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Biomedical subjects

D Levy

Publications and source records attributed to D Levy.

At least 127 records · Page 7Linked to original sources

A sequence-specific gene correction by an RNA-DNA oligonucleotide in mammalian cells characterized by transfection and nuclear extract using a lacZ shuttle system.

The variability in gene conversion frequency by an RNA-DNA oligonucleotide (RDO) prompted us to develop a system as a means of measuring the conversion frequency rapidly and reproducibly. A shuttle vector was constructed to measure the frequency of targeted gene correction by RDO of the E. coli beta-galactosidase gene containing a single point mutation (G --> A), that resulted in inactivation of enzymatic activity. An RDO corrected the point mutation and restored the enzymatic activity, approximately 1%, determined by a histochemical staining in mammalian cells and by a color selection (blue or white) of bacteria transformed with Hirt DNA. In addition, we established an in vitro system capable of gene correction using nuclear extracts. CHO-K1 nuclear extracts corrected the point mutation approximately 0.1%, determined by bacterial transformation. Using the in vitro reaction, frequency of gene conversion in different cell types was measured. The embryonic fibroblasts from p53-/- mouse showed higher gene correction than that of the isogenic p53+/+ cells. Nuclear extracts from DT40 cells, which have a higher homologous recombination rate than any other mammalian cells exhibited 0.1-0.6% of gene correction. These results indicated that recombination may be rate-limiting in gene conversion by RDO in cells with competent mismatch repair activities. Utilizing transfection and in vitro reaction, we demonstrated that such a shuttle system might be useful in comparing the frequency of targeting among different cell types and to investigate the mechanism of gene conversion by RDO.

Animals↗

Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency.

UNLABELLED: Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. BACKGROUND: Little is known about the prevalence of cardiovascular disease (CVD) and associated risk factors in individuals with mild renal insufficiency (RI). Furthermore, the long-term outcomes associated with mild RI in the community have not been described. METHODS: Serum creatinine (SCr) was measured in 6233 adult participants of the Framingham Heart Study (mean age 54 years, 54% women). Mild RI was defined as SCr 136 to 265 micromol/liter (1.5 to 3.0 mg/dl) in men and 120 to 265 micromol/liter (1.4 to 3.0 mg/dl) in women. The lower limits for mild RI were defined by the sex-specific 95th percentile SCr values in a healthy subgroup of our sample. The upper limit for mild RI was chosen to exclude those subjects with more advanced renal failure. Cox proportional hazards analyses were used to determine the relationship of baseline RI to CVD and all-cause mortality. RESULTS: At baseline, 8.7% of men (N = 246) and 8.0% of women (N = 270) had mild RI. Nineteen percent of the subjects with mild RI had prevalent CVD. During 15 years of follow-up, there were 1000 CVD events and 1406 deaths. In women, mild RI was not associated with increased risk for CVD events [hazards ratio (HR) 1.04, 95% CI, 0.79 to 1.37] or all-cause mortality (HR 1.08, 95% CI, 0.87 to 1.34). In men, mild RI showed no significant associations with CVD events (HR 1.17, 95% CI, 0.88 to 1.57), but it was associated with all-cause mortality in age-adjusted (HR 1.42, 95% CI, 1.12 to 1.79) and multivariable adjusted (HR 1.31, 95% CI, 1.02 to 1.67) analyses. CONCLUSION: Mild RI in the community is common and is associated with a high prevalence of CVD. The association of RI with risk for adverse outcomes is strongly related to coexisting CVD and CVD risk factors.

Aged↗

Why is left ventricular hypertrophy so predictive of morbidity and mortality?

The prevalence, prognosis, and predictors of left ventricular hypertrophy (LVH) are reviewed, and theories of the pathogenesis of the relation between LVH and poor prognosis are summarized to highlight controversies in the field. In the Framingham Heart Study, which consists largely of white people, echocardiographic LVH has a prevalence of 14% in men and 18% in women. The prevalence of LVH is reported to be elevated in African Americans compared with whites, although the higher prevalence has been attributed to the increased prevalence of hypertension and obesity. Echocardiographic LVH is independently associated with a variety of cardiovascular endpoints, including coronary heart disease and stroke. Furthermore, after adjusting for other cardiovascular disease risk factors, LVH is associated with a doubling in mortality in both white and African American cohorts. Despite the intensive investigation of LVH, there remain many unanswered questions: To what extent do genetic or other factors account for the large portion of the variance in LVH that remains unexplained? What is the prognosis of LVH and left ventricular geometry in a population-based African American cohort? How does the development and progression of LVH relate to other risk factors and their treatment? What is the relation of LVH to poor prognosis? The proposed Jackson Heart Study will help address many important unanswered questions regarding LVH.

