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E Boerwinkle

Publications and source records attributed to E Boerwinkle.

At least 37 records · Page 2Linked to original sources
PubMed2001

Gender- and age-dependent relationships between the E-selectin S128R polymorphism and coronary artery calcification.

Development and progression of atherosclerosis involves recruitment and binding of circulating leukocytes to areas of inflammation within the vascular endothelium mediated by a diverse array of cellular adhesion molecules. A polymorphism in the endothelial-leukocyte adhesion molecule 1 (E-selectin) gene has been implicated in early-onset, angiographically defined, severe atherosclerotic disease because it profoundly affects ligand recognition and binding specificity, resulting in a significant increase in cellular adhesion. Relationships between the E-selectin S128R polymorphism and coronary artery calcification (CAC), a marker of atherosclerosis detected with noninvasive electron beam computed tomography, were examined in 294 asymptomatic women aged 40--88 years and 314 asymptomatic men aged 30--80 years from the Epidemiology of Coronary Artery Calcification Study. The E-selectin polymorphism was not associated with presence of CAC in men of any age or in women over age 50. In women 50 years of age or younger the E-selectin polymorphism was significantly associated with presence of CAC after adjustment for age, body mass index, systolic blood pressure, ratio of total cholesterol to high-density lipoprotein cholesterol, and smoking. The significant association between E-selectin and CAC in women 50 years of age or younger may suggest that the 128R allele is a risk factor for coronary atherosclerosis in younger asymptomatic women, who typically have lower levels of traditional risk factors and reduced adhesion molecule expression due to the presence of higher levels of endogenous hormones.

Adult↗
PubMed2001

Use of gene markers to guide antihypertensive therapy.

Sequencing of the human genome has elevated the potential for genetic information to aid in the prevention, diagnosis, and treatment of common chronic diseases. One beneficial application of genetic information is the identification of variants that influence response to pharmaceutical agents used to lower blood pressure and prevent target organ complications of hypertension. Knowledge of genetic variants that influence blood pressure response to antihypertensive drugs may allow more individualized tailoring of antihypertensive drug therapy, and provide greater insight into the molecular mechanisms regulating blood pressure levels and causing hypertension.

Antihypertensive Agents↗
PubMed2001

Influence of lipoprotein lipase serine 447 stop polymorphism on tracking of triglycerides and HDL cholesterol from childhood to adulthood and familial risk of coronary artery disease: the Bogalusa heart study.

The effects of the lipoprotein lipase (LPL) Serine 447 Stop (S447X) polymorphism on high-density lipoprotein cholesterol (HDLC) and triglycerides (TG) have been demonstrated. However, little is known about its effect on the tracking of HDLC and TG over time and familial risk of coronary artery disease (CAD). This aspect was examined in black and white individuals (n=829) aged 5-18 year at baseline, followed on average 18.8 yr. The frequency of the X447 allele was lower in Blacks than Whites (0.043 vs. 0.087, P=0.002). Carriers vs. noncarriers of the X447 allele had lower TG (99.3 vs 122.1 mg/dl, P<0.01) and higher HDLC (51.1 vs. 49.7 mg/dl, P<0.05) in adulthood, but not in childhood. The trends in genotype-specific means of childhood and adulthood levels of HDLC and TG in sex or race subgroups were similar to those in the total sample. With respect to tracking over time, of those in the bottom quartile of HDLC in childhood, 46.1% of the noncarriers vs. 23.1% of the carriers remained in this lowest quartile into adulthood (P=0.03); corresponding values for the top quartile of HDLC were 37.5% for the noncarriers vs. 57.1% for the carriers (P=0.03). Although TG tended to track better among the carriers in the bottom quartile and among the noncarriers in the top quartile, this trend was not significant. Carriers showed lower prevalence of parental history of CAD than noncarriers (6.9% vs. 14.1%, P=0.02) independently of lipoprotein variables, adiposity, blood pressure, age, sex and race. Thus, the X447 allele of the LPL gene is associated with an increase in HDLC and a decrease in TG in adults, tracking of HDLC since childhood, and a lower family history of CAD.

