Arlene B Chapman

Emory University, Atlanta, Georgia, United States

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Publications (133)874.61 Total impact

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    ABSTRACT: Hypokalemia is a recognized adverse effect of thiazide diuretic treatment. This phenomenon, which may impair insulin secretion, has been suggested to be a reason for the adverse effects on glucose metabolism associated with thiazide diuretic treatment of hypertension. However, the mechanisms underlying thiazide diuretic-induced hypokalemia are not well understood. In an effort to identify genes or genomic regions associated with potassium response to hydrochlorothiazide, without a priori knowledge of biologic effects, we performed a genome-wide association study and a multiethnic meta-analysis in 718 European- and African-American hypertensive participants from two different pharmacogenetic studies. Single-nucleotide polymorphisms rs10845697 (Bayes factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes factor=5.258) on chromosome 8, near to the Mitoferrin-1 gene, reached genome-wide association study significance (Bayes factor >5). These results, if replicated, suggest a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.The Pharmacogenomics Journal advance online publication, 9 September 2014; doi:10.1038/tpj.2014.46.
    The pharmacogenomics journal. 09/2014;
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    ABSTRACT: Study Objective To develop and validate a predictive model for glucose change and risk for new-onset impaired fasting glucose in hypertensive participants following treatment with atenolol or hydrochlorothiazide (HCTZ).DesignRandomized multicenter clinical trial.PatientsA total of 735 white or African-American men and women with uncomplicated hypertension.Measurements and Main ResultsPharmacogenomic Evaluation of Antihypertensive Responses (PEAR) is a randomized clinical trial to assess the genetic and nongenetic predictors of blood pressure response and adverse metabolic effects following treatment with atenolol or HCTZ. To develop and validate predictive models for glucose change, PEAR participants were randomly divided into a derivation cohort of 367 and a validation cohort of 368. Linear and logistic regression modeling were used to build models of drug-associated glucose change and impaired fasting glucose (IFG), respectively, in the derivation cohorts. These models were then evaluated in the validation cohorts. For glucose change after atenolol or HCTZ treatment, baseline glucose was a significant (p<0.0001) predictor, explaining 13% of the variability in glucose change after atenolol and 12% of the variability in glucose change after HCTZ. Baseline glucose was also the strongest and most consistent predictor (p<0.0001) for development of IFG after atenolol or HCTZ monotherapy. The area under the receiver operating curve was 0.77 for IFG after atenolol and 0.71 after HCTZ treatment, respectively.Conclusion Baseline glucose is the primary predictor of atenolol or HCTZ-associated glucose increase and development of IFG after treatment with either drug.
    Pharmacotherapy 09/2014; · 2.31 Impact Factor
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    ABSTRACT: Polycystic liver disease (PLD), the most common extra-renal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent due to increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes associate with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes.
    Clinical Gastroenterology and Hepatology. 08/2014;
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    ABSTRACT: Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis worldwide and is histologically characterized by the deposition of IgA1 and consequent inflammation in the glomerular mesangium. Prior studies suggested that serum IgA1 from IgAN patients contains aberrant, undergalactosylated O-glycans, e.g. Tn antigen and its sialylated version, SialylTn (STn), but the mechanisms underlying aberrant O-glycosylation are not well understood. Here we have used serial lectin separation technologies, Western blot, enzymatic modifications, and mass spectrometry to explore whether there are different glycoforms of IgA1 in plasma from patients with IgAN and healthy individuals. While total plasma IgA in IgAN patients was elevated ~1.6-fold compared to that in healthy donors, IgA1 in all samples was unexpectedly separable into two distinct glycoforms: one with core 1 based O-glycans, and the other exclusively containing Tn/STn structures. Importantly, Tn antigen present on IgA1 from IgAN patients and controls was convertible into the core 1 structure in vitro by recombinant T-synthase. Our results demonstrate that undergalactosylation of O-glycans in IgA1 is not restricted to IgAN and suggest that in vivo inefficiency of T-synthase toward IgA1 in a subpopulation of B or plasma cells, as well as overall elevation of IgA, may contribute to IgAN pathogenesis.
