Biomedical subjects

Eric Boerwinkle

Publications and source records attributed to Eric Boerwinkle.

138 records · Page 8Linked to original sources

PubMed2002

Beta 2 adrenergic receptor 5' haplotypes influence promoter activity.

1. Transcriptional control of the human beta(2) adrenergic receptor gene (ADRB2) predominantly resides within a 549 base pair region immediately 5' to the start of translation. Within this region, four naturally occurring polymorphisms, -468 C-->G, -367 T-->C, -47 T-->C, and -20 T-->C, have been identified. 2. To determine the individual site and haplotype effects of these polymorphisms, we generated 16 luciferase-based mutant constructs which were transiently transfected into HEK293 cells, and measured ADRB2 promoter-driven luciferase activity. 3. Two of the 16 mutant constructs, GCCT (-468G, -367C, -47C, -20T) and CTCT, showed a highly significant 3 fold decrease in luciferase induction relative to the reference CTTT. These haplotype effects could not be accounted for by the separate and additive effects of each site. 4. These findings indicate that promoter polymorphisms interact to significantly alter beta(2) adrenergic receptor expression, and should be examined further for their association with disease-related phenotypes.

Cell Line↗

PubMed2002

Predictors of antihypertensive response to a standard dose of hydrochlorothiazide for essential hypertension.

BACKGROUND: Determinants of inter-individual variation in blood pressure (BP) response to antihypertensive therapy remain largely unknown. Although differences in race, age and measures of the renin-angiotensin-aldosterone system (RAAS) have been associated with variation in blood pressure response to hydrochlorothiazide, whether these characteristics make additive contributions to predicting response has not been established. We conducted a comprehensive search for predictors of BP response to a standard dose of hydrochlorothiazide in a biracial sample to estimate how much inter-individual variation in BP response could be explained by all of the identified predictors. METHODS: After withdrawal of antihypertensive medications for at least four weeks (baseline) and stabilization on a diet approximating 150 mmol sodium per day, 225 African American and 280 Caucasian subjects with diagnosed essential hypertension were treated for four weeks with hydrochlorothiazide 25 mg per day. At baseline and the end of treatment, subjects were admitted to the General Clinical Research Center for measurement of activity of the RAAS and other regulators of BP. Characteristics measured at study enrollment, at baseline, and in response to drug treatment were incorporated stepwise into linear regression models in order to quantify their additive contributions to predicting BP responses to hydrochlorothiazide. RESULTS: Black race and female gender were both associated with significantly greater systolic (SBP) and diastolic (DBP) blood pressure responses to hydrochlorothiazide. Together the combined effects of race and gender accounted for 11% inter-individual variation in SBP response (P < 0.0001) and 4% of inter-individual variation in DBP response (P < 0.0001). Additional statistically significant predictors of greater systolic and diastolic responses to hydrochlorothiazide included, shorter duration of diagnosed or treated hypertension (P < 0.001), higher baseline BP level (P < 0.0001), lower baseline plasma renin activity (P < 0.05), lower baseline urinary aldosterone excretion (P < 0.002), and greater decrease in urinary sodium excretion (P < or = 0.004). Greater decrease in weight was an additional statistically significant predictor of SBP but not DBP response, and older age was a predictor of diastolic but not SBP response. The combined effects of all identified predictors accounted for 38% of inter-individual variation in SBP response (P < 0.0001) and 20% of inter-individual variation in DBP response (P < 0.0001). CONCLUSIONS: A systematic search reveals numerous predictors of BP response to a standard antihypertensive dose of hydrochlorothiazide. However, because the majority of inter-individual variation in SBP and DBP responses remains unexplained, there is considerable opportunity for future investigations to improve the ability to predict individual BP responses to antihypertensive drug therapy.

Adult↗

PubMed2002

Interacting effects of gender and genotype on blood pressure response to hydrochlorothiazide.

