Genome-wide Association Studies Of Hypertension Research Articles

Evaluating cardiovascular disease risk stratification using multiple-polygenic risk scores and pooled cohort equations: insights from a 17-year longitudinal Korean cohort study.

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, caused by a complex interplay of genetic and environmental factors. This study aimed to evaluate the combined efficacy of multi-polygenic risk scores and pooled cohort equations (PCE) for predicting future CVD risks in the Korean population. In this longitudinal study, 7,612 individuals from the Ansan and Ansung cohorts were analyzed over a 17-year follow-up period. The participants were genotyped using the Korea Biobank Array, and quality-controlled genetic data were subjected to imputation analysis. The weighted sum of the PRSs (wPRSsum) was calculated using PRS-CS with summary statistics from myocardial infarction, ischemic stroke, coronary artery disease, and hypertension genome-wide association studies. The recalibrated PCE was used to assess clinical risk, and the participants were stratified into risk groups based on the wPRSsum and PCE. Associations between these risk scores and incident CVD were evaluated using Cox proportional hazards models and Kaplan-Meier analysis. The wPRSsum approach showed a significant association with incident CVD (HR = 1.15, p = 7.49 × 10-5), and the top 20% high-risk genetic group had an HR of 1.50 (p = 5.04 × 10-4). The recalibrated PCE effectively differentiated between the low and high 10-year CVD risk groups, with a marked difference in survival rates. The predictive models constructed using the wPRSsum and PCE demonstrated a slight improvement in prediction accuracy, particularly among males aged <55 years (C-index = 0.640). We demonstrated that while the integration of wPRSsum with PCE did not significantly outperform the PCE-only model (C-index: 0.703 for combined and 0.704 for PCE-only), it provided enhanced stratification of CVD risk. The highest risk group, identified through the combination of high wPRSsum and PCE scores, exhibited an HR of 4.99 for incident CVD (p = 1.45 × 10-15). These findings highlight the potential of integrating genetic risk assessments with traditional clinical tools for effective CVD risk stratification. Although the addition of wPRSsum to the PCE provided a marginal predictive improvement, it proved valuable in identifying high-risk individuals and supporting personalized treatment strategies. This study reinforces the utility of multi-PRS in conjunction with clinical risk assessment tools, paving the way for more tailored approaches for CVD prevention and management in diverse populations.

An update on genome-wide association studies of hypertension

Hypertension is a major global health problem associated with cardiovascular and cerebrovascular diseases. It is well established that blood pressure and hypertension are common complex phenotypes affected by multiple genetic and environmental factors. Contemporary genomic tools make it possible to genotype millions of genetic variants across the human genome in an efficient, reliable, and cost-effective manner, which has transformed hypertension genetics research. International collaborations/consortia have enabled the use of unprecedentedly large sample sizes for gene discovery and replication. Genome-wide association studies have reported more than 60 loci associated with blood pressure or hypertension, most of which were not expected to have any association with these phenotypes. In contrast to linkage and candidate gene studies, the reproducibility of genome-wide association studies is much higher and some results have been verified across different ethnicities. These novel findings have provided potential targets for pharmacotherapy and clues for personalized prevention and treatment of hypertension. Although only a small proportion of blood pressure variation is attributed to the genetic variants identified so far, more variants are likely to be discovered by employing larger sample sizes, studying gene–environment interactions, or by exploring low-frequency or rare variants. Advances in epigenetics, which examines trait variation not caused by differences in DNA sequences, will probably reveal a new and important class of genetic components for hypertension.

Joseph A. Vita, MD, 1956-2014.

Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment. We conducted a genome-wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study is a double-blind, placebo-controlled cross-over study where each subject received amlodipine, bisoprolol,hydrochlorothiazide, and losartan, each as a monotherapy, in a randomized order. Replication analyses were performed in 4 studies with patients of European ancestry (PEAR Study, N=386; GERA I and II Studies, N=196 and N=198; SOPHIA Study, N=372). We identified 3 single-nucleotide polymorphisms within the ACY3 gene that showed associations with bisoprolol response reaching genome-wide significance (P<5x10(-8))however, this could not be replicated in the PEAR Study using atenolol. In addition, 39 single-nucleotide polymorphisms showed P values of 10(-5) to 10(-7). The 20 top-associated single-nucleotide polymorphisms were different for each antihypertensive drug. None of these top single-nucleotide polymorphisms co-localized with the panel of >40 genes identified in genome-wide association studies of hypertension. Replication analyses of GENRES results provided suggestive evidence for a missense variant (rs3814995) in the NPHS1 (nephrin) gene influencing losartan response, and for 2 variants influencing hydrochlorothiazide response, located within or close to the ALDH1A3 (rs3825926) and CLIC5 (rs321329) genes. These data provide some evidence for a link between biology of the glomerular protein nephrin and antihypertensive action of angiotensin receptor antagonists and encourage additional studies on aldehyde dehydrogenase–mediated reactions in antihypertensive drug action.