Cohort Studies↗

Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study.

The platelet glycoprotein IIb/IIIa (GP IIb/IIIa) plays a pivotal role in platelet aggregation. Recent data suggest that the PlA2 polymorphism of GPIIIa may be associated with an increased risk for cardiovascular disease. However, it is unknown if there is any association between this polymorphism and platelet reactivity. We determined GP IIIa genotype and platelet reactivity phenotype data in 1422 subjects from the Framingham Offspring Study. Genotyping was performed using PCR-based restriction fragment length polymorphism analysis. Platelet aggregability was evaluated by the Born method. The threshold concentrations of epinephrine and ADP were determined. Allele frequencies of PlA1 and PlA2 were 0.84 and 0.16, respectively. The presence of 1 or 2 PlA2 alleles was associated with increased platelet aggregability as indicated by incrementally lower threshold concentrations for epinephrine and ADP. For epinephrine, the mean concentrations were 0.9 micromol/L (0.9 to 1.0) for homozygous PlA1, 0.7 mmol/L (0.7 to 0.9) for the heterozygous PlA1/PlA2, and 0.6 micromol/L (0.4 to 1.0) for homozygous PlA2 individuals, P=0.009. The increase in aggregability induced by epinephrine remained highly significant (P=0.007) after adjustment for covariates. For ADP-induced aggregation, the respective mean concentrations were 3.1 micromol/L (3.0 to 3.2), 3.0 micromol/L (2.9 to 3.2), and 2.8 micromol/L (2.4 to 3.3); P=0.19 after adjustment for covariates. Our findings indicate that molecular variants of the gene encoding GP IIIa play a role in platelet reactivity in vitro. Our observations are compatible with and provide an explanation for the reported association of the PlA2 allotype with increased risk for cardiovascular disease.

Adenosine Diphosphate↗

Differential impact of systolic and diastolic blood pressure level on JNC-VI staging. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

The sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classifies blood pressure into stages on the basis of both systolic (SBP) and diastolic (DBP) blood pressure levels. When a disparity exists between SBP and DBP stages, patients are classified into the higher stage ("up-staged"). We evaluated the effect of disparate levels of SBP and DBP on blood pressure staging and eligibility for therapy. We examined 4962 Framingham Heart Study subjects between 1990 and 1995 and determined blood pressure stages on the basis of SBP alone, DBP alone, or both. After the exclusion of subjects on antihypertensive therapy (n=1306), 3656 subjects (mean age 58+/-13 years; 55% women) were eligible. In this sample, 64.6% of subjects had congruent stages of SBP and DBP, 31.6% were up-staged on the basis of SBP, and 3.8% on the basis of DBP; thus, SBP alone correctly classified JNC-VI stage in approximately 96% (64.6%+31.6%) of the subjects. Among subjects >60 years of age, SBP alone correctly classified 99% of subjects; in those </=60 years old, SBP alone correctly classified 95%. Of 1488 subjects with high-normal blood pressure or hypertension, who were potentially eligible for drug therapy, 13.0% had congruent elevations of SBP and DBP, 77.7% were up-staged on the basis of SBP, and 9.3% were up-staged on the basis of DBP; SBP alone correctly classified 91%, whereas DBP alone correctly classified only 22%. SBP elevation out of proportion to DBP is common in middle-aged and older persons. SBP appears to play a greater role in the determination of JNC-VI blood pressure stage and eligibility for therapy. Given these results, combined with evidence from hypertension treatment trials, future guidelines might consider a greater role for SBP than for DBP in determining the presence of hypertension, risk of cardiovascular events, eligibility for therapy, and benefits of treatment.