    Molecular & cellular proteomics : MCP. 07/2014;
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    ABSTRACT: The rate of renal disease progression varies widely among patients with autosomal dominant polycystic kidney disease (ADPKD), necessitating optimal patient selection for enrollment into clinical trials. Patients from the Mayo Clinic Translational PKD Center with ADPKD (n=590) with computed tomography/magnetic resonance images and three or more eGFR measurements over ≥6 months were classified radiologically as typical (n=538) or atypical (n=52). Total kidney volume (TKV) was measured using stereology (TKVs) and ellipsoid equation (TKVe). Typical patients were randomly partitioned into development and internal validation sets and subclassified according to height-adjusted TKV (HtTKV) ranges for age (1A–1E, in increasing order). Consortium for Radiologic Imaging Study of PKD (CRISP) participants (n=173) were used for external validation. TKVe correlated strongly with TKVs, without systematic underestimation or overestimation. A longitudinal mixed regression model to predict eGFR decline showed that log2HtTKV and age significantly interacted with time in typical patients, but not in atypical patients. When 1A–1E classifications were used instead of log2HtTKV, eGFR slopes were significantly different among subclasses and, except for 1A, different from those in healthy kidney donors. The equation derived from the development set predicted eGFR in both validation sets. The frequency of ESRD at 10 years increased from subclass 1A (2.4%) to 1E (66.9%) in the Mayo cohort and from 1C (2.2%) to 1E (22.3%) in the younger CRISP cohort. Class and subclass designations were stable. An easily applied classification of ADPKD based on HtTKV and age should optimize patient selection for enrollment into clinical trials and for treatment when one becomes available.
    Journal of the American Society of Nephrology : JASN. 06/2014;
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    ABSTRACT: Metoprolol is a selective β-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme, CYP2D6. Our objective was to investigate the influence of CYP2D6 polymorphisms on efficacy and tolerability of metoprolol tartrate. 281 study participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes by using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (p-value <0.0001) with poor metabolizers & intermediate metabolizers showing greater HR reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not a determinant of the variability in response or tolerability to metoprolol.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 17 March 2014. doi:10.1038/clpt.2014.62.
    Clinical Pharmacology &#38 Therapeutics 03/2014; · 6.85 Impact Factor
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    ABSTRACT: -The five amino acid (AA) signature including isoleucine (Ile), leucine (Leu), valine (Val), tyrosine (Tyr), and phenylalanine (Phe) has been associated with incident diabetes and insulin resistance. We investigated whether this same AA signature, single nucleotide polymorphisms (SNPs) in genes in their catabolic pathway, were associated with development of impaired fasting glucose (IFG) after atenolol treatment. -Among 234 European American participants enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study and treated with atenolol for 9 weeks, we prospectively followed a nested cohort that had both metabolomics profiling and genotype data available, for the development of IFG. We assessed the association between baseline circulating levels of Ile, Leu, Val, Tyr and Phe, as well as SNPs in BCAT1 and PAH with development of IFG. All baseline AA levels were strongly associated with IFG development. Each increment in standard deviation of the five AAs was associated with the following odds ratio and 95% confidence interval for IFG based on fully adjusted model: Ile 2.29 (1.31-4.01), Leu 1.80 (1.10-2.96), Val 1.77 (1.07-2.92), Tyr 2.13 (1.20-3.78) and Phe 2.04 (1.16-3.59). The composite p value was 2x10(-5). Those with PAH (rs2245360) AA genotype had the highest incidence of IFG (p for trend=0.0003). -Our data provide important insight into the metabolic and genetic mechanisms underlying atenolol associated adverse metabolic effects. Clinical Trial; Unique Identifier: NCT00246519.
    Circulation Cardiovascular Genetics 03/2014; · 6.73 Impact Factor
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    ABSTRACT: Elevated central systolic blood pressure (BP) increases the risk of cardiovascular events and appears superior to peripheral BP for long term risk prediction. The objective of this study was to identify demographic and clinical factors associated with central pressures in patients with uncomplicated hypertension. We prospectively examined peripheral BP, central aortic BP, and arterial wall properties and wave reflection in 57 subjects with uncomplicated essential hypertension in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study. Significant predictors of central SBP included height, smoking status, heart rate (HR), and peripheral systolic BP (SBP), while central diastolic BP (DBP) was explained by peripheral DBP and HR. These variables accounted for nearly all of the variability in central SBP and central DBP (R(2) = 0.94 and R(2) = 0.98, respectively). Central pulse pressure variability was largely explained by gender, ex-smoking status, HR, peripheral SBP, and peripheral DBP (R(2) = 0.94). Central augmented pressure had a direct relationship with smoking status, peripheral SBP, and duration of hypertension, whereas it was indirectly related to height, HR, and peripheral DBP. Easily obtainable demographic and clinical factors are associated with central pressures in essential hypertensive persons. These relationships should be considered in future studies to improve assessment of BP to reduce cardiovascular risk and mortality.