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HomeCirculationVol. 128, No. 2Circulation Editors’ Picks Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation Editors’ PicksMost Read Articles in Hypertension The Editors The Editors Search for more papers by this author Originally published9 Jul 2013https://doi.org/10.1161/CIRCULATIONAHA.113.004244Circulation. 2013;128:e14–e27National Surveillance Definitions for Hypertension Prevalence and Control Among AdultsSummary—Hypertension is highly prevalent in the US and around the world and its control is suboptimal. A variety of surveillance definitions for hypertension and hypertension control are in frequent use. We found a wide variation of prevalence of hypertension and hypertension control when different definitions, inclusion/exclusion criteria and age adjustment schemes were used by examining 19 published studies using NHANES 2003 to 2004 or more recent cycles. We proposed standard surveillance definitions of hypertension prevalence and control among adults and standard parameters for age-adjustment and population composition to enable meaningful population comparisons and monitoring of trends. We reported the age-standardized prevalence of hypertension and hypertension control rate for NHANES 2007 to 2008 using the recommended definitions.Conclusions—Surveillance definitions of hypertension and hypertension control vary in the literature. We present standard definitions of hypertension prevalence and control among adults and standard parameters for age-adjustment and population composition that will enable meaningful population comparisons and monitoring of trends.1Incidence and Prognosis of Resistant Hypertension in Hypertensive PatientsSummary—The American Heart Association has defined resistant hypertension as blood pressure that remains above goal despite the concurrent use of 3 different antihypertensive medication classes. Despite the recognition that these patients are a potentially higher-risk subset, patients with resistant hypertension have been poorly characterized in the literature. Among a large community cohort of patients with incident hypertension in whom hypertension treatment was begun, we found that 1.9% developed resistant hypertension within a median of 1.5 years from initial treatment, or 0.7 cases per 100 patient-years. In addition, we found that ≈1 in 6 patients taking ≥3 hypertension medication classes for at least 1 month will continue to meet criteria for resistant hypertension over follow-up. Patients with resistant hypertension were almost 50% more likely to experience a cardiovascular event (death or incident myocardial infarction, heart failure, stroke, or chronic kidney disease) over a median 3.8 years of follow-up as patients without resistant hypertension. These findings support the need for greater efforts toward improving outcomes among patients with resistant hypertension.Conclusions—Among patients with incident hypertension in whom treatment was begun, 1 in 50 patients developed resistant hypertension. Patients with resistant hypertension had an increased risk of cardiovascular events, which supports the need for greater efforts toward improving hypertension outcomes in this population.2Body Mass Index and Risk of Incident Hypertension Over the Life Course: The Johns Hopkins Precursors StudySummary—In this long-term prospective cohort study, we studied the association of body mass index with risk of developing hypertension from young adulthood into middle age and through late life. Repeated assessments of body mass index, blood pressure, and risk factors for developing hypertension over the life course enabled us to examine the influence of lifestyle and behavior in young adult life through middle age on health later in life. Obesity in young adulthood conferred a 3-fold risk of hypertension after 46 years of follow-up, even after we accounted for change in lifestyle factors over the life course. Men who were of normal weight in early adulthood but who became overweight or obese in midlife were twice as likely to develop hypertension as men who maintained a normal weight. Loss of weight between young adulthood and middle age conferred no additional risk. Rate of change of body mass index over the life course was an independent predictor of risk of hypertension, independent of the level of body mass index, cigarette smoking, alcohol intake, physical activity, and coffee drinking. Although the data were observational, the temporal relationship established by the long follow-up and repeated assessment of both body weight and blood pressure provided strong evidence for the association between body mass index and hypertension. This study showed that increase of weight at any time in the life course increased the risk of developing hypertension after adjustment for other risk factors.Conclusions—Our findings underscore the importance of higher weight and weight gain in increasing the risk of hypertension from young adulthood through middle age and into late life.3Trends in Blood Pressure and Hypertension Detection, Treatment, and Control 1980 to 2009: The Minnesota Heart SurveySummary—Hypertension is common in the United States, afflicting more than 76 million adults aged ≥25 years. Treatment is well established, which reduces the cardiovascular complications of hypertension, particularly stroke. In a large metropolitan