Diane M Becker

Johns Hopkins Medicine, Baltimore, Maryland, United States

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Publications (164)1162.88 Total impact

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    ABSTRACT: Background: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors. Methods: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus <55, sex, current smoking, obesity, hypertension, diabetes and low-density lipoprotein >160 mg/dl. Results: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26). Conclusions: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population. © 2014 S. Karger AG, Basel.
    Cerebrovascular Diseases 03/2014; 37(4):244-250. · 2.81 Impact Factor
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    ABSTRACT: In single-nucleotide polymorphism (SNP) scans, SNP-phenotype association hypotheses are tested, however there is biological interpretation only for genes that span multiple SNPs. We demonstrate and validate a method of combining gene-wide evidence using data for high-density lipoprotein cholesterol (HDLC). In a family based study (N=1782 from 482 families), we used 1000 phenotype-permuted datasets to determine the correlation of z-test statistics for 592 SNP-HDLC association tests comprising 14 genes previously reported to be associated with HDLC. We generated gene-wide p-values using the distribution of the sum of correlated z-statistics. Of the 14 genes, CETP was significant (p=4.0×10(-5) <0.05/14), while PLTP was significant at the borderline (p=6.7×10(-3) <0.1/14). These p-values were confirmed using empirical distributions of the sum of χ(2) association statistics as a gold standard (2.9×10(-6) and 1.8×10(-3), respectively). Genewide p-values were more significant than Bonferroni-corrected p-value for the most significant SNP in 11 of 14 genes (p=0.023). Genewide p-values calculated from SNP correlations derived for 20 simulated normally distributed phenotypes reproduced those derived from the 1000 phenotype-permuted datasets were correlated with the empirical distributions (Spearman correlation = 0.92 for both). We have validated a simple scalable method to combine polymorphism-level evidence into gene-wide statistical evidence. High-throughput gene-wide hypothesis tests may be used in biologically interpretable genomewide association scans. Genewide association tests may be used to meaningfully replicate findings in populations with different linkage disequilibrium structure, when SNP-level replication is not expected.
    British journal of medicine and medical research. 03/2014; 4(6):1413-1422.
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    ABSTRACT: -Although age and sex distributions of calcified plaque (CCP) have been well described in the general population, noncalcified plaque (NCP) distributions remain unknown. This is important because NCP is a putative precursor for clinical CAD and could serve as a sentinel for aggressive primary prevention, especially in higher risk populations. We examined the distributions of NCP and CCP in healthy 30-74 year old individuals from families with early-onset coronary artery disease (CAD). -Participants in the GeneSTAR family study (N=805), mean age 51.1 ± 10.8 years, 56% female, were screened for CAD risk factors and for coronary plaque using dual-source CT angiography. Plaque volumes (mm(3)) were quantified using a validated automated method. The prevalence of coronary plaque was 57.8% in males and 35.8% in females (p<0.0001). NCP volume increased with age (p<0.001) and was higher in males than females (p<0.001). Although NCP, as a percent of total plaque, was inversely related to age (p<0.01), NCP accounted for most of the total plaque volume at all ages, especially in males and females <55 years (>70% and >80%, respectively). Higher Framingham risk was associated with the number of affected vessels (p<0.01) but 44% of males and 20.8% of females considered intermediate risk had left main and/or 3-vessel disease involvement. -The majority of coronary plaque was noncalcified, particularly in younger individuals. These findings support the importance of assessing family history and suggest that early primary prevention interventions may be warranted at younger ages in families with early onset CAD.