Adolescent↗
PubMed2001

Combined effects of endothelial nitric oxide synthase gene polymorphism (G894T) and insulin resistance status on blood pressure and familial risk of hypertension in young adults: the Bogalusa Heart Study.

Impaired endothelial function with decreased nitric oxide production is shared by insulin resistance and essential hypertension. Although there are limited data on the association between the endothelial nitric oxide synthase (eNOS) G894T polymorphism and hypertension, information is absent on the combined effects of eNOS G894T genotype and insulin resistance status on blood pressure (BP) levels and the familial risk of hypertension. This aspect was examined in a community-based sample of 1021 unrelated African American and white young adults aged 19 to 38 years. African Americans displayed a lower frequency of the T894 allele than whites (0.105 v 0.324, P < .001). After adjusting for sex, age, and body mass index (BMI), noncarriers versus carriers of the T894 allele had significantly higher systolic (SBP), diastolic (DBP) BP and mean arterial pressure (MAP) levels (111.7 v 109.2 mm Hg for SBP; 73.6 v 72.3 mm Hg for DBP; 86.3 v 84.6 mm Hg for MAP), with both African Americans and whites showing similar trends. This association was modulated by insulin resistance status, measured by the homeostasis model assessment of insulin resistance (HOMA IR) using fasting insulin and glucose. Subjects with high insulin resistance (above the median HOMA IR) showed significantly greater differences in BP levels between noncarriers and carriers of the T894 allele. Furthermore, the G894T genotype and insulin resistance also showed a combined effect on the prevalence of parental hypertension, a measure of familial risk, with noncarriers versus carriers in the high insulin resistance group showing higher prevalence (70.5% v 51.3%, P = .006, adjusted for race). Thus, the allelic variation (G894T) in the eNOS gene locus in conjunction with insulin resistance may be one factor contributing to the predisposition to hypertension.

Adolescent↗
PubMed2001

Beta-fibrinogen gene -455G/A polymorphism and coronary heart disease incidence: the Atherosclerosis Risk in Communities (ARIC) Study.

PURPOSE: The -455G/A (HaeIII) polymorphism of the beta-fibrinogen gene influences levels of plasma fibrinogen. We determined whether it influences risk of coronary heart disease. METHODS: We conducted a case-cohort study nested within a prospective investigation, the Atherosclerosis Risk in Communities Study. We accumulated 398 incident coronary heart disease cases over a median of 5.3 years of follow-up and compared their -455G/A status with a random sample of the cohort (n = 498). RESULTS: Plasma fibrinogen was higher (p = 0.04) in AA homozygous participants (341 mg/dL) than in persons carrying the G allele: GA (290 mg/dL), GG (298 mg/dL). However, there was no significant association between -455G/A and incident CHD. CONCLUSIONS: Although a small effect cannot be excluded, -455G/A does not appear to be an important genetic determinant of CHD.

Adenine↗
PubMed2001

The Ser(447)-Stop polymorphism of lipoprotein lipase is associated with variation in longitudinal serum high-density lipoprotein-cholesterol profiles: the Bogalusa Heart Study.

The Ser(447)-Stop polymorphism of lipoprotein lipase (LPL) has been associated with altered high-density lipoprotein-cholesterol (HDL-C) and triglyceride (TG) levels at individual measurements, but nothing is known of its associations with lipid profiles derived from serial measurements. We used multilevel statistical models to study effects of this polymorphism on longitudinal lipid profiles in 1,006 Bogalusa Heart Study subjects examined 4 to 9 times between the ages of 4 and 38 years. Stop(447) allele frequencies in African Americans (0.053 +/- 0.011) and whites (0.091 +/- 0.009) differed significantly (chi(2) = 7.595, 1 df, P =.006; Stop(447) homozygotes and heterozygotes combined). Overall, TG levels were lower and HDL-C levels higher in blacks than in whites of the same age and sex. Longitudinal TG profiles were lower in Stop(447) carriers at all ages. However, longitudinal HDL-C profiles differed among genotype groups with age: the Stop(447) allele was associated with higher HDL-C only in subjects above approximately 10 years of age. Genotype-specific HDL-C profiles also differed significantly among race/sex groups. Thus, we found evidence of LPL genotype effects that vary within individuals with age. Possible mechanisms, which could account for age-related changes in the effects of LPL variants, are discussed.