area, hypertension detection and control has been a goal for many years. The results of this sustained focus are shown in the present report, in which ≈70% of hypertensive subjects in the adult population were aware of their hypertension, were treated, and had their blood pressure controlled to recommended levels. This may in part be because of higher rates of insurance, education, and income in the state of Minnesota; however, it also points to quality healthcare systems that have targeted high blood pressure as an important goal for cardiovascular disease prevention. With this combination of factors, it is possible to have high levels of blood pressure control and resulting declines in stroke deaths.Conclusions—The rate of hypertension detection and control in this community is among the highest observed in a US population and already exceeds Healthy People 2020 goals.4Hypertension Control Among Patients Followed by CardiologistsSummary—Hypertension is one of the most prevalent modifiable risk factors for cardiovascular disease. Only half of the patients with hypertension in the United States achieve adequate blood pressure control. Nearly one-third of patients followed routinely by cardiologists at a large academic center did not reach blood pressure targets. Blood pressure is often not addressed, even when elevated, at clinic visits. Significant physician variability in hypertension control performance exists, suggesting room for quality improvement.Conclusions—Up to one-third of patients followed routinely by cardiologists in clinic have suboptimally controlled BP, with wide variability in performance across individual clinicians. This variability, alongside evidence that elevated BP is often not acted on during clinic visits, demonstrates a potential opportunity for quality improvement.5Simultaneous Control of Diabetes Mellitus, Hypertension, and Hyperlipidemia in 2 Health SystemsSummary—Individuals with diabetes mellitus must manage multiple cardiovascular risk factors, such as glucose, blood pressure, and cholesterol levels, at the same time. Previous studies have found low levels of simultaneous control of these factors, but have been cross-sectional and thus unable to follow risk factor changes over time. In these 2 health systems over a median follow-up of over 4 years, simultaneous control of diabetes mellitus, hypertension, and hyperlipidemia was uncommon and generally transient. Small changes in the treatment targets had large effects on the proportion of individuals achieving simultaneous control of glucose, blood pressure, and cholesterol levels.Conclusions—Simultaneous control of diabetes mellitus, hypertension, and hyperlipidemia was uncommon and generally transient. Less stringent goals had a relatively large effect on the proportion achieving simultaneous control. Individuals who simultaneously achieve multiple treatment goals may provide insight into self-care strategies for individuals with comorbid health conditions.6Integrated Computational and Experimental Analysis of the Neuroendocrine Transcriptome in Genetic Hypertension Identifies Novel Control Points for the Cardiometabolic SyndromeSummary—Essential hypertension is a common complex disease with a substantial yet incompletely understood genetic basis. Hypertension often clusters with metabolic abnormalities, which themselves also have genetic underpinnings, in a collection of disorders known as the cardiometabolic syndrome. It is unclear if these phenotypes share common genetic contributors. We developed a novel, integrative method (combining animal models, transcriptomics, bioinformatics, molecular biology, and trait-extreme phenotypes) to identify candidate genes for the cardiometabolic syndrome. Uniquely, we focused on transcription factors as “master switches” because functional changes in them are likely to be pleiotropic and, therefore, might provide a unifying genetic mechanism for multiple traits. A transcriptomic, bioinformatic, and molecular biological analysis of a murine model of genetic hypertension led us to hypothesize that genetic variation at the HOXA3,SRY, and YY1 loci might predict blood pressure and other cardiometabolic syndrome traits in humans. Genetic variants for each locus were significantly associated in a human population blood pressure extreme sample with the most extensive associations for YY1 single nucleotide polymorphism rs11625658 on systolic blood pressure, diastolic blood pressure, body mass index, and fasting glucose. Meta-analysis extended the YY1 results into 2 additional large population samples with significant effects preserved on diastolic blood pressure, body mass index, and fasting glucose. The results suggest shared genetic contributors for multiple phenotypes of the cardiometabolic syndrome and specifically point to transcription factor YY1 as a potential candidate gene “master switch.”Conclusions—The results outline an innovative, systematic approach to the genetic pathogenesis of complex cardiovascular disease traits and point to transcription factor YY1 as a potential candidate gene involved in essential hypertension and the cardiometabolic syndrome.7Oxysterol-Induced Soluble Endoglin Release and Its Involvement in HypertensionSummary—Preeclampsia is one of the most severe complications of pregnancy. Characterized by systemic hypertension, proteinuria, and edema in the third trimester of