    Journal of the American Society of Hypertension (JASH) 03/2014; 8(3):152-8.
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    ABSTRACT: Aim: To develop and assess a semiautomated method for segmenting and counting individual renal cysts from mid-slice MR images in patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: A semiautomated method was developed to segment and count individual renal cysts from mid-slice MR images in 241 subjects with ADPKD from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease. For each subject, a mid-slice MR image was selected from each set of coronal T2-weighted MR images covering the entire kidney. The selected mid-slice image was processed with the semiautomated method to segment and count individual renal cysts. The number of cysts from the mid-slice image of each kidney was also measured by manual counting. The level of agreement between the semiautomated and manual cyst counts was compared using intraclass correlation (ICC) and a Bland-Altman plot. Results: Individual renal cysts were successfully segmented using the semiautomated method in all 241 cases. The number of cysts in each kidney measured with the semiautomated and manual counting methods correlated well (ICC = 0.96 for the right or left kidney), with a small average difference (-0.52, with higher semiautomated counts, for the right kidney, and 0.13, with higher manual counts, for the left kidney) in the semiautomated method. However, there was substantial variation in a small number of subjects; 6 of 241 participants (2.5%) had a difference in the total cyst count of more than 15. Conclusion: We have developed a semiautomated method to segment individual renal cysts from mid-slice MR images in ADPKD kidneys as a quantitative indicator of characterization and disease progression of ADPKD. © 2014 S. Karger AG, Basel.
    American Journal of Nephrology 02/2014; 39(3):210-217. · 2.62 Impact Factor
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    ABSTRACT: Objective Elevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single-nucleotide polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)-induced elevations in UA and hyperuricaemia. MethodsA genome-wide association study of HCTZ-induced changes in UA was performed in Caucasian and African American participants from the Pharmacogenomic Evaluation of Antihypertensive Response (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add-on therapy. Replicated regions were followed up through expression and pathway analysis. ResultsFive unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B) and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg/dL were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ-induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the ‘top’ SNP from each gene region, was strongly associated with HCTZ-induced UA elevations (P = 1.79x10-7) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs. Conclusion Several novel gene regions were associated with HCTZ-induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B) and one region was associated with these elevations in Caucasians (GRIN3A).This article is protected by copyright. All rights reserved.
    Journal of Internal Medicine 02/2014; · 6.46 Impact Factor
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    ABSTRACT: While metabolomics has tremendous potential for diagnostic biomarker and therapeutic target discovery, its utility may be diminished by the variability that occurs due to environmental exposures including diet and the influences of the human circadian rhythm. For successful translation of metabolomics findings into the clinical setting, it is necessary to exhaustively define the sources of metabolome variation. To address these issues and to measure the variability of urinary and plasma metabolomes throughout the day, we have undertaken a comprehensive inpatient study in which we have performed non-targeted metabolomics analysis of blood and urine in 26 volunteers (13 healthy subjects with no known disease and 13 healthy subjects with autosomal dominant polycystic kidney disease not taking medication). These individuals were evaluated in a clinical research facility on two separate occasions, over three days, while on a standardized, weight-based diet. Subjects provided pre- and post-prandial blood and urine samples at the same time of day, and all samples were analyzed by "fast lane" LC-MS-based global metabolomics. The largest source of variability in blood and urine metabolomes was attributable to technical issues such as sample preparation and analysis, and less variability was due to biological variables, meals, and time of day. Higher metabolome variability was observed after the morning as compared to the evening meal, yet day-to-day variability was minimal and urine metabolome variability was greater than that of blood. Thus we suggest that blood and urine are suitable biofluids for metabolomics studies, though nontargeted mass spectrometry alone may not offer sufficient precision to reveal subtle changes in the metabolome. Additional targeted analyses may be needed to support the data from nontargeted mass spectrometric analyses. In light of these findings, future metabolomics studies should consider these sources of variability to allow for appropriate metabolomics testing and reliable clinical translation of metabolomics data.