Adolescent↗
PubMed2001

Antihypertensive pharmacogenetics: getting the right drug into the right patient.

Pharmacogenetic investigation seeks to identify genetic factors that contribute to interpatient and interdrug variation in responses to antihypertensive drug therapy. Classical studies have characterized single gene polymorphisms of drug metabolizing enzymes that are responsible for large interindividual differences in pharmacokinetic responses to several antihypertensive drugs. Progress is being made using candidate gene and genome scanning approaches to identify and characterize many additional genes influencing pharmacodynamic mechanisms that contribute to interindividual differences in responses to antihypertensive drug therapy. Knowledge of polymorphic variation in these genes will help to predict individual patients' blood pressure responses to antihypertensive drug therapy and may also provide new insights into molecular mechanisms responsible for elevation of blood pressure.

Antihypertensive Agents↗
PubMed2001

Linkage of hypertension to chromosome 2q14-q23 in Chinese families.

OBJECTIVES: To identify chromosome regions containing hypertension susceptibility genes in Chinese. SUBJECTS AND METHODS: A three-stage study was carried out in Chinese siblings ascertained through outpatient clinics. In the first stage, 283 affected sib-pairs from 79 nuclear families were subjected to a genome-wide scan with 240 microsatellite marker loci. The second stage focused on chromosome 2 with additional markers resulting in an average distance of 5 cM and used an independent sample of 637 affected sib-pairs from 161 families. In the third stage, a fine-scale mapping study on the suggestive region was performed in an independent set of 777 affected sib-pairs from 106 families. Fourteen markers were used with an average distance less than 2 cM. Non-parametric linkage analyses (NPL), parametric linkage analyses and transmission-disequilibrium tests were used to assess evidence for linkage and association. RESULTS: Three markers (D2S168 at 27.06 cM, D2S151 at 152.04 cM and D2S142 at 161.26 cM) on chromosome 2 with suggestive linkage to hypertension susceptibility genes were identified in the genome-wide scan. In stage II, the suggestive region around D2S151 and D2S142 was replicated, while the linkage around D2S168 was not. In the stage III fine-scale mapping study, multipoint linkage analyses showed LOD scores greater than 2.0 throughout a region between 157.16 cM and 162.46 cM (all P < 0.001) with a maximum peak of 2.24 (P= 0.00067) at 160.52 cM. We also observed a NPL Z-score peak of 3.27 at 157.55 cM (P= 0.00086). CONCLUSIONS: The results of a suggestive region on chromosome 2q14-q23 (D2S112-D2S2370) were consistent between each of the three studies. Interestingly, this region overlaps a syntenic region that contains blood pressure quantitative trait loci identified in rat models of hypertension. These data suggest that the region near D2S142 and D2S151 deserves to be further screened for hypertension susceptibility genes.

China↗
PubMed2001

Metabolic and lifestyle determinants of postprandial lipemia differ from those of fasting triglycerides: The Atherosclerosis Risk In Communities (ARIC) study.

Despite the reported association of lipoprotein responses to a fatty meal with atherosclerosis, little is known about the determinants of these responses. Plasma triglyceride, retinyl palmitate, and apolipoprotein B-48 responses to a standardized fatty meal containing a vitamin A marker were measured in 602 Atherosclerosis Risk in Communities (ARIC) study participants. To focus on postprandial responses specifically, which have been reported to be related to atherosclerosis independently of fasting triglycerides, analyses for determinants of postprandial responses were adjusted for fasting triglycerides. Major determinants of fasting triglycerides, namely, diabetes, obesity, other factors related to insulin resistance, and male sex, were not independently associated with postprandial responses. Fasting triglycerides were the strongest predictor of postprandial lipids, but independent of triglycerides, the predictors of postprandial responses were smoking, diet, creatinine, and alcohol. Smokers had substantially increased retinyl palmitate and apolipoprotein B-48 responses, indicators of chylomicrons and their remnants. Persons who consume more calories or omega3 fatty acids had reduced chylomicron responses. Triglyceride responses were associated positively with serum creatinine levels and negatively with moderate alcohol consumption. Thus, determinants of fasting and postprandial lipids differ. The independent atherogenic influence of postprandial lipids may relate more to smoking and diet than to obesity and insulin resistance.