Adult↗

Autocatalytic degradation and stability of obidoxime.

The degradation of obidoxime chloride (toxogonin), a reactivator of inhibited cholinesterase in organophosphorus poisoning, in concentrated (250 mg mL(-1)) acidic solutions was studied by HPLC at several temperatures to determine the degradation mechanism. The degradation had an autocatalytic profile, which was found to result from the formation of formaldehyde during the degradation process. The activation energy of the hydrolysis was 26.2 kcal mol(-1). The shelf-life (t90, the time by which 10% of the drug has degraded) at 25 degrees C was calculated by several methods and found to be more than 37 years. Autocatalysis, a mechanism found only rarely in the degradation of pharmaceuticals, has not been reported in previous studies of obidoxime hydrolysis.

Cholinesterase Reactivators↗

Evidence for decline in disability and improved health among persons aged 55 to 70 years: the Framingham Heart Study.

OBJECTIVES: This study detected secular change in disability and health among persons aged 55 to 70 years, the life period when increases in disability and morbidity begin and retirement occurs. METHODS: Cross-sectional comparisons were completed with data from similarly aged members of the original (n = 1760) and offspring (n = 1688) cohorts of the Framingham Heart Study, which represent 2 generations. Analyses were conducted by gender and on chronic disease subgroups by logistic regression. RESULTS: There was substantially less disability in the offspring cohort than in the original cohort. Thirty-six percent of offspring men were disabled vs 52% of original cohort men (P = .001); among women, these proportions were 54% vs 72% (P = .001). Fewer offspring perceived their health as fair or poor and fewer had chronic diseases. Offspring were more physically active and less likely to smoke or consume high amounts of alcohol, but their average weight was greater. The secular decline in disability was strongly evident among individuals with chronic diseases. CONCLUSIONS: Our findings depict a secular change toward a less disabled and globally healthier population in the period of life when retirement occurs.

Activities of Daily Living↗

Resurgence of sleeping sickness in Tambura County, Sudan.

Endemic foci of human African trypanosomiasis are present in southern Sudan. In 1996 and 1997, trypanosomiasis increased sharply in Tambura County. To define the magnitude and geographic distribution of the outbreak, we conducted a prevalence survey using population-based cluster sampling in 16 villages: 1,358 participants answered questions about routine activities and tsetse fly contact and received serologic testing. Seroprevalence in the surveyed area was 19.4% (95% confidence interval = 16.9%, 21.8%). We confirmed infection in 66% of seropositive persons who received one parasitologic examination and in 95% of those who had serial examinations of lymph node fluid and blood. Activities related to the civil war, such as temporary migration, were not associated with seropositive status. Since the previous population screening in 1988, the trypanosomiasis prevalence increased two orders of magnitude, and the proportion of villages affected increased from 54% to 100%. Our results suggest that there may be 5,000 cases in Tambura County. The absence of trypanosomiasis control for nearly a decade is a factor in the resurgence of the disease.

Adolescent↗

The role of systolic blood pressure in determining risk for cardiovascular disease.

Hypertension increases in prevalence with advancing age and is a leading cause of morbidity and mortality from cardiovascular disease. Patients with hypertension are at increased risk for the development of myocardial infarction, stroke, and congestive heart failure compared with their normotensive counterparts. Early hypertension intervention trials in patients with diastolic hypertension documented the benefits of blood pressure control in reducing the risk for cardiovascular disease events. In recent years, several trials have demonstrated the benefits of treating older patients with isolated systolic hypertension. Consequently, hypertension guidelines have evolved to reflect the important role of systolic blood pressure in determining hypertension status and have devoted much attention to isolated systolic hypertension as a distinct blood pressure category. These data have important implications for the elderly, in whom isolated systolic hypertension is the most common form of high blood pressure; in addition, the absolute risk of cardiovascular disease is higher in older than in younger persons. Since the number of older persons in developed countries is increasing, hypertension has become a growing public health concern.

Blood Pressure↗

Effects of ambient air pollution on nonelderly asthma hospital admissions in Seattle, Washington, 1987-1994.