pregnancy, preeclampsia is responsible for the highest rates of morbidity and mortality for both pregnant women and neonates in the developed world. Treatment of hypertension in preeclampsia is especially needed because of the absence of effective therapies except for the delivery of the baby and placenta. Hypoxia in the placenta is considered a key event in the pathogenesis of preeclampsia, whereas soluble endoglin (sEng) is a prognostic marker and plays a pathogenic role. In this article, we report that the hypoxia-dependent cholesterol derivatives oxysterols, via the liver X receptors, are able to increase sEng levels in vitro and in vivo by a mechanism involving activation of matrix metalloproteinase-14. Interestingly, mice treated with oxysterols or liver X receptor agonists underwent an increase in plasmatic sEng levels and an augmentation of arterial pressure. In addition, administration of an endoglin fragment containing the matrix metalloproteinase-14 cleavage site prevented the oxysterol-dependent increase in arterial pressure and sEng levels in mice. These data reveal for the first time the involvement of the liver X receptor pathway in sEng release and its contribution to vascular homeostasis. They also suggest that administration of endoglin peptides in preeclamptic women might serve to counteract the pathogenic effect of the elevated circulating sEng. Further studies are needed to confirm the beneficial effect of these peptides in experimental models of preeclampsia and in clinical trials.Conclusions—These studies provide a clue to the involvement of the LXR pathway in sEng release and its pathogenic role in vascular disorders such as preeclampsia.8Childhood Physical, Environmental, and Genetic Predictors of Adult Hypertension: The Cardiovascular Risk in Young Finns StudySummary—Hypertension is a major cardiovascular risk factor influenced by genetic propensity and various environmental stimuli. The present longitudinal study aimed to examine the best combination of childhood physical and environmental factors to predict adult hypertension. Furthermore, we examined whether newly identified genetic variants for blood pressure enhance the prediction of adult hypertension. In this longitudinal study, 2625 individuals who participated in the Cardiovascular Risk in Young Finns Study in the baseline year 1980 (when 3–18 years of age) were followed up 21 to 27 years (then 24–45 years of age). Youth risk factors independently associated with adult hypertension were the individual’s own systolic and diastolic blood pressures, parental hypertension, youth overweight/obesity, low parental occupational status, and high genetic risk score. We also found that both parental hypertension history and the genetic risk score enhanced the prediction of adult hypertension when added separately to the prediction model compared with the model consisting of only childhood blood pressure. Furthermore, the prediction power was significantly stronger when both of these variables were added to the same model. From these findings, it seems that the genetic risk score and parental hypertension provide complementary information. Present data suggest that a multifactorial approach, if implemented, could improve the identification of children with a high risk of adult hypertension. Moreover, these data demonstrate that the prediction of adult hypertension was enhanced when the novel genetic variants were taken into account. In terms of the care of individual patients with elevated blood pressure, our data emphasize the importance of overweight as a potential modifiable risk factor.Conclusions—Prediction of adult hypertension was enhanced by taking into account known physical and environmental childhood risk factors, family history of hypertension, and novel genetic variants. A multifactorial approach may be useful in identifying children at high risk for adult hypertension.9Exosomes Mediate the Cytoprotective Action of Mesenchymal Stromal Cells on Hypoxia-Induced Pulmonary HypertensionSummary—Pulmonary arterial hypertension remains without cure despite significant progress in our understanding of its pathophysiology. Given the complex molecular and cellular pathways underlying the development of pulmonary arterial hypertension, therapies aimed at multiple pathways and cellular targets may prove to be more efficacious. Stem cell–based therapies hold such a promise because they can simultaneously target diverse signaling pathways and have long-lasting effects. Accumulating studies support an important cytoprotective, anti-inflammatory role for mesenchymal stem cells with demonstrated efficacy against pulmonary hypertension in animal models of disease. We previously reported both prevention and reversal of severe pulmonary hypertension and right heart failure in a mouse model of hypoxia-induced pulmonary hypertension and have postulated a paracrine mode of mesenchymal stem cell protective functions. In this report, we show that mesenchymal stem cells secrete microvesicles (exosomes), which are the vectors of their action, being both necessary and sufficient to confer cytoprotection on the lung vasculature. We show that, potentially through epigenetic mechanisms involving microRNA signaling, mesenchymal stromal cell exosome preparations can have long-lasting therapeutic effects on pulmonary hypertension. These findings may lead to the development of