Aged↗
PubMed2001

Genome-wide linkage analysis reveals evidence of multiple regions that influence variation in plasma lipid and apolipoprotein levels associated with risk of coronary heart disease.

Results of genome-wide linkage analyses to identify chromosomal regions that influence interindividual variation in plasma lipid and apolipoprotein levels in the Rochester, Minn, population are reported. Analyses were conducted for total cholesterol (total-C), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, apolipoprotein C-II, apolipoprotein C-III, apolipoprotein E, the total-C/HDL-C ratio, and the TG/HDL-C ratio. Genotypes were measured for 373 genome-wide marker loci on 1484 individuals distributed among 232 multigeneration pedigrees sampled without regard to health status. LOD scores and estimates of additive genetic variance associated with map locations were obtained by using the variance-component method of linkage analysis. No evidence of linkage with genes influencing variation in age served as a negative control. Plasma apolipoprotein E levels and the apolipoprotein E gene served as a positive control (LOD score 4.20). Evidence (LOD score >2.00) was provided that was suggestive of a gene or genes on chromosomes 4 and 5 influencing variation in the apolipoprotein A-II level, on chromosome 12 influencing variation in the apolipoprotein A-I level, and on chromosome 17 influencing variation of total-C/HDL-C. These analyses provide new information about genomic regions in humans that influence interindividual variation in plasma lipid and apolipoprotein levels and serve as a basis for further fine-mapping studies to identify new genes involved in lipid metabolism.

Adolescent↗
PubMed2001

C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic.

The T allele of the C825T polymorphism of the gene encoding the beta(3)-subunit of G proteins has been associated with increased sodium-hydrogen exchange and low renin in patients with essential hypertension. To assess its association with blood pressure response to diuretic therapy, we measured the C825T polymorphism in 197 blacks (134 men, 63 women) and 190 non-Hispanic whites (76 men, 114 women) with essential hypertension (mean+/-SD age 48+/-7 years), who underwent monotherapy with hydrochlorothiazide for 4 weeks. Mean declines in systolic and diastolic blood pressures were 6+/-2 (P:<0.001) and 5+/-1 (P:<0.001) mm Hg greater, respectively, in TT than in CC homozygotes. Responses in heterozygotes were intermediate between the homozygous groups. Other univariate predictors of greater blood pressure responses included black race, female gender, higher pretreatment blood pressure, older age, lower waist-to-hip ratio, and measures of lower renin-angiotensin-aldosterone system activity. After the effects of the other predictors were considered, the TT genotype remained a significant predictor of greater declines in systolic and diastolic blood pressures. Thus, the C825T polymorphism of the G protein beta(3)-subunit may help identify patients with essential hypertension who are more responsive to diuretic therapy.

Adult↗
PubMed2001

G-protein beta3 subunit and alpha-adducin polymorphisms and risk of subclinical and clinical stroke.