As part of the Clean Air Act, Congress has directed EPA to set air quality standards to protect sensitive population groups from air pollutants in the ambient environment. People with asthma represent one such group. We undertook a study of the relation between measured ambient air pollutants in Seattle and nonelderly hospital admissions with a principal diagnosis of asthma. We regressed daily hospital admissions to local hospitals for area residents from 1987 through 1994 on particulate matter less than 10 and 2.5 microm in aerodynamic diameter (PM10 and PM2.5, respectively); coarse particulate mass; sulfur dioxide (SO2); ozone (O3); and carbon monoxide (CO) in a Poisson regression model with control for time trends, seasonal variations, and temperature-related weather effects. With the exception of seasonally monitored O3, we supplemented incomplete pollutant measures in a multiple imputation model to create a complete time series of exposure measures. We found an estimated 4-5% increase in the rate of asthma hospital admissions associated with an interquartile range change in PM (19 microg/m3 PM(10),11.8 microg/m3 PM2.5, and 9.3 microg/m3 coarse particulate mass) lagged 1 day; relative rates were as follows: for PM10, 1.05 [95% confidence interval (CI) = 1.02-1.08]; for PM2.5, 1.04 (95% CI = 1.02-1.07); and for coarse particulate mass, 1.04 (95% CI = 1.01-1.07). In single-pollutant models we also found that a 6% increase in the rate of admission was associated with an interquartile range change in CO (interquartile range, 924 parts per billion; 95% CI = 1.03-1.09) at a lag of 3 days and an interquartile range change in O3 (interquartile range, 20 parts per billion; 95% CI = 1.02-1.11) at a lag of 2 days. We did not observe an association for SO2. We found PM and CO to be jointly associated with asthma admissions. We estimated the highest increase in risk in the spring and fall seasons.

Adult↗

Stability of trimedoxime in concentrated acidic injectable solutions.

The degradation of trimedoxime in concentrated (114 mg/ml) acidic solutions was studied at several temperatures in the pH range 3.0 to 4.3. The degradation profile showed a relationship indicative of first-order kinetics. Trimedoxime was found to be stable in the pH range 3.0 to 3.8, with maximum stability at pH 3.0. The activation energy of the hydrolysis reaction at pH 3.0 was found to be 19.4 kcal/mol, and the half-life was 124 years. General equations were derived relating the half-life of trimedoxime solution to pH and temperature. The t90 value at 25 degrees C was calculated for each pH value studied and was found to be 11 to 18 years within the pH range 3.0 to 3.8.

Antidotes↗

Accuracy of death certificates for coding coronary heart disease as the cause of death.

BACKGROUND: Death certificates are widely used in epidemiologic and clinical investigations and for national statistics. OBJECTIVE: To examine the accuracy of death certificates for coding coronary heart disease as the underlying cause of death. DESIGN: Community-based inception cohort followed since 1948. SETTING: Framingham, Massachusetts. PATIENTS: 2683 deceased Framingham Heart Study participants. MEASUREMENTS: Sensitivity, specificity, and predictive values of the death certificate. The reference standard was cause of death adjudicated by a panel of three physicians. RESULTS: Among 2683 decedents, the death certificate coded coronary heart disease as the underlying cause of death for 942; the physician panel assigned coronary heart disease for 758. The death certificate had a sensitivity of 83.8% (95% CI, 81.1 % to 86.4%), positive predictive value of 67.4% (CI, 64.4% to 70.4%), specificity of 84.1% (CI, 82.4% to 85.7%), and negative predictive value of 92.9% (CI, 91.7% to 94.1%) for coronary heart disease. The death certificate assigned coronary heart disease in 51.2% of 242 deaths (9.0% of total deaths) for which the physician panel could not determine a cause. Compared with the physician panel, the death certificate attributed 24.3% more deaths to coronary heart disease overall and more than twice as many deaths to coronary heart disease in decedents who were at least 85 years of age. When deaths that were assigned unknown cause by the physician panel were excluded, the death certificate still assigned more deaths to coronary heart disease (7.9% overall and 43.1% in the oldest age group). CONCLUSIONS: Coronary heart disease may be overrepresented as a cause of death on death certificates. National mortality statistics, which are based on death certificate data, may overestimate the frequency of coronary heart disease by 7.9% to 24.3% overall and by as much as two-fold in older persons.