BACKGROUND: Genetic factors may influence blood pressure (BP) response to diuretic therapy through their effects on activity of the renin-angiotensin-aldosterone system (RAAS). The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with variation in serum ACE activity and may influence BP in a gender-specific manner. METHODS: We measured the I/D polymorphism in 206 non-Hispanic women (130 blacks, 76 whites) and 170 non-Hispanic men (62 blacks, 108 whites) with essential hypertension (age 48 +/- 7 years, mean +/- SD) who underwent monotherapy with hydrochlorothiazide (HCTZ) 25 mg daily for four weeks. RESULTS: In both genders, serum ACE activity increased in a co-dominant fashion in association with the D-allele (P < 0.001 for both genders). In regression models that considered the effects of baseline BP, race, gender, age, waist-to-hip ratio, and measures of the RAAS, there was significant interaction between the effects of the ACE genotype and gender on the responses of both systolic and diastolic BP to HCTZ (for systolic BP response, P = 0.03; for diastolic BP response, P = 0.001). Among women, mean declines in systolic and diastolic BP were greater in II than in DD homozygotes; whereas among men, mean declines in systolic and diastolic BP were greater in DD than in II homozygotes. In models that included the effects of race, gender, age, and waist-to-hip ratio, there was also significant interaction between the effects of the ACE genotype and gender on pre-treatment urinary aldosterone excretion (P = 0.01) and change in urinary aldosterone excretion in response to HCTZ (P = 0.007). The genotypes that were associated with the greatest BP responses to HCTZ (II homozygotes in women and DD homozygotes in men) had the lowest pre-treatment urinary aldosterone excretion and the greatest increase in urinary aldosterone excretion in response to HCTZ. CONCLUSION: The relationship between the ACE I/D polymorphism and antihypertensive response to a standard dose of HCTZ differs significantly between women and men. Because the D-allele was associated with significant, co-dominant increases in serum ACE activity in both genders, the gender-specific effects of the I/D polymorphism on BP response to HCTZ may be mediated subsequent to the enzymatic generation of angiotensin II.

Adult↗

PubMed2002

Neighboring-nucleotide effects on single nucleotide polymorphisms: a study of 2.6 million polymorphisms across the human genome.

We investigated substitution patterns and neighboring-nucleotide effects for 2,576,903 single nucleotide polymorphisms (SNPs) publicly available through the National Center for Biotechnology Information (NCBI). The proportions of substitutions were A/G, 32.77%; C/T, 32.81%; A/C, 8.98%; G/T, 9.06%; A/T, 7.46%; and C/G, 8.92%. The two nucleotides immediately neighboring the variable site showed major deviation from genome-wide and chromosome-specific expectations, although lesser biases extended as far as 200 bp. On the 5' side, the biases for A, C, G, and T were 1.43%, 4.91%, -1.70%, and -4.62%, respectively. These biases were -4.44%, -1.59%, 5.05%, and 0.99%, respectively, on the 3' side. The neighboring-nucleotide patterns for transitions were dominated by the hypermutability effects of CpG dinucleotides. Transitions were more common than transversions, and the probability of a transversion increased with increasing A + T content at the two adjacent sites. Neighboring-nucleotide biases were not consistent among chromosomes, with Chromosomes 19 and 22 standing out as different from the others. These data provide genome-wide information about the effects of neighboring nucleotides on mutational and evolutionary processes giving rise to contemporary patterns of nucleotide occurrence surrounding SNPs.

Base Composition↗

PubMed2002

ADD1 460W allele associated with cardiovascular disease in hypertensive individuals.