alternative strategies in the field of stem cell–based therapies, at least for certain lung diseases, in that delivery of in vitro purified exosomes could substitute for the delivery of intact cells. Exosome treatment, in addition to its enhanced practicality in terms of storage and administration, does not carry the danger of oncogenic potential of donor cells, an important consideration in all stem cell–based therapies.Conclusions—This study indicates that MEX exert a pleiotropic protective effect on the lung and inhibit pulmonary hypertension through suppression of hyperproliferative pathways, including STAT3-mediated signaling induced by hypoxia.10Gremlin Plays a Key Role in the Pathogenesis of Pulmonary HypertensionSummary—Pulmonary hypertension is a disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance. It occurs commonly in chronic hypoxic lung diseases and leads to increased morbidity and mortality. A major breakthrough in our understanding of pulmonary hypertension was achieved with the identification of heterozygous mutations in the bone morphogenetic receptor type 2 as the cause of the rare heritable form of pulmonary arterial hypertension. It was subsequently found that bone morphogenetic protein signaling was reduced in many other common forms of pulmonary hypertension, including hypoxic pulmonary hypertension. However, the mechanism underlying this reduction has not been clearly elucidated. Here, we report that gremlin, a secreted extracellular antagonist of bone morphogenetic proteins, was expressed more highly in pulmonary endothelial cells in vitro than in the endothelium of other organs and was markedly increased in response to hypoxia. We show that gremlin was increased selectively in the hypoxic mouse lung and that genetically manipulated mice with reduced gremlin expression showed attenuation of hypoxic pulmonary vascular remodeling and reduced pulmonary vascular resistance. Furthermore, we found that gremlin was increased in the small intrapulmonary vessels of lungs explanted from patients with pulmonary arterial hypertension. Thus, we have identified a novel mechanism contributing to the development of pulmonary hypertension, which, because it is an extracellular protein, represents an attractive potential therapeutic target.Conclusions—These findings demonstrate a central role for increased gremlin in hypoxia-induced pulmonary vascular remodeling and the increased pulmonary vascular resistance in hypoxic pulmonary hypertension. High levels of basal gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMP type 2 receptor in pulmonary arterial hypertension.11Percutaneous Transluminal Pulmonary Angioplasty for the Treatment of Chronic Thromboembolic Pulmonary HypertensionSummary—Surgical pulmonary endarterectomy is the most powerful interventional therapeutic strategy for chronic thromboembolic pulmonary hypertension. Limited studies have shown that percutaneous transluminal pulmonary angioplasty can improve subjective symptoms and pulmonary hemodynamics of the patients with chronic thromboembolic pulmonary hypertension. This study suggests that percutaneous transluminal pulmonary angioplasty can treat the distal narrow lesions that cannot be reached by pulmonary endarterectomy with tolerable complications. Percutaneous transluminal pulmonary angioplasty may be a promising therapeutic strategy for the treatment of chronic thromboembolic pulmonary hypertension.Conclusions—percutaneous transluminal pulmonary angioplasty (PTPA) improved subjective symptoms and objective variables, including pulmonary hemodynamics. PTPA may be a promising therapeutic strategy for the treatment of chronic thromboembolic pulmonary hypertension.12Histone Deacetylation Inhibition in Pulmonary Hypertension: Therapeutic Potential of Valproic Acid and Suberoylanilide Hydroxamic AcidSummary—Histone deacetylases (HDACs) have emerged as key targets to reverse aberrant epigenetic changes associated with cancer and autoimmune disease, and HDAC inhibitors show promise as anticancer and anti-inflammatory agents. We examined the pattern of HDAC expression in lungs from patients with pulmonary arterial hypertension and investigated the effect of HDAC inhibition on the reversal of pulmonary hypertension in a rat model. Coupled to this, we explored the effects on mechanisms (proliferation, apoptosis, and inflammation) relevant to the pathology of pulmonary arterial hypertension in human and animal cell model systems. Our results demonstrate that increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of the HDAC inhibitors valproic acid and suberoylanilide hydroxamic acid in models of pulmonary arterial hypertension supports a therapeutic strategy based on HDAC inhibition in pulmonary arterial hypertension.Conclusions—Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors, valproic acid, and suberoylanilide hydroxamic acid, in models of pulmonary arterial hypertension supports a therapeutic strategy based on HDAC inhibition in pulmonary arterial hypertension.13Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives: Results From the Pharmacogenomic Evaluation of Antihypertensive Responses StudySummary—Hypertension is the most common chronic disease for which medications are prescribed, and controlling blood pressure (BP) is important in reducing long-term mortality and morbidity. Response rates to monotherapy with any given