    PLoS ONE 01/2014; 9(1):e86223. · 3.53 Impact Factor
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    ABSTRACT: PURPOSE Clinical trials for Autosomal Dominant Polycystic Kidney Disease (ADPKD) therapies began after the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) showed Total Kidney Volume (TKV) correlates with disease progression, detects change in individuals with normal labs, and can do so after as little as 12 months. However, ADPKD exhibits highly variable presentation, and TKV does not perform well in all cases. A novel physiologically relevant image feature called Cyst-Parenchyma Surface Area (CPSA) was developed to handle atypical cases. CPSA represents cyst surface area in contact with normal kidney parenchyma, excluding the external surface of exophytic cysts. We hypothesize that, while atypical cases with large exophytic cysts are often outliers in TKV correlations, our new feature will correlate better with such cases. METHOD AND MATERIALS Twenty-five cases were selected from the CRISP cohort. Ten each were Rapid Progressors (RP) or Slow Progressors (SP), measured by year 6 eGFR; the remaining five were Atypical Cases (AC) exhibiting large TKV but paradoxically slow progression. Analysis was conducted on T2-weighted SSFSE fat-suppressed data. TKV (via stereology) and expert manual tracings of kidneys and cysts were obtained using Analyze 11. Surfaces were calculated with marching cubes, and the CPSA metric was obtained by removing cyst surface regions within a small tolerance of kidney surface. Both TKV and CPSA metrics were log transformed (yielding lnTKV and lnCPSA) for correlation analysis. RESULTS Our new lnCPSA metric correlated with year 6 eGFR better (R2 = 0.551) than the current standard lnTKV (R2 = 0.386). Conducting the same analysis without atypical cases yielded similar correlations for lnCPSA (R2 = 0.560) and the current standard lnTKV (R2 = 0.553). CONCLUSION lnCPSA correlated better with year 6 eGFR than lnTKV, validating our hypothesis. Excluding atypical cases, lnTKV and lnCPSA correlate equally well with year 6 eGFR indicating that, from a predictive standpoint, lnCPSA has the potential to replace lnTKV. Presently, lnCPSA requires significantly more time investment than lnTKV, however, efforts are underway to acquire lnCPSA data semi-automatically. CLINICAL RELEVANCE/APPLICATION CPSA, a novel ADPKD image feature, correlates with eGFR decline better than TKV for datasets including atypical cases, allowing broader clinical trial inclusion or fewer exclusion criteria.
    Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
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    ABSTRACT: To assess the relationship of the 33 single nucleotide polymorphisms (SNPs) previously associated with fasting glucose in Caucasians in genome-wide association studies (GWAS) with glucose response to antihypertensive drugs shown to increase risk for hyperglycemia and diabetes. Randomized, multicenter clinical trial. A total of 456 Caucasian men and women with uncomplicated hypertension. The Pharmacogenomic Evaluation of Antihypertensives Responses study evaluated blood pressure and glucose response in uncomplicated hypertensive patients randomized to either atenolol or hydrochlorothiazide (HCTZ) monotherapy, followed by combination therapy with both agents. Association of these SNPs with atenolol- or HCTZ-induced glucose response was evaluated in 456 Caucasian patients using linear regression adjusting for age, sex, body mass index, baseline glucose, baseline insulin, and principal component for ancestry. The SNP rs340874 in the 5' region of PROX1 gene was significantly associated with atenolol-induced glucose change (p=0.0013). Participants harboring the C allele of this SNP had greater glucose elevation after approximately 9 weeks of atenolol monotherapy (β = +2.39 mg/dl per C allele), consistent with the direction of effect in fasting glucose GWAS, that showed the C allele is associated with higher fasting glucose. These data suggest that PROX1 SNP rs340874, discovered in fasting glucose GWAS, may also be a pharmacogenetic risk factor for antihypertensive-induced hyperglycemia. β-blockers and thiazides may interact with genetic risk factors to increase risk for dysglycemia and diabetes.