High blood pressure is a predictor of cardiovascular disease. Hence, genes contributing to essential hypertension may play a role in the etiology of cardiovascular disease. For this reason, we examined the association between the alpha-adducin (ADD1) G460W and G-protein beta3 subunit (GNB3) 825C>T polymorphisms and the prevalence of peripheral arterial disease (PAD) and incidence of coronary heart disease (CHD) in non-Hispanic whites from the Atherosclerosis Risk in Communities (ARIC) Study. PAD prevalence was defined by an ankle-brachial index, ie, the ratio of ankle systolic blood pressure to brachial artery systolic blood pressure, of </=0.90 for men and </=0.85 for women. CHD incidence was determined by following the ARIC cohort for a median of 5.3 years for potential coronary events. Stratified random samples of the ARIC cohort (n=703 and n=684) were used, respectively, as the comparison groups for the PAD (n=144) and incident CHD (n=408) cases. The GNB3 825T allele and the ADD1 460W allele were not significantly associated with prevalence of PAD or incidence of CHD. However, a test of the interaction between hypertension status and the ADD1 G460W polymorphism indicated that further evaluation of the ADD1 polymorphism in only hypertensive individuals was warranted. The ADD1 460W allele was significantly associated with PAD (odds ratio [OR]: 2.61, 95% CI, 1.27-5.37, P=0.01) and CHD (hazard rate ratio [HRR]: 2.30, 95% CI, 1.20-4.42, P=0.01) in hypertensive individuals after adjustment for multiple cardiovascular disease risk factors. An interaction with hypertension in the association between the ADD1 G460W polymorphism and cardiovascular disease merits further testing in additional populations.

Alleles↗

PubMed2002

Polymorphism in soluble epoxide hydrolase and blood pressure in spontaneously hypertensive rats.

We measured soluble epoxide hydrolase (sEH) renal gene expression in prehypertensive (4 to 5 weeks old) spontaneously hypertensive rats of the Heidelberg SP substrain (SHR [Heid]) and when blood pressure levels entered the hypertensive plateau (17 to 18 weeks old) and compared expression with matched Wistar-Kyoto (WKY [Heid]) rats. Less expression of the gene encoding sEH (EPHX2) was observed in SHR (Heid) than in WKY (Heid). Analysis of sEH protein abundance showed a similar difference. However, no correlation between sEH abundance and blood pressure was observed in the F(2) progeny of a parental strain cross. Measurement of protein abundance in SHR and WKY obtained from Charles River confirmed a recent report that abundance of sEH was greater in SHR (CRiv) than WKY (CRiv) strains. Polymorphisms were detected in EPHX2. Resequencing revealed that 2 alleles of EPHX2 exist in these 4 rat strains, differing by 4 single nucleotide polymorphisms, of which 3 produce nonsynonymous amino acid substitutions. The ancestral allele was shared by SHR (Heid) and WKY (CRiv), and the variant allele was shared by WKY (Heid) and SHR (CRiv). Activity of sEH was greater in animals carrying the variant allele. However, inheritance of this allele was not correlated with blood pressure in the F(2) progeny of a cross between SHR (Heid) and WKY (Heid). These data indicate that sequence variation determining functional alterations in EPHX2 is not likely to contribute to blood pressure levels in SHR.

Animals↗

PubMed2002

SNP43 of CAPN10 and the risk of type 2 Diabetes in African-Americans: the Atherosclerosis Risk in Communities Study.

Recently, an A-to-G variant in intron 3 (SNP43) of the calcium-activated neutral protease 10 gene (CAPN10) was identified as a possible type 2 diabetes susceptibility gene through positional cloning in Mexican-Americans. We conducted cross-sectional and prospective studies to evaluate the relation between SNP43 and type 2 diabetes and related traits in middle-aged African-American participants of the Atherosclerosis Risk in Communities Study, a population-based longitudinal study. At baseline, 269 prevalent diabetes cases and 1,159 nondiabetic control subjects were studied. Those with the G/G genotype were more likely to have diabetes than those with the A/G or A/A genotype (odds ratio [OR] 1.41, 95% CI 1.00-1.99, P = 0.05). In the prospective study, 166 of the control subjects developed incident diabetes over 9 years of follow-up. The incidence of diabetes for individuals with the G/G genotype did not differ significantly from those with at least one copy of the A allele (23.3 vs. 19.5 per 1,000 person years, P = 0.29). Pooling prevalent and incident diabetic cases together, individuals with the G/G genotype were approximately 40% more likely to have diabetes than those without (OR 1.38, 95% CI 1.04-1.83, P = 0.03). Because of the high frequency of the G allele (0.88), approximately 25% of the susceptibility to type 2 diabetes in African-Americans may be attributed to the G/G genotype at SNP43 of CAPN10, although most of the subjects with the G/G genotype did not develop diabetes over the 9 years of follow-up. We conclude from this large prospective study that the G allele of SNP43 of CAPN10 or another allele or gene that is in linkage disequilibrium with it increases susceptibility to type 2 diabetes in African-Americans.