antihypertensive drug are only ≈50%, and those who fail to response to 1 drug class are more likely to respond to a drug with an alternate mechanism. Current selection of initial antihypertensive therapy is essentially by trial and error. The difficulty in determining the most appropriate antihypertensive drug for a specific patient likely contributes to the fact that less than half of the hypertensive patients in the United States (and worldwide) currently have their BP controlled. Pharmacogenomics offers the clinical promise of individualization of therapy based on a person’s genetic makeup. Through genome-wide association studies, 39 genetic polymorphisms have been associated with BP or hypertension in white individuals to date. However, whether these genetic markers are also associated with BP response to commonly used antihypertensives is unclear. In this study, we assessed the association of these genetic markers with BP responses after 9 weeks of monotherapy in white patients with essential hypertension who were randomized to a β-blocker (atenolol) or a thiazide diuretic (hydrochlorothiazide) in a randomized clinical trial. Six of these markers were nominally associated with BP response to either atenolol or hydrochlorothiazide when evaluated individually. However, these markers were much more strongly associated with the BP response to the antihypertensives when considered collectively. These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring.Conclusions—These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring.14Trends in Antihypertensive Medication Use and Blood Pressure Control Among United States Adults With Hypertension: The National Health and Nutrition Examination Survey, 2001 to 2010Summary—Trends in antihypertensive medication use and blood pressure control for US adults were examined at a population level during the decade 2001 to 2010 with the use of National Health and Nutrition Examination Survey data. The decade showed significant increases in the percentage of people with hypertension who are treated with medication (from 64% to 77%). Blood pressure control rates have improved from 29% to 47%, and treated control rates have improved from 45% to 60%. Consistent with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines, significantly more patients with hypertension are on combination therapy now than a decade ago. In addition, the current data indicate that those receiving antihypertensive polytherapy were significantly more likely to meet their blood pressure goals than those who were on monotherapy regimens. Increased usage of multiple antihypertensive drugs has made substantial contributions to the overall control of blood pressure in the general population. This underscores the important role of antihypertensive polytherapy for achieving blood pressure control previously demonstrated in clinical drug trials. Patients whose hypertension is not controlled with monotherapy could benefit from more effective polytherapy regimens. The data also identify key population subgroups that apparently continue to lag behind. Younger adults and Mexican-American people appeared to be undertreated, as did those without health insurance. Older adults and non-Hispanic black people were more likely to be treated, but their hypertension was less likely to be controlled once they were on treatment. The same was true for those with chronic kidney disease and diabetes mellitus. Continued efforts are needed to close these gaps in treatment and to control rates and maximize the public health and clinical benefits of hypertensive therapy.Conclusions—Antihypertensive medication use and blood pressure control among US adults with hypertension significantly increased over the past 10 years. Combination therapy regimens can facilitate achievement of blood pressure goals.15Refined Balloon Pulmonary Angioplasty for Inoperable Patients with Chronic Thromboembolic Pulmonary HypertensionSummary—The efficacy of balloon pulmonary angioplasty (BPA) was previously reported in a small series of inoperable patients with chronic thromboembolic pulmonary hypertension, who have a poor prognosis. However, BPA has not been widely adopted owing to relatively less improvement and higher mortality compared with surgical pulmonary endarterectomy. We have refined the procedure of BPA by using intravascular ultrasound to provide more accurate estimates of the diameters of target pulmonary arteries. We performed BPA in a staged fashion over multiple procedures to reduce the risk of pulmonary reperfusion injury while still achieving an effective therapeutic result. Although there is a learning curve in performing this procedure, our refined approach to BPA may be a treatment option for patients with inoperable chronic thromboembolic pulmonary hypertension.Conclusions—Our refined BPA procedure improves clinical status and hemodynamics of inoperable patients with chronic thromboembolic pulmonary hypertension, with a low mortality. A refined BPA procedure could be considered as a therapeutic approach for patients with inoperable chronic thromboembolic pulmonary hypertension.16Prognostic Value of Right Ventricular Longitudinal Peak Systolic Strain in Patients With Pulmonary HypertensionSummary—Right ventricular (RV) function is an important prognostic factor in patients with pulmonary hypertension. Therefore, timely and accurate detection of