or the comparative agents, parenteral ceftriaxone (1 to 2 g once to twice daily) and/or oral cefuroxime axetil (500 mg twice daily). Erythromycin or doxycycline could be added to the comparator arm at the investigator's discretion. The decision to use an intravenous or oral antimicrobial agent for initial therapy was made by the investigator. Clinical and microbiological evaluations were completed at the baseline, during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Four hundred fifty-six patients (226 given levofloxacin and 230 administered ceftriaxone and/or cefuroxime axetil) were evaluable for clinical efficacy. Streptococcus pneumoniae and Haemophilus influenzae were isolated in 15 and 12%, respectively, of clinically evaluable patients. One hundred fifty atypical pathogens were identified: 101 were Chlamydia pneumoniae, 41 were Mycoplasma pneumoniae, and 8 were Legionella pneumophila. Clinical success at 5 to 7 days posttherapy was superior for the levofloxacin group (96%) compared with the ceftriaxone and/or cefuroxime axetil group (90%) (95% confidence interval [CI] of -10.7 to -1.3). Among patients with typical respiratory pathogens who were evaluable for microbiological efficacy, the overall bacteriologic eradication rates were superior for levofloxacin (98%) compared with the ceftriaxone and/or cefuroxime axetil group (85%) (95% CI of -21.6 to -4.8). Levofloxacin eradicated 100% of the most frequently reported respiratory pathogens (i.e., H. influenzae and S. pneumoniae) and provided a >98% clinical success rate in patients with atypical pathogens. Both levofloxacin and ceftriaxone-cefuroxime axetil eradicated 100% of the S. pneumoniae cells detected in blood culture. Drug-related adverse events were reported in 5.8% of patients receiving levofloxacin and in 8.5% of patients administered ceftriaxone and/or cefuroxime axetil. Gastrointestinal and central and peripheral nervous system adverse events were the most common events reported in each treatment group. In conclusion, these results demonstrate that treatment with levofloxacin is superior to ceftriaxone and/or cefuroxime axetil therapy in the management of community-acquired pneumonia in adults.

Administration, Oral↗

PubMed1997

Lipoprotein(a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease.

An interaction between high plasma lipoprotein(a) [Lp(a)], unfavorable plasma lipids, and other risk factors may lead to very high risk for premature CAD. Plasma Lp(a), lipids, and other coronary risk factors were examined in 170 cases with early familial CAD and 165 control subjects to test this hypothesis. In univariate analysis, relative odds for CAD were 2.95 (P < .001) for plasma Lp(a) above 40 mg/dL. Nearly all the risk associated with elevated Lp(a) was found to be restricted to persons with historically elevated plasma total cholesterol (6.72 mmol/L [260 mg/dL] or higher) or with a total/HDL cholesterol ratio > 5.8. Nonlipid risk factors were also found to at least multiply the risk associated with Lp(a). When Lp(a) was over 40 mg/dL and plasma total/HDL cholesterol > 5.8, relative odds for CAD were 25 (P = .0001) in multiple logistic regression. If two or more nonlipid risk factors were also present (including hypertension, diabetes, cigarette smoking, high total homocysteine, or low serum bilirubin), relative odds were 122 (P < 1 x 10(-12)). The ability of nonlipid risk factors to increase risk associated with Lp(a) was dependent on at least a mildly elevated total/HDL cholesterol ratio. In conclusion, high Lp(a) was found to greatly increase risk only if the total/HDL cholesterol ratio was at least mildly elevated, an effect exaggerated by other risk factors. Aggressive lipid lowering in those with elevated Lp(a) therefore appears indicated.

Age of Onset↗

PubMed1997

Association of genetic variations in apolipoprotein B with hypercholesterolemia, coronary artery disease, and receptor binding of low density lipoproteins.

To search for unique mutations in the apolipoprotein B (apoB) gene that disrupt the binding of LDL to its receptor and cause hypercholesterolemia, we examined more than 800 patients with high LDL cholesterol levels and/or coronary artery disease (CAD). Analysis of patient DNA by single-strand conformation polymorphism and allele-specific oligonucleotide hybridization of the sequence surrounding the putative receptor- binding domain of apoB (amino acid positions 2965 to 3534) revealed seven variations. LDL from heterozygotes with either Arg 3500 Gln or Arg 3531 Cys bound defectively with the LDL receptor in competitive binding assays. The Arg 3500 Gln substitution was statistically more prevalent in patients with hypercholesterolemia (P = 0.0003). Total cholesterol and LDL-cholesterol were significantly higher (P< 0.0004) in 34 apoB 3500 Gln carriers than in the controls. The allele encoding the Arg 3531 Cys substitution was more prevalent (0.8%) in the CAD group (P = 0.05) than in the controls. A Ser 3252 Gly variant was statistically more prevalent in the hypercholesterolemic group (P = 0.03), but LDL with this mutation had normal LDL receptor-binding activity. The other four variants identified (Leu 3350 Leu, Gln 3405 Glu, Val 3396 Met, and Ser 3455 Arg) were not associated with defective LDL-receptor binding, hypercholesterolemia, or CAD, nor were the apoB mutations associated with elevated lipid levels in family members. The surprising result that only two mutations of apoB in the receptor-binding domain (Arg 3500 Gln and Arg 3531 Cys) were associated with defective LDL binding, hypercholesterolemia, or CAD is in stark contrast with familial hypercholesterolemia, where nearly 150 mutations of the LDL receptor have been described that disrupt its function. This study strongly suggests that a limited number of mutations of apoB markedly influence LDL binding to its receptor.