    Pharmacotherapy 10/2013; · 2.31 Impact Factor
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    ABSTRACT: Objective: To evaluate whether kidney and cyst volumes can be accurately estimated based on limited area measurements from magnetic resonance (MR) images of patients with autosomal dominant polycystic kidney disease (ADPKD). Materials and Methods: MR coronal images of 178 ADPKD participants from the Consortium for Radiologic Imaging Studies of ADPKD (CRISP) were analyzed. For each MR image slice, we measured kidney and renal cyst areas using stereology and region-based thresholding methods, respectively. The kidney and cyst 'observed' volumes were calculated by summing up the area measurements of all the slices covering the kidney. To estimate the volume, we selected a coronal mid-slice in each kidney and multiplied its area by the total number of slices ('PANK2' for kidney and 'PANC2' for cyst). We then compared the kidney and cyst volumes predicted from PANK2 and PANC2, respectively, to the corresponding observed volumes, using a linear regression analysis. Results: The kidney volume predicted from PANK2 correlated extremely well with the observed kidney volume (R(2) = 0.994 for the right kidney and 0.991 for the left kidney). The linear regression coefficient multiplier to PANK2 that best fit the kidney volume was 0.637 (95% CI: 0.629-0.644) for the right kidney and 0.624 (95% CI: 0.616-0.633) for the left kidney. The correlation between the cyst volume predicted from PANC2 and the observed cyst volume was also very high (R(2) = 0.984 for the right kidney and 0.967 for the left kidney). The least squares linear regression coefficient for PANC2 was 0.637 (95% CI: 0.624-0.649) for the right kidney and 0.608 (95% CI: 0.591-0.625) for the left kidney. Conclusion: Kidney and cyst volumes can be closely approximated by multiplying the product of the mid-slice area measurement and the total number of slices in the coronal MR images of ADPKD kidneys by 0.61-0.64. This information will help save processing time needed to estimate total kidney and cyst volumes of ADPKD kidneys. © 2013 S. Karger AG, Basel.
    American Journal of Nephrology 10/2013; 38(4):333-341. · 2.62 Impact Factor
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    ABSTRACT: BACKGROUND—The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V 2 -receptor antagonists inhibit cyst growth and slow the decline of kidney function.
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    ABSTRACT: Night blood pressure (BP) predicts patient outcomes. Variables associated with night BP response to antihypertensive agents have not been fully evaluated in essential hypertension. We sought to measure night BP responses to hydrochlorothiazide (HCTZ), atenolol (ATEN), and combined therapy using ambulatory blood pressure (ABP) monitoring in 204 black and 281 white essential hypertensive patients. Initial therapy was randomized; HCTZ and ATEN once daily doses were doubled after 3 weeks and continued for 6 more weeks with the alternate medication added for combined therapy arms. ABP was measured at baseline and after completion of each drug. Night, day, and night/day BP ratio responses (treatment - baseline) were compared in race/sex subgroups. Baseline night systolic BP and diastolic BP, and night/day ratios were greater in blacks than whites (P < 0.01, all comparisons). Night BP responses to ATEN were absent and night/day ratios increased significantly in blacks (P < 0.05). At the end of combined therapy, women, blacks, and those starting with HCTZ as opposed to ATEN had significantly greater night BP responses (P < 0.01). Variables that significantly associated with ATEN response differed from those that associated with HCTZ response and those that associated with night BP response differed from those that associated with day BP response. In summary, after completion of HCTZ and ATEN therapy, women, blacks, and those who started with HCTZ had greater night BP responses. Reduced night BP response and increased night/day BP ratios occured with ATEN in blacks. Given the prognostic significance of night BP, strategies for optimizing night BP antihypertensive therapy should be considered. identifier NCT00246519.
    American Journal of Hypertension 07/2013; · 3.67 Impact Factor
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    ABSTRACT: To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ≈1.1 million single-nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses study (n=228) and the Genetic Epidemiology of Responses to Antihypertensive study (n=196). Polymorphisms associated with blood pressure response at P<10(-5) were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, α replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem study (n=420) and the Genetics of Drug Responsiveness in Essential Hypertension study (n=206), and the combined 4-study meta-analysis P value achieved genome-wide significance (P=3.3×10(-8)). Systolic or diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (>4/4 mm Hg) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem study, and the combined 3-study meta-analysis P value approached genome-wide significance (P=5.5×10(-8)). The findings document clinically important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.