Arteriosclerosis↗

PubMed2002

Screening for primary aldosteronism: implications of an increased plasma aldosterone/renin ratio.

BACKGROUND: The value of the ratio of plasma aldosterone concentration (aldosterone) to plasma renin activity (renin) to identify patients at risk for primary aldosteronism is controversial. We determined the sensitivity, specificity, and predictive value of the ratio to identify combinations of renin and aldosterone compatible with primary aldosteronism. METHODS: The ratio was calculated in 505 adults with essential hypertension (143 black women, 82 black men, 122 white women, and 158 white men). We used a conventional cutpoint for an increased ratio (i.e., 20 mL/dL x h). The primary combination of renin and aldosterone considered compatible with primary aldosteronism was increased aldosterone for the concomitant renin, defined as aldosterone in the highest quartile predicted by linear regression on renin. Renin was considered low if it was in the lowest quartile of the sample distribution. RESULTS: The sensitivity of the ratio to identify individuals with increased aldosterone for the concomitant renin was 66% (80% in blacks and 56% in whites; P = 0.009), and the specificity of the ratio was 67% (46% in blacks and 84% in whites; P <0.0001). In 36% of instances of an increased ratio, it was a measure of low renin alone without increased aldosterone for renin (32% in blacks and 45% in whites; P = 0.072). The positive predictive value of the ratio to identify individuals with increased aldosterone for the concomitant renin was 34% (49% in whites and 27% in blacks; P <0.002). CONCLUSION: The aldosterone/renin ratio lacks sensitivity and specificity and has only a modest predictive value for combinations of renin and aldosterone that are compatible with primary aldosteronism.

Adult↗

PubMed2002

Relationship of blood pressure measures with coronary artery calcification.

BACKGROUND: Increased blood pressure level is a major risk factor for coronary artery disease. Previous studies of relationships of blood pressure level and hypertension status with coronary artery calcification (CAC), a measure of subclinical atherosclerosis, were restricted to participants who were physician- or self-referred, high risk, selected on hypertension status, or young adults. MATERIAL/METHODS: 803 asymptomatic individuals at least age 40 years were studied from a community. Blood pressure level was measured and blood pressure diagnostic category (i.e. hypertension vs. normotension) was determined by considering reported history of physician-diagnosed hypertension, use of antihypertensive medication, and measured blood pressure levels. CAC was measured non-invasively with electron beam computed tomography. Tobit regression models allowed simultaneous modeling of presence and quantity of CAC. RESULTS: In men, age, having ever smoked, having hypertension, LDL-C level, and body mass index were significantly and positively associated with presence and quantity of CAC. In women, age, systolic blood pressure level, use of lipid lowering medications, and waist-to-hip ratio were significantly and positively associated with presence and quantity of CAC. Relationships of measures of blood pressure with CAC were modified by age, but no other risk factors, in both sexes. CONCLUSIONS: Our results indicated that measures of blood pressure make a relatively large contribution to predictions of CAC at younger ages. CAC quantification, especially among younger individuals, may allow for early assessment of the presence and extent of target organ disease.

Adult↗

PubMedDate not supplied

Genetic discoveries and nursing implications for complex disease prevention and management.