RV dysfunction is of clinical importance. However, RV function assessment is challenging with conventional 2-dimensional echocardiography. The advent of 2-dimensional speckle-tracking echocardiography has permitted to accurately assess active myocardial contraction and overcome the limitations of conventional 2-dimensional parameters of RV function. In 150 patients with pulmonary hypertension of different causes, RV longitudinal strain assessed with 2-dimensional speckle tracking was independently associated with survival, after adjusting for age, New York Heart Association functional class, left ventricular ejection fraction, and systolic pulmonary arterial pressure. Patients with pulmonary hypertension and RV longitudinal strain greater than or equal to −19% had more than 3 fold risk of death compared with their counterparts with RV longitudinal strain less than −19%. RV longitudinal strain may be a valuable parameter for risk stratification of patients with pulmonary hypertension. Future studies are needed to confirm these results in the pulmonary hypertension subgroups.Conclusions—In patients with pulmonary hypertension, RV longitudinal peak systolic strain (LPSS) is significantly associated with all-cause mortality. RV LPSS may be a valuable parameter for risk stratification of these patients. Future studies are needed to confirm these results in the pulmonary hypertension subgroups.17Association Between Sodium Intake and Change in Uric Acid, Urine Albumin Excretion, and the Risk of Developing HypertensionSummary—Although a short-term sodium load does not usually raise blood pressure, a long-term high sodium intake is associated with increases in blood pressure. The reasons for this are unclear. Our study suggests that a high-sodium diet over the long term may lead to endothelial dysfunction and vascular damage, generating a biological state in which continuance of the high-sodium diet may produce hypertension (a sodium amplification loop).Conclusions—Over time, higher sodium intake is associated with increases in serum uric acid (SUA) and urine albumin excretion (UAE). Among individuals with higher SUA and urine UAE

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HomeCirculationVol. 127, No. 22Circulation Editors’ Picks Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation Editors’ PicksMost Read Articles in Cardiovascular Genetics The Editors The Editors Search for more papers by this author Originally published4 Jun 2013https://doi.org/10.1161/CIRCULATIONAHA.113.003502Circulation. 2013;127:e646–e657Ca2+/Calmodulin-Dependent Protein Kinase II–Based Regulation of Voltage-Gated Na+ Channel in Cardiac DiseaseSummary—Defects in ion channel activity have been linked to increased susceptibility to cardiac arrhythmia in congenital and acquired forms of heart disease. Over the past 20 years, gene variants in ion channels have been discovered that increase arrhythmia susceptibility by altering ion channel biophysics. Although these studies have generated insight into molecular mechanisms underlying human disease and have advanced our understanding of ion channel function, the mechanistic link between specific molecular defects and arrhythmias remains elusive in many cases. Membrane protein posttranslational modifications are an essential mechanism for regulating cell function in heart. Importantly, alterations in posttranslational modification of ion channel proteins have now been identified in heart disease. Our findings demonstrate that human variants that modify a validated phosphorylation motif for Ca2+/calmodulin-dependent kinase in the cardiac sodium channel confer a proarrhythmic cellular phenotype by mimicking the Ca2+/calmodulin-dependent protein kinase II–phosphorylated channel. Moreover, we provide data that a similar defect in posttranslational modification of Nav1.5 is present in a large-animal model of ischemic heart disease and human heart failure. We propose that the A572D and Q573E human arrhythmia variants belong to an emerging class of atypical ion channel mutations that confer arrhythmia susceptibility by affecting posttranslational modification. These studies add to mounting evidence that defects in local signaling and protein posttranslational modification help define disease phenotypes associated with a broad range of cardiac arrhythmia syndromes.Conclusions—We identify the mechanism for 2 human arrhythmia variants that affect Nav1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Nav1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Nav1.5 in congenital and acquired cardiac disease.1Modeling Supravalvular Aortic Stenosis Syndrome With Human Induced Pluripotent Stem CellsSummary—Currently, treatment of proliferation-based pathologies relies on drugs like rapamycin that may have a broad impact on patient physiology. Such treatment risks unintended effects in targeted and off-target cell types, potentially initiating new dysfunction. To effectively treat patients, it is critical to root out the mechanisms of proliferative diseases so that treatments can be developed to specifically attack the existing pathology without risking further complication. This study shows for the first time that the hyperproliferation in smooth muscle cells (SMCs) that causes supravalvular aortic stenosis (SVAS) syndrome is, in turn, accompanied by a marked decrease in actin filament bundle formation and an