    Circulation Cardiovascular Imaging 02/2014; · 5.80 Impact Factor
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    ABSTRACT: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA. Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke. We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
    Arteriosclerosis Thrombosis and Vascular Biology 02/2014; · 6.34 Impact Factor
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    ABSTRACT: Objective Controversy exists about the coronary artery disease (CAD) risk conveyed by diabetes in young and middle-aged women. We investigated gender differences in CAD by diabetes-status among healthy individuals with different underlying risks of heart disease.Research Design/Methods We examined subjects aged<60 years without CAD at enrollment in the high-risk GeneSTAR Study (n=1448;follow-up∼12years), Multi-Ethnic Study of Atherosclerosis (n=3072;follow-up∼7years) and NHANES III Mortality Follow-up Study (n=6997;follow-up∼15years). Diabetes was defined by report, hypoglycemics use, and/or fasting glucose≥126 mg/dl. The outcome was any CAD event during follow-up (fatal CAD in NHANES).ResultsIn the absence of diabetes, CAD rates were lower among women in GeneSTAR, MESA, and NHANES (4.27, 1.66, 0.40/1000 person-years,respectively) versus men (11.22, 5.64, 0.88/1000 person-years); log-rank p-value<0.001(GeneSTAR/MESA) and p=0.07(NHANES). In the presence of diabetes, CAD event rates were similar among women (17.65, 7.34, 2.37/1000 person-years) versus men (12.86, 9.71, 1.83/1000 person-years); all log-rank p-value>0.05. Adjusting for demographics, diabetes was associated with a significant four-to-five-fold higher CAD rate among women in each cohort, without differences in men. In meta-analyses of three cohorts, additionally adjusted for body-mass index,smoking,hypertension,HDL and non-HDL cholesterol,anti-hypertensive and cholesterol-lowering medication use, the hazard ratio(HR) of CAD in men versus women among non-diabetes was 2.43(1.76-3.35) and diabetes 0.89(0.43-1.83), p=0.013 interaction by diabetes-status.Conclusions Though young and middle-aged women are less likely to develop CAD in the absence of diabetes, the presence of diabetes equalizes the risk by gender. Our findings support aggressive CAD prevention strategies in women with diabetes, and at similar levels to those that exist in men.
    Diabetes care 10/2013; · 7.74 Impact Factor
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    ABSTRACT: Coronary atherosclerosis has been associated with systemic arterial remodeling even in nonatherosclerotic vessels. However, it is not known whether systemic remodeling is differentially associated with the cumulative atherosclerotic process, reflected by putatively quiescent calcified plaque (CP), or with active atherosclerosis, consisting of noncalcified plaque (NCP). We thus examined the association of brachial artery diameter (BAD), an artery that does not suffer clinical atherosclerosis, with the presence and the extent of coronary CP and NCP. We studied 688 apparently healthy, asymptomatic participants from 350 families with a history of early-onset coronary artery disease (<60 years of age) by measuring coronary artery disease risk factors and coronary plaque using dual-source computed tomographic angiography. Plaque volumes were quantified using a validated automated method. BAD was measured during diastole using B-mode ultrasound. The association of resting BAD with any detectable plaque, and log-transformed CP and NCP volumes if detectable, was tested using generalized estimating equations adjusted for age, sex, race, current smoking, diabetes, hypertension, BMI, and non-HDL and HDL cholesterol. Higher quintiles of BAD were associated with greater age and male sex (both P<0.001). In the fully adjusted analysis, CP volume was not associated with BAD (P=0.65) but a 1 ml greater NCP volume was associated with a 0.65 mm larger BAD (P=0.027). Our results suggest that systemic arterial remodeling of nonatherosclerotic arteries is a dynamic process that is correlated with the extent of putatively active atherosclerotic processes in distant beds but not with inactive accumulated plaque burden.
    Coronary artery disease 09/2013; · 1.56 Impact Factor
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    ABSTRACT: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation. We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5x10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE. We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
    Circulation 08/2013; · 15.20 Impact Factor
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    ABSTRACT: Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10(-8); RREB1: p = 5.7×10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
    PLoS Genetics 08/2013; 9(8):e1003681. · 8.52 Impact Factor
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    ABSTRACT: Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants. We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis. Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region. While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations.