Adult↗

Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates.

Atrial fibrillation (AF) is the most common of the serious cardiac rhythm disturbances and is responsible for substantial morbidity and mortality in the general population. Its prevalence doubles with each advancing decade of age, from 0.5% at age 50-59 years to almost 9% at age 80-89 years. It is also becoming more prevalent, increasing in men aged 65-84 years from 3.2% in 1968-1970 to 9.1% in 1987-1989. This statistically significant increase in men was not explained by an increase in age, valve disease, or myocardial infarctions in the cohort. The incidence of new onset of AF also doubled with each decade of age, independent of the increasing prevalence of known predisposing conditions. Based on 38-year follow-up data from the Framingham Study, men had a 1.5-fold greater risk of developing AF than women after adjustment for age and predisposing conditions. Of the cardiovascular risk factors, only hypertension and diabetes were significant independent predictors of AF, adjusting for age and other predisposing conditions. Cigarette smoking was a significant risk factor in women adjusting only for age (OR = 1.4), but was just short of significance on adjustment for other risk factors. Neither obesity nor alcohol intake was associated with AF incidence in either sex. For men and women, respectively, diabetes conferred a 1.4- and 1.6-fold risk, and hypertension a 1.5- and 1.4-fold risk, after adjusting for other associated conditions. Because of its high prevalence in the population, hypertension was responsible for more AF in the population (14%) than any other risk factor. Intrinsic overt cardiac conditions imposed a substantially higher risk. Adjusting for other relevant conditions, heart failure was associated with a 4.5- and 5.9-fold risk, and valvular heart disease a 1.8- and 3.4-fold risk for AF in men and women, respectively. Myocardial infarction significantly increased the risk factor-adjusted likelihood of AF by 40% in men only. Echocardiographic predictors of nonrheumatic AF include left atrial enlargement (39%/ increase in risk per 5-mm increment), left ventricular fractional shortening (34% per 5% decrement), and left ventricular wall thickness (28% per 4-mm increment). These echocardiographic features offer prognostic information for AF beyond the traditional clinical risk factors. Electrocardiographic left ventricular hypertrophy increased risk of AF 3-4-fold after adjusting only for age, but this risk ratio is decreased to 1.4 after adjustment for the other associated conditions. The chief hazard of AF is stroke, the risk of which is increased 4-5-fold. Because of its high prevalence in advanced age, AF assumes great importance as a risk factor for stroke and by the ninth decade becomes a dominant factor. The attributable risk for stroke associated with AF increases steeply from 1.5% at age 50-59 years to 23.5% at age 80-89 years. AF is associated with a doubling of mortality in both sexes, which is decreased to 1.5-1.9-fold after adjusting for associated cardiovascular conditions. Decreased survival associated with AF occurs across a wide range of ages.

Aged↗

Calcium antagonists and mortality risk in men and women with hypertension in the Framingham Heart Study.

BACKGROUND: Several recent studies have suggested that calcium antagonist drugs, which are widely used for the treatment of hypertension, are associated with increased risk of cardiovascular disease. These studies have cast doubts on the long-term safety of calcium antagonists. OBJECTIVE: To examine the association of calcium antagonist use with mortality in subjects with hypertension followed up in the Framingham Heart Study. SUBJECTS AND METHODS: We stratified 3539 subjects (mean+/-SD age, 64+/-13 years) from the Framingham Heart Study who had hypertension at routine clinic examinations, according to the use of calcium antagonists and presence of coronary heart disease at the baseline examination. At each follow-up examination (every 2-4 years), subjects were reclassified with regard to the use of calcium antagonists. The end point of the study was all-cause mortality. Hazard ratios and 95% confidence intervals associated with the use of calcium antagonists were obtained using Cox proportional hazards regression models. RESULTS: There were 970 deaths during follow-up. Hazard ratios for mortality associated with the use of calcium antagonists were 0.93 (95% confidence interval, 0.72-1.21; P=.59) for subjects with hypertension without coronary heart disease, and 0.92 (95% confidence interval, 0.69-1.24; P=.58) for those with coronary heart disease at baseline. All models were adjusted for age, sex, current smoking, systolic and diastolic blood pressure, use of beta-blockers, and use of other antihypertensive medications. CONCLUSIONS: In this cohort of 3539 subjects with hypertension there were no differences in mortality among subjects with hypertension using a calcium antagonist compared with those who were not. Results were similar among subjects with hypertension with and without coronary heart disease. The results of ongoing long-term, randomized clinical trials will provide more definitive data on the safety of calcium antagonists.

