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Articles by E. Boerwinkle
Total Records ( 6 ) for E. Boerwinkle
  A Brautbar , C. M Ballantyne , K Lawson , V Nambi , L Chambless , A. R Folsom , J. T Willerson and E. Boerwinkle

Background— A single-nucleotide polymorphism on chromosome 9p21, rs10757274 (9p21 allele), has been shown to predict coronary heart disease (CHD) in whites. We evaluated whether adding the 9p21 allele to traditional risk factors (RFs) improved CHD risk prediction in whites from the Atherosclerosis Risk in Communities study and whether changes in risk prediction would modify lipid therapy recommendations.

Methods and Results— Whites (n=9998) in the Atherosclerosis Risk in Communities study for whom the 9p21 genotype and traditional RF information was available were included. Using Cox proportional hazards models, the Atherosclerosis Risk in Communities Cardiovascular Risk Score, which is based on traditional RFs, was determined. A total of 1349 individuals (13.5%) developed incident CHD events during a period of 14.6 years. Adding the 9p21 allele to traditional RFs was associated with a hazard ratio of incident CHD of 1.2 per allele (P<0.000003) and a significant increase in the area under the curve of the receiver operating characteristic from 0.782 to 0.786 (95% CI, 0.001, 0.007). The 9p21 allele’s greatest influence to the Atherosclerosis Risk in Communities Cardiovascular Risk Score was observed in the intermediate-low (>5% to ≤10% 10-year CHD risk) and intermediate-high (>10% to ≤20% 10-year CHD risk) categories, with 12.1% and 12.6% reclassified, respectively. This may impact therapy because 90% of these reclassified individuals had low-density lipoprotein cholesterol >100 mg/dL.

Conclusion— Adding the 9p21 allele to traditional RFs in whites in the Atherosclerosis Risk in Communities study modestly improved CHD risk prediction in the intermediate categories.

  L Wagenknecht , B Wasserman , L Chambless , J Coresh , A Folsom , T Mosley , C Ballantyne , R Sharrett and E. Boerwinkle

Background— The composition of atherosclerotic plaque affects the likelihood of an atherothrombotic event, but prospective studies relating risk factors to carotid wall and plaque characteristics measured by MRI are lacking. We hypothesized that traditional risk factors are predictors of carotid wall and plaque characteristics measured 2 decades later.

Methods and Results— A high-resolution contrast-enhanced MRI examination of the carotid artery was performed in 1769 participants. Measures of carotid wall volume and maximum thickness; lipid core presence, volume and maximum area; and fibrous cap thickness were performed centrally. The sample was, on average, 70 years of age, 57% female, 81% white, and 19% black. Greater age, total and low-density lipoprotein cholesterol, male sex, white race, diabetes, hypertension, and smoking as measured at baseline were all significant predictors of increased wall volume and maximum wall thickness 18 years later. An analysis of lipid core was restricted to the 1180 participants with maximum wall thickness ≥1.5 mm. Lipid core was observed in 569 individuals (weighted percentage, 42%). Baseline age and total and low-density lipoprotein cholesterol were predictors of presence of lipid core 18 years later; however, these relationships were attenuated after adjustment for wall thickness. Concurrently measured low-density lipoprotein cholesterol was associated with greater lipid core volume, independent of wall thickness. Concurrently measured glucose and body mass index were inversely associated fibrous cap thickness.

Conclusions— Traditional atherosclerosis risk factors are related to increased wall volume and wall thickness 2 decades later, but they do not discriminate characteristics of plaque composition (core and cap) independent of wall size.

  K. A Volcik , D Catellier , A. R Folsom , N Matijevic , B Wasserman and E. Boerwinkle

Background: P-selectin (SELP) and its ligand, P-selectin glycoprotein ligand 1 (SELPLG), play key roles in both the inflammatory response and the atherosclerotic process. Previous studies have shown genetic variation in the SELP gene [selectin P (granule membrane protein 140kDa, antigen CD62)] to be associated with plasma SELP concentrations; however, the major biological function of SELP (and SELPLG) is at the cell surface. We therefore investigated the association of SELP polymorphisms with platelet SELP measures and polymorphisms in the SELPLG gene (selectin P ligand) with lymphocyte, granulocyte, and monocyte SELPLG measures among 1870 participants in the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study.

Methods: Whole-blood flow cytometry was used to analyze leukocyte and platelet markers in the ARIC Carotid MRI Study. The allele frequencies for the SELP and SELPLG polymorphisms of whites and African Americans were markedly different; therefore, all analyses were race specific.

Results: SELP T715P was significantly associated with lower values for platelet SELP measures in whites (P = 0.0001), whereas SELP N562D was significantly associated with higher values for SELP measures in African Americans (P = 0.02). SELPLG M62I was significantly associated with lower granulocyte and monocyte SELPLG measures in African Americans (P = 0.003 and P = 0.0002, respectively) and with lower lymphocyte SELPLG measures in whites (P = 0.01).

Conclusions: Specific SELP and SELPLG polymorphisms were associated with cell surface measures of SELP and SELPLG in both whites and African Americans in the ARIC Carotid MRI Study. To our knowledge, this study is the first to examine the association of SELP and SELPLG genetic variation with measures of cell surface SELP and SELPLG.

  X Liu , Y. X Fu , T. J Maxwell and E. Boerwinkle

It is known that sequencing error can bias estimation of evolutionary or population genetic parameters. This problem is more prominent in deep resequencing studies because of their large sample size n, and a higher probability of error at each nucleotide site. We propose a new method based on the composite likelihood of the observed SNP configurations to infer population mutation rate = 4Neµ, population exponential growth rate R, and error rate , simultaneously. Using simulation, we show the combined effects of the parameters, , n, , and R on the accuracy of parameter estimation. We compared our maximum composite likelihood estimator (MCLE) of with other estimators that take into account the error. The results show the MCLE performs well when the sample size is large or the error rate is high. Using parametric bootstrap, composite likelihood can also be used as a statistic for testing the model goodness-of-fit of the observed DNA sequences. The MCLE method is applied to sequence data on the ANGPTL4 gene in 1832 African American and 1045 European American individuals.

  M Barbalic , G. L Schwartz , A. B Chapman , S. T Turner and E. Boerwinkle

Recent experimental and clinical studies suggested that apart from playing an essential role in blood pressure homeostasis, aldosterone is involved in the pathophysiology of cardiovascular and renal diseases by inducing structural changes in the heart, kidney, and vessel wall. The interindividual variation of aldosterone response to antihypertensive treatment is considerable, and is at least partially explained by genetic variation. In this study, we investigated aldosterone response to two antihypertensive drugs—a thiazide diuretic and an angiotensin receptor blocker (ARB). Genetic variations in 50 candidate genes were tested for association with aldosterone response in four independent samples: African American (AA) responders to a diuretic (n = 289), AA responders to an ARB (n = 252), European American (EA) responders to a diuretic (n = 295) and EA responders to an ARB (n = 300). Linear regression was used to test the association with inclusion of age, sex, and body mass index as covariates. The results indicated the existence of one or more variants in the kininogen gene (KNG) that influence interindividual variation in aldosterone response. The significant association was replicated in three of four studied groups. The single nucleotide polymorphism rs4686799 was associated in AA and EA responders to the diuretic (P = 0.04 and P = 0.07, respectively), and rs5030062 and rs698078 were significantly associated in EA responders to the diuretic (P = 0.05 and P = 0.01) and EA responders to the ARB (P = 0.04 and P = 0.02). Although the clinical implication of KNG gene variation to antihypertensive drug response is yet to be determined, this novel candidate locus provides important new insights into drug response physiology.

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