    Hypertension 06/2013; · 6.87 Impact Factor
  • Value in Health 05/2013; 16(3):A181. · 2.19 Impact Factor
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    ABSTRACT: Cosmc is the specific molecular chaperone in the endoplasmic reticulum for T-synthase, a Golgi β3-galactosyltransferase that generates the core 1 O-glycan, Galβ1-3GalNAcα-Ser/Thr, in glycoproteins. Dysfunctional Cosmc results in the formation of inactive T-synthase and consequent expression of the Tn antigen (GalNAcα1-Ser/Thr), which is associated with several human diseases. However, the molecular regulation of expression of Cosmc, which is encoded by a single gene on Xq24, is poorly understood. Here we show that epigenetic silencing of Cosmc through hypermethylation of its promoter leads to loss of Cosmc transcripts in Tn4 cells, an immortalized B cell line from a male patient with a Tn-syndrome-like phenotype. These cells lack T-synthase activity and express the Tn antigen. Treatment of cells with 5-aza-2'-deoxycytidine causes restoration of Cosmc transcripts, restores T-synthase activity, and reduces Tn antigen expression. Bisulfite sequencing shows that CG dinucleotides in the Cosmc core promoter are hypermethylated. Interestingly, several other X-linked genes associated with glycosylation are not silenced in Tn4 cells, and we observed no correlation of a particular DNA methyltransferase to aberrant methylation of Cosmc in these cells. Thus, hypermethylation of the Cosmc promoter in Tn4 cells is relatively specific. Epigenetic silencing of Cosmc provides another mechanism underlying the abnormal expression of the Tn antigen, which may be important in understanding aberrant Tn antigen expression in human diseases, including IgA nephropathy and cancer.
    Journal of Biological Chemistry 04/2013; 288(16):11505. · 4.65 Impact Factor
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    ABSTRACT: BACKGROUND: Strategies for initial drug therapy of hypertension are a thiazide diuretic for all or drug selection based on age/race criteria or on plasma renin activity (PRA). It is uncertain which of these strategies will achieve the highest control rate among patients with stage 1 essential hypertension. We sought to compare control rates among 3 drug selection strategies: (i) thiazide diuretic for all, (ii) thiazide diuretic for all black subjects and white subjects aged ≥50 years and a renin-angiotensin system blocker for white subjects aged <50 years, or (iii) thiazide diuretic for PRA < 0.6ng/ml/h (suppressed PRA) and a renin-angiotensin system blocker for PRA ≥ 0.6ng/ml/h (nonsuppressed PRA). METHODS: Blood pressure responses from the Genetic Epidemiology of Responses to Antihypertensives (GERA) study were used to determine control rates for each of the 3 strategies. In GERA, hypertensive adults were treated with hydrochlorothiazide (n = 286 black subjects and 284 white subjects) or with candesartan (n = 248 black subjects and 278 white subjects). RESULTS: In the overall sample, the PRA strategy was associated with the highest control rate of 69.4% vs. 61.3% with the age/race strategy (P < 0.001) and 53.8% with the thiazide for all strategy (P < 0.001). This was also true in each racial subgroup (in black subjects: 62.1% vs. 55.2% for the other 2 strategies, P = 0.02; in white subjects: 76.3% vs. 67.1% with the age/race strategy (P < 0.001) and 52.4% with the thiazide for all strategy (P < 0.001)). CONCLUSIONS: This exploratory analysis suggests that choice of initial therapy for hypertension using a PRA strategy may be associated with higher control rates than alternative strategies recommended in current guidelines.
    American Journal of Hypertension 04/2013; · 3.67 Impact Factor

Publication Stats

3k Citations
874.61 Total Impact Points


  • 2002–2014
    • Emory University
      • • School of Medicine
      • • Division of Renal Medicine
      Atlanta, Georgia, United States
  • 2013
    • Tufts Medical Center
      Boston, Massachusetts, United States
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 2009–2013
    • University of Florida
      • Department of Pharmacotherapy and Translational Research
      Gainesville, FL, United States
  • 2005–2013
    • University of Texas Health Science Center at Houston
      • Human Genetics Center
      Houston, TX, United States
  • 2001–2011
    • Mayo Foundation for Medical Education and Research
      • • Division of Nephrology and Hypertension
      • • Department of Internal Medicine
      Scottsdale, AZ, United States
  • 2010
    • University of Maryland, Baltimore
      • Department of Medicine
      Baltimore, MD, United States
  • 2008
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
  • 2002–2007
    • Mayo Clinic - Rochester
      • Department of Hospital Internal Medicine
      Rochester, Minnesota, United States
  • 2006
    • University of Alabama
      Tuscaloosa, Alabama, United States
    • University of Washington Seattle
      • Department of Radiology
      Seattle, WA, United States
  • 2004
    • Shire Human Genetic Therapies
      Lexington, Massachusetts, United States
  • 1990–2003
    • University of Colorado
      • • Department of Medicine
      • • Division of Renal Diseases and Hypertension
      Denver, CO, United States