BACKGROUND AND PURPOSE: Essential hypertension is a significant risk factor for stroke. Genes contributing to interindividual variation in blood pressure levels and essential hypertension status may play a role in the etiology of stroke either through their effects on blood pressure levels or through separate pathways. For this reason, we sought to examine the association between the alpha-adducin (ADD1) G/W460 and G-protein beta3 subunit (GNbeta3) 825C/T polymorphisms and subclinical and clinical stroke in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: Subclinical stroke was determined by cerebral MRI. Subclinical cerebral infarct cases (n=202) were compared with a stratified random sample (MRI-CRS) identified from individuals participating in the MRI examination (n=211). Incidence of clinical ischemic stroke was determined by following the ARIC cohort for an average of 7.2 years for potential cerebrovascular events; 231 validated clinical ischemic strokes were identified. A stratified random sample of the ARIC cohort (CRS) (n=984) was used as the comparison group for the clinical cases. RESULTS: The frequency of the ADD1 W460 allele was determined for the subclinical cases (0.12), MRI-CRS (0.16), clinical cases (0.14), and CRS (0.17). The frequency of the GNbeta3 825T allele was determined in whites and blacks, respectively, for the subclinical cases (0.26, 0.73), MRI-CRS (0.31, 0.75), clinical cases (0.36, 0.72), and CRS (0.30, 0.72). The ADD1 W460 and GNbeta3 825T alleles were not significantly associated with subclinical stroke. The ADD1 W460 allele was also not a significant predictor of clinical stroke. The GNbeta3 825T allele was significantly associated with clinical stroke in whites after adjustment for age and sex (hazard rate ratio, 1.45; 95% CI, 1.05 to 2.00) and after further adjustment for multiple stroke risk factors (hazard rate ratio, 1.68; 95% CI, 1.18 to 2.41). The GNbeta3 825T allele was not significantly associated with clinical stroke in blacks for either adjustment model. CONCLUSIONS: The GNbeta3 gene 825C/T polymorphism is significantly associated with incident clinical ischemic stroke in a white middle-aged American population, but not in blacks. This association does not appear to be mediated by established stroke risk factors, specifically blood pressure levels or hypertension status.

Age Distribution↗
PubMed2001

Validity of the aldosterone-renin ratio used to screen for primary aldosteronism.

OBJECTIVE: To determine whether the calculated ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA), a proposed screening test for primary aldosteronism, provides a renin-independent measure of circulating aldosterone that is suitable to judge whether PAC is inappropriately elevated relative to PRA. SUBJECTS AND METHODS: This study consisting of 221 black and 276 white subjects with previously diagnosed essential hypertension was conducted between 1996 and 2000. Antihypertensive drugs were withdrawn for at least 4 weeks; PAC and PRA were measured while subjects were supine and then seated after 30 minutes of ambulation. The seated measurements were repeated after 4 weeks of oral diuretic therapy with hydrochlorothiazide (25 mg/d). RESULTS: The variation in the aldosterone-renin ratio was strongly and inversely dependent on PRA (R2=0.71; P<.001). When subjects changed position from supine to seated, the increase in mean +/- SD PRA (from 1.18 +/- 1.06 to 1.31 +/- 1.19 ng x mL(-1) x h(-1); P<.001) was associated with an increase in the mean ratio (from 18.6 +/- 52.8 to 25.8 +/- 38.1 h x 10(2); P<.001), whereas the increase in mean +/- SD PRA in response to diuretic therapy (from 1.31 +/- 1.19 to 2.72 +/- 2.67 ng x mL(-1) x h(-1); P=.007) was associated with a decrease in the mean ratio (from 25.8 +/- 38.1 to 16.4 +/- 31.6 h 10(2); P<.001). CONCLUSION: In patients with previously diagnosed essential hypertension, calculation of the aldosterone-renin ratio does not provide a renin-independent measure of circulating aldosterone that is suitable for determining whether PAC is elevated relative to PRA. Because elevation of the aldosterone-renin ratio is predominantly an indicator of low PRA, its perceived value in screening for primary aldosteronism most likely derives from additional diagnostic tests being done in patients with low-renin hypertension.

Age Distribution↗
PubMed2000

Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium.

Gene flow between genetically distinct populations creates linkage disequilibrium (admixture linkage disequilibrium [ALD]) among all loci (linked and unlinked) that have different allele frequencies in the founding populations. We have explored the distribution of ALD by using computer simulation of two extreme models of admixture: the hybrid-isolation (HI) model, in which admixture occurs in a single generation, and the continuous-gene-flow (CGF) model, in which admixture occurs at a steady rate in every generation. Linkage disequilibrium patterns in African American population samples from Jackson, MS, and from coastal South Carolina resemble patterns observed in the simulated CGF populations, in two respects. First, significant association between two loci (FY and AT3) separated by 22 cM was detected in both samples. The retention of ALD over relatively large (>10 cM) chromosomal segments is characteristic of a CGF pattern of admixture but not of an HI pattern. Second, significant associations were also detected between many pairs of unlinked loci, as observed in the CGF simulation results but not in the simulated HI populations. Such a high rate of association between unlinked markers in these populations could result in false-positive linkage signals in an admixture-mapping study. However, we demonstrate that by conditioning on parental admixture, we can distinguish between true linkage and association resulting from shared ancestry. Therefore, populations with a CGF history of admixture not only are appropriate for admixture mapping but also have greater power for detection of linkage disequilibrium over large chromosomal regions than do populations that have experienced a pattern of admixture more similar to the HI model, if methods are employed that detect and adjust for disequilibrium caused by continuous admixture.