    BMC Medical Genetics 07/2013; 14(1):75. · 2.54 Impact Factor
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    ABSTRACT: Although negative emotions and psychiatric morbidity have often been found to increase incident coronary artery disease (CAD) risk, fewer studies have shown positive emotions to be protective against CAD; none have been performed in high-risk healthy populations, taking risk factors into account. Thus, we examined the effect of positive well-being on incident CAD in both a high-risk initially healthy population and a national probability sample. We screened healthy siblings of probands with documented early-onset CAD from 1985 to 2007 in the GeneSTAR (Genetic Study of Atherosclerosis Risk) population and examined sociodemographic data, risk factors, and positive well-being using the General Well-Being Schedule. We further classified siblings into high-, intermediate-, and low-risk strata according to the Framingham risk score and followed them for 5 to 25 years. Siblings (n = 1,483) with greater baseline General Well-Being Schedule total scores were significantly less likely to develop CAD (hazard ratio 0.67, 95% confidence interval 0.58 to 0.79), independent of age, gender, race, and traditional risk factors. Protection was strongest in the high Framingham risk score stratum (hazard ratio 0.52, 95% confidence interval 0.30 to 0.90). The findings were replicated in the first National Health and Nutrition Examination Survey and Epidemiologic Follow-up Study (n = 5,992; hazard ratio 0.87, 95% confidence interval 0.83 to 0.93). In conclusion, positive well-being was associated with nearly a 1/3 reduction in CAD in a high-risk population with a positive family history, a nearly 50% reduction in incident CAD in the highest risk stratum in those with a positive family history, and a 13% reduction in incident CAD in a national probability sample, independent of the traditional CAD risk factors.
    The American journal of cardiology 06/2013; · 3.58 Impact Factor
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    ABSTRACT: White matter disease (WMD) of the brain is associated with incident stroke. Similarly, subclinical calcified coronary artery plaque has been associated with incident coronary artery disease (CAD) events. Although atherogenesis in both vascular beds may share some common mechanisms, the extent to which subclinical CAD is associated with WMD across age ranges in subjects with a family history of early-onset CAD remains unknown. We screened 405 apparently healthy participants in the Genetic Study of Atherosclerotic Risk for CAD risk factors and for the presence of noncalcified and calcified coronary plaque using dual-source multidetector cardiac computed tomographic angiography. The presence and volumes of WMD were assessed by 3-Tesla brain magnetic resonance imaging. Participants were 60% women, 36% African-American, mean age 51.6 ± 10.6 years. The overall prevalence of coronary plaque was 43.0%. Subjects with coronary plaque had significantly greater WMD volumes (median 1,222 mm(3), interquartile range 448 to 3,871) compared with those without coronary plaque (median 551 mm(3), interquartile range 105 to 1,523, p <0.001). In multivariate regression analysis, adjusting for age, gender, race, traditional risk factors, total brain volume, and intrafamilial correlations, the presence of coronary plaque was independently associated with WMD volume (p = 0.05). This study shows a significant association between WMD and noncalcified and calcified coronary plaque in healthy subjects, independent of age and risk factors. In conclusion, these findings support the premise of possible shared causal pathways in 2 vascular beds in families at increased risk for early-onset vascular disease.
    The American journal of cardiology 06/2013; · 3.58 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10-11) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10-10). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10-8). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10-7), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
    Nature Genetics 04/2013; · 35.21 Impact Factor
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    ABSTRACT: Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ∼16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.
    Human Molecular Genetics 03/2013; · 7.69 Impact Factor
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    ABSTRACT: Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1) gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13) selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate). Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5%) were noted in African Americans compared to European Americans (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in African Americans (p = 4.020×10(-4)); no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331). Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965) supports the results noted in the sequenced discovery sample: p = 3.56×10(-4), 2.27×10(-7), 5.20×10(-5) for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans, and show that exonic variants play an additional role in platelet aggregation in European Americans.