Adult↗

PubMed1996

Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine. METHODS AND RESULTS: To assess the potential interaction between this mutation and vitamin coenzymes in homocysteine metabolism, we screened 365 individuals from the NHLBI Family Heart Study. Among individuals with lower plasma folate concentrations ( < 15.4 nmol/L), those with the homozygous mutant genotype had total fasting homocysteine levels that were 24% greater (P<.05) than individuals with the normal genotype. A difference between genotypes was not seen among individuals with folate levels > or = 15.4 nmol/L. CONCLUSIONS: Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons.

Adult↗

PubMed1996

Blunted renal vascular response to angiotensin II is associated with a common variant of the angiotensinogen gene and obesity.

OBJECTIVE: Recently, we reported evidence for genetic linkage between human essential hypertension and the angiotensinogen gene (AGT) and an association with a common molecular variant of this gene (methionine 235 --> threonine or T235). Other studies had led us to hypothesize that blunted renal plasma flow responses to infused angiotensin II (Ang II) when in high salt balance may reflect increased intrarenal formation of Ang II, a condition that might promote hypertension. Here we examine the relationship between AGT genotype and renal vascular response to infused Ang II. METHODS: Hypertensive (n = 34, all off medication) and normotensive (n = 57) members of families with a history of hypertension (age 18-60 years) as well as 29 normotensive volunteers without a family history of hypertension were studied after controlled diets with 200 mequiv./day sodium. Ang II was infused at a mildly pressor dose (3 ng/kg/min) and renal plasma flow was determined by steady-state plasma para-aminohippurate concentration. RESULTS: After correction for covariates in multivariate analyses, participants homozygous for the T235 variant had significantly diminished renal plasma flow responses to the Ang II infusion (P = 0.005). Changes in renal arterial resistance were also blunted in the T235 homozygotes. Similar results were found when analysis was restricted to normotensive participants or subdivided based on family history of hypertension. No confounding factors associated with AGT genotype that could explain these differences were found. Furthermore, obesity, which also suppressed renovascular response to Ang II, was found to interact significantly (P = 0.017) with genotype such that, among T235 homozygotes, obesity had a greater blunting effect on renal vascular response. CONCLUSIONS: Expected renovascular response to infused Ang II was blunted in persons with the AGT TT genotype. This is the first report of an association between a specific gene variant and altered renal physiology in humans with particular relevance to essential hypertension.

Adolescent↗

PubMed1996

Hypertension, dyslipidemia, and insulin resistance: links in a chain or spokes on a wheel?

Rather than a link in a causal chain leading to hypertension, insulin resistance and resultant hyperinsulinemia may be 'spokes on a wheel', with central or visceral obesity as the postulated hub of the wheel. Hypertension, hypertriglyceridemia and high density lipoprotein cholesterol are depicted as other spokes. Newly identified metabolic pathways in adipose tissue or the modulating effects of various predisposing genes may lead to variable expression of various components of the multiple metabolic syndrome in individuals with a predisposition to the collection of visceral fat.

Adipose Tissue↗

PubMed1996

Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease.

Mildly increased serum bilirubin has recently been suggested as a protective factor, possibly reducing the risk of coronary artery disease (CAD) by acting as an antioxidant. We tested this hypothesis by examining serum bilirubin concentrations and other coronary risk factors in 120 men and 41 women with early familial CAD and 155 control subjects. At screening, both cases and control subjects were 38 to 68 years old. Early familial CAD patients had experienced myocardial infarction, coronary artery bypass grafting, or coronary angioplasty by age 55 years for men and 65 for women and had another sibling similarly affected. The average total serum bilirubin concentration was 8.9 +/- 6.1 mumol/L in cases and 12.4 +/- 8.1 mumol/L in control subjects (P = .0001 for difference). In univariate analysis stratified by sex, serum bilirubin was strongly and inversely related to CAD risk, with relative odds of 0.4 to 0.1 (relative to the lowest quintile, P = .04 to .00001) in both men and women as bilirubin increased into the upper two quintiles. Multiple logistic regression analysis was performed including age, sex, smoking, body mass index, diabetes, hypertension, plasma measured LDL cholesterol, HDL cholesterol, triglycerides, and serum bilirubin as potential risk factors. Bilirubin entered as an independent protective factor with an odds ratio of 0.25 (P = .0015) for an increase of 17 mumol/L (1 mg/dL). The standardized logistic regression coefficient for bilirubin was -.33 compared with -.34 for HDL, suggesting that the protective effect of bilirubin on CAD risk in the population is comparable to that of HDL cholesterol. A history of cigarette smoking was associated with significantly lower serum bilirubin concentration and appeared to attenuate the protective effect of bilirubin.

Aged↗