Africa↗
PubMed2000

Platelet Pl(A2) allele and incidence of coronary heart disease: results from the Atherosclerosis Risk In Communities (ARIC) Study.

BACKGROUND: The major platelet integrin glycoprotein IIb-IIIa plays a primary role in platelet aggregation and acute thrombus formation at the site of vascular injury. A genetic polymorphism of glycoprotein IIb-IIIa (Pl(A)) has recently been proposed as a potential genetic factor linking to platelet hyperaggregability and increased risk of myocardial infarction. Despite numerous, mostly nonprospective studies, the role of this polymorphism as a clinically relevant, inherited risk factor for coronary heart disease (CHD) is still controversial. The purpose of this study was to determine whether Pl(A2) is a risk factor for incident CHD and whether it is correlated with increased platelet activation in a case-cohort study nested within a prospective epidemiologic investigation. METHODS AND RESULTS: Blood samples were collected and processed from the Atherosclerosis Risk in Communities Study cohort at the baseline examination (1987 to 1989). They were stored at -80 degrees C. Pl(A1/A2) genotype and plasma beta-thromboglobulin levels were determined in 439 incident CHD cases and a reference cohort sample of 544 (of whom 18 were also CHD cases). The prevalence of the Pl(A2) allele was not different in cases versus noncases. No significant correlation between CHD risk factors and the Pl(A2) allele was noted either. Platelet activation, as measured by plasma beta-thromboglobulin levels, was not enhanced in individuals with the Pl(A2) allele. CONCLUSIONS: This prospective study indicates that healthy individuals carrying the Pl(A2) allele do not have an increased risk of CHD.

Alleles↗
PubMed2000

Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism.

Three common protein isoforms of apolipoprotein E (apoE), encoded by the epsilon2, epsilon3, and epsilon4 alleles of the APOE gene, differ in their association with cardiovascular and Alzheimer's disease risk. To gain a better understanding of the genetic variation underlying this important polymorphism, we identified sequence haplotype variation in 5.5 kb of genomic DNA encompassing the whole of the APOE locus and adjoining flanking regions in 96 individuals from four populations: blacks from Jackson, MS (n=48 chromosomes), Mayans from Campeche, Mexico (n=48), Finns from North Karelia, Finland (n=48), and non-Hispanic whites from Rochester, MN (n=48). In the region sequenced, 23 sites varied (21 single nucleotide polymorphisms, or SNPs, 1 diallelic indel, and 1 multiallelic indel). The 22 diallelic sites defined 31 distinct haplotypes in the sample. The estimate of nucleotide diversity (site-specific heterozygosity) for the locus was 0.0005+/-0.0003. Sequence analysis of the chimpanzee APOE gene showed that it was most closely related to human epsilon4-type haplotypes, differing from the human consensus sequence at 67 synonymous (54 substitutions and 13 indels) and 9 nonsynonymous fixed positions. The evolutionary history of allelic divergence within humans was inferred from the pattern of haplotype relationships. This analysis suggests that haplotypes defining the epsilon3 and epsilon2 alleles are derived from the ancestral epsilon4s and that the epsilon3 group of haplotypes have increased in frequency, relative to epsilon4s, in the past 200,000 years. Substantial heterogeneity exists within all three classes of sequence haplotypes, and there are important interpopulation differences in the sequence variation underlying the protein isoforms that may be relevant to interpreting conflicting reports of phenotypic associations with variation in the common protein isoforms.

Alleles↗