    PLoS ONE 01/2013; 8(5):e64179. · 3.73 Impact Factor
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    ABSTRACT: High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 x 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
    The American Journal of Human Genetics 01/2013; 93(3):545-54. · 11.20 Impact Factor
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    ABSTRACT: Variance components analysis (VCA), the traditional method for handling correlations within families in genetic association studies, is computationally intensive for genome-wide analyses, and the computational burden of VCA increases with family size and the number of genetic markers. Alternative approaches that do not require the computation of familial correlations are preferable, provided that they do not inflate type I error or decrease power. We performed a simulation study to evaluate practical alternatives to VCA that use regression with generalized estimating equations (GEE) in extended family data. We compared the properties of linear regression with GEE applied to an entire extended family structure (GEE-EXT) and GEE applied to nuclear family structures split from these extended families (GEE-SPL) to variance components likelihood-based methods (FastAssoc). GEE-EXT was evaluated with and without robust variance estimators to estimate the standard errors. We observed similar average type I error rates from GEE-EXT and FastAssoc compared to GEE-SPL. Type I error rates for the GEE-EXT method with a robust variance estimator were marginally higher than the nominal rate when the minor allele frequency (MAF) was <0.1, but were close to the nominal rate when the MAF was ≥0.2. All methods gave consistent effect estimates and had similar power. In summary, the GEE framework with the robust variance estimator, the computationally fastest and least data management-intensive approach, appears to work well in extended families and thus provides a reasonable alternative to full variance components approaches for extended pedigrees in a genome-wide association study setting.
    Human Heredity 10/2012; 74(1):17-26. · 1.57 Impact Factor
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    ABSTRACT: We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19,599 subjects, followed by replication analysis of genome-wide significant (P<5x10(-8)) single nucleotide polymorphisms (SNPs) in 10,796 independent samples. We further examined associations with type 2 diabetes (T2D) and coronary artery disease (CAD), assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P=3.4x10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P=3.0x10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P=2.9x10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with T2D and CAD at ARNTL (P<0.05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL, and a SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
    Blood 09/2012; · 9.06 Impact Factor
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    Translational Psychiatry. 04/2012;
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    ABSTRACT: Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N = 16,388) with p<5×10(-8) of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p = 9.1×10(-9)), 7q11 (rs13236689, CD36, p = 2.8×10(-9)), 10q21 (rs7896518, JMJD1C, p = 2.3×10(-12)), 11q13 (rs477895, BAD, p = 4.9×10(-8)), and 20q13 (rs151361, SLMO2, p = 9.4×10(-9)). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N = 14,909) and one (11q13) in Hispanic Americans (N = 3,462). For MPV (N = 4,531), genetic variants in 3 regions were significant at p<5×10(-8), two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis.
    PLoS Genetics 03/2012; 8(3):e1002491. · 8.52 Impact Factor
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    ABSTRACT: The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.
    Translational psychiatry. 02/2012; 2:e119.

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Institutions

  • 1988–2013
    • Johns Hopkins Medicine
      • • Department of Medicine
      • • Division of General Internal Medicine
      • • Department of Anesthesiology and Critical Care Medicine
      Baltimore, Maryland, United States
  • 1987–2013
    • Johns Hopkins University
      • • Department of Medicine
      • • Division of General Internal Medicine
      • • Department of Anesthesiology and Critical Care Medicine
      Baltimore, MD, United States
  • 2010
    • National Human Genome Research Institute
      Maryland, United States
    • National Heart, Lung, and Blood Institute
      • Division of Cardiovascular Sciences (DCVS)
      Maryland, United States
    • Harvard Medical School
      • Department of Population Medicine
      Boston, MA, United States
  • 2008–2009
    • deCODE genetics, Inc.
      Reikiavik, Capital Region, Iceland
  • 2007
    • Thomas Jefferson University
      Philadelphia, Pennsylvania, United States
  • 2005
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1990
    • Georgetown University
      Washington, Washington, D.C., United States