Adult↗

Impact of atrial fibrillation on the risk of death: the Framingham Heart Study.

BACKGROUND: Atrial fibrillation (AF) causes substantial morbidity. It is uncertain whether AF is associated with excess mortality independent of associated cardiac conditions and risk factors. METHODS AND RESULTS: We examined the mortality of subjects 55 to 94 years of age who developed AF during 40 years of follow-up of the original Framingham Heart Study cohort. Of the original 5209 subjects, 296 men and 325 women (mean ages, 74 and 76 years, respectively) developed AF and met eligibility criteria. By pooled logistic regression, after adjustment for age, hypertension, smoking, diabetes, left ventricular hypertrophy, myocardial infarction, congestive heart failure, valvular heart disease, and stroke or transient ischemic attack, AF was associated with an OR for death of 1.5 (95% CI, 1.2 to 1.8) in men and 1.9 (95% CI, 1.5 to 2.2) in women. The risk of mortality conferred by AF did not significantly vary by age. However, there was a significant AF-sex interaction: AF diminished the female advantage in survival. In secondary multivariate analyses, in subjects free of valvular heart disease and preexisting cardiovascular disease, AF remained significantly associated with excess mortality, with about a doubling of mortality in both sexes. CONCLUSIONS: In subjects from the original cohort of the Framingham Heart Study, AF was associated with a 1.5- to 1.9-fold mortality risk after adjustment for the preexisting cardiovascular conditions with which AF was related. The decreased survival seen with AF was present in men and women and across a wide range of ages.

Adult↗

Identification of a structural requirement for thyroid Na+/I- symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism.

Patients with congenital lack of I transport do not accumulate I in their thyroids, often resulting in severe hypothyroidism. A single amino acid substitution in the thyroid Na+/I- symporter (NIS), proline replacing threonine at position 354 (T354P), was recently identified as the cause of this condition in two independent patients. Here we report that the lack of I- transport activity in T354P NIS generated by site-directed mutagenesis, is not due to a structural change induced by proline, but rather to the absence of a hydroxyl group at the beta-carbon of the amino acid residue at position 354. Hence, this hydroxyl group is essential for NIS function.

Animals↗

Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study.

BACKGROUND: There is controversy regarding the association of the angiotensin-converting enzyme deletion-insertion (ACE D/I) polymorphism with systemic hypertension and with blood pressure. We investigated these relations in a large population-based sample of men and women by using association and linkage analyses. METHODS AND RESULTS: The study sample consisted of 3095 participants in the Framingham Heart Study. Blood pressure measurements were obtained at regular examinations. The ACE D/I polymorphism was identified by using a polymerase chain reaction assay. In logistic regression analysis, the adjusted odds ratios for hypertension among men for the DD and DI genotypes were 1.59 (95% confidence interval [CI], 1.13 to 2.23) and 1.18 (95% CI, 0.87 to 1.62), respectively, versus II (chi2 P=.02). In women, adjusted odds ratios for the DD and DI genotypes were 1.00 (95% CI, 0.70 to 1.44) and 0.78 (95% CI, 0.56 to 1.09), respectively (P=.14). In linear regression analysis, there was an association of the ACE DD genotype with increased diastolic blood pressure in men (age-adjusted P=.03, multivariate-adjusted P=.14) but not women. Quantitative trait linkage analyses in 1044 pairs of siblings, by using both ACE D/I and a nearby microsatellite polymorphism of the human growth hormone gene, supported a role of the ACE locus in influencing blood pressure in men but not in women. CONCLUSIONS: In our large, population-based sample, there is evidence for association and genetic linkage of the ACE locus with hypertension and with diastolic blood pressure in men but not women. Our data support the hypothesis that ACE, or a nearby gene, is a sex-specific candidate gene for hypertension. Confirmatory studies in other large population-based samples are warranted.

Adult↗