The purpose of this article is to examine the management of patients with complex diseases, in light of recent genetic discoveries, and to explore how these genetic discoveries will impact nursing practice and nursing research. The nursing science processes discussed are not comprehensive of all nursing practice but, instead, are concentrated in areas where genetics will have the greatest influence. Advances in genetic science will revolutionize our approach to patients and to health care in the prevention, diagnosis, and treatment of disease, raising many issues for nursing research and practice. As the scope of genetics expands to encompass multifactorial disease processes, a continuing reexamination of the knowledge base is required for nursing practice, with incorporation of genetic knowledge into the repertoire of every nurse, and with advanced knowledge for nurses who select specialty roles in the genetics area. This article explores the impact of this revolution on nursing science and practice as well as the opportunities for nursing science and practice to participate fully in this revolution. Because of the high proportion of the population at risk for complex diseases and because nurses are occupied every day in the prevention, assessment, treatment, and therapeutic intervention of patients with such diseases in practice and research, there is great opportunity for nurses to improve health care through the application (nursing practice) and discovery (nursing research) of genetic knowledge.

Ecology↗

PubMedDate not supplied

Relationship between low-density lipoprotein subclasses and asymptomatic atherosclerosis in subjects from the Atherosclerosis Risk in Communities (ARIC) Study.

Low-density lipoprotein (LDL) particle size has been associated with coronary heart disease, but an association between LDL size and preclinical atherosclerosis is less well established. Using gradient gel electrophoresis, large (A), intermediate (I) and small (B) LDL size subclasses were determined in 198 cases with asymptomatic carotid artery atherosclerosis (determined by B-mode ultrasonography) and 318 controls from the Atherosclerosis Risk in Communities (ARIC) Study. In Caucasians, a smaller LDL size was more prevalent in men and associated with a higher body mass index, hypertension prevalence, and plasma total- and LDL-cholesterol and triglycerides, but lower HDL-cholesterol. In African-Americans, a smaller LDL size was associated with higher triglycerides and lower HDL-cholesterol and hypertension prevalence. In Caucasians, Subclass B prevalence was 29.1% among cases and 14.8% among controls. The odds ratio (95% confidence interval) for Subclass B rather than Subclass A in Caucasian cases was 2.94 (1.67-5.17); the association remained significant after controlling for age, body mass index, smoking, and either plasma triglycerides or HDL-cholesterol. In African-Americans, however, there was no significant association between LDL subclass and case status. A predominance of smaller LDL particles is associated with asymptomatic carotid artery atherosclerosis in Caucasians, through mechanisms that remain to be elucidated.

Arteriosclerosis↗

PubMedDate not supplied

Reproducibility of blood pressure response to hydrochlorothiazide.

Few studies have investigated the reproducibility of responses to antihypertensive therapies. The purpose of this study was to assess the reproducibility of the blood pressure response to a thiazide diuretic, a preferred initial treatment for hypertension. Twenty-two subjects who underwent monotherapy with hydrochlorothiazide as part of a study to identify predictors of blood pressure response agreed to undergo the same protocol a second time, 26.6+/-11.8 (range, 4-52) months after their first participation. The mean systolic and diastolic blood pressure responses to hydrochlorothiazide did not differ significantly between the first and second participation (systolic response, -14.2+/-16.4 mm Hg vs. -16.0+/-16.5 mm Hg; diastolic response, -7.1+/-11.8 mm Hg vs. -6.6+/-8.6 mm Hg), and these responses were significantly correlated between the two trials (systolic response, r=0.61 and p<0.01; diastolic response, r=0.64 and p<0.01). However, both the direction and magnitude of responses for individual subjects varied considerably, with the limits of agreement between the first and second participations (i.e., 2 standard deviations above and below the mean difference between responses) ranging from 27.4 mm Hg to -23.8 mm Hg for systolic blood pressure response and from 17.4 mm Hg to -18.4 mm Hg for diastolic blood pressure response. These results show that the average systolic and diastolic blood pressure responses to hydrochlorothiazide for a group of subjects are reproducible; however, the responses for individual subjects are unpredictable.

Black or African American↗