increase in migration. More important, we have shown that treatment with exogenous elastin monomers rescues the actin filament bundle formation in supravalvular aortic stenosis cells. With these results taken together, it can be hypothesized that a switch from a contractile to a proliferative phenotype in smooth muscle cells is caused by an elastin deficiency. Induced, pluripotent stem cell models of proliferative diseases such as the one used here should prove valuable in the search for candidate pathways and pharmaceutical agents. As a result, clinical interventions focusing on the enhancement of smooth muscle cell actin filament bundle formation and/or elastin production of affected vessel walls promise higher efficacy and lower risk to the patient than current treatments. There are several avenues through which such interventions can be realized, but given a candidate drug specific to actin filament bundle formation and/or elastin production, the goal of curing deadly proliferation-based smooth muscle cell diseases appears to be close at hand.Conclusions—SVAS iPSC-SMCs recapitulate key pathological features of patients with SVAS and may provide a promising strategy to study disease mechanisms and to develop novel therapies.2High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With HeterotaxySummary—Heterotaxy patients have some of the most complex congenital heart disease. Although surgical advances now allow palliation and repair of even the most complex structural heart defects, the clinical management of heterotaxy patients remains challenging. Heterotaxy patients have unexplained higher morbidity and mortality, often with long clinical courses and increased respiratory complications. Although this higher morbidity and mortality is usually attributed to the heart disease, the underlying cause remains largely unknown. Because motile cilia are required both for left-right patterning and for mucociliary clearance in the airway, we hypothesize that heterotaxy patients may have risk for airway clearance defects that overlap with that of primary ciliary dyskinesia (PCD). PCD is a heritable disorder characterized by both laterality defects and also sinopulmonary disease arising from airway cilia motility defects that compromise mucus clearance. Using 2 simple tests normally used for PCD assessment, we showed that 42% of heterotaxy patients with CHD have airway ciliary dysfunction (CD). This included the observation of abnormal cilia motility by videomicroscopy of nasal scrapes, and also low nasal nitric oxide (NO) levels similar to the low NO levels seen with PCD. Furthermore, sequencing analysis showed that heterotaxy patients with CD are significantly enriched for novel coding variants in genes known to cause PCD. Together these findings suggest that CHD patients with heterotaxy may benefit from preoperative screening for CD, with pulmonary therapy to be provided prophylactically to enhance airway clearance in patients with CD. Such a change in the standard of care may improve outcome and reduce morbidity/mortality in CHD patients with heterotaxy.Conclusions—Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD.3Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events: Implications for Mutation-Specific Response to β-Blocker Therapy in Type 1 Long-QT SyndromeSummary—Long-QT syndrome type 1 (LQT1) arises from a decrease in repolarizing potassium current resulting from mutations in the KCNQ1 gene. The main trigger for cardiac arrhythmic events in patients with LQT1 is activation of β1-adrenergic receptors during exercise. Despite the observed reduction in the risk of cardiac events with β-blocker therapy among LQT1 patients, there is still a considerable cardiac residual event rate, suggesting that subgroups of LQT1 patients have differential response to β-blockers. The present study of 860 patients from the International LQTS Registry shows that the presence of missense mutations in distinct functional domains of the KCNQ1 protein, the S2-S3 and S4-S5 cytoplasmic loops (C loops), is associated with a significantly increased risk for life-threatening cardiac events compared with other mutations. Furthermore, patients with missense C-loop mutations gained greater benefit when treated with β-blockers compared with patients having other KCNQ1 mutations independently of clinical risk factors, demonstrating that LQT1 patients have differential response to β-blocker therapy depending on mutation location. Both a decrease in basal function and altered adrenergic regulation of the IKs channel underlie the increased cardiac risk and response to β-blockers in this subgroup of patients. Patients with missense C-loop mutations should be considered a high-risk group of patients but with a pronounced response to β-blockers.Conclusions—Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.4A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)Summary—Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Much of this variability is explained by common reduced-function variants in 2 genes, CYP2C9 and VKORC1. Pharmacogenetic (PG) guidance of warfarin initiation could improve dosing efficiency and safety, but evidence from clinical trials is still meager. To increase understanding of the potential role of PG guidance in warfarin dose initiation and to build on an earlier study (CoumaGen-I), we designed a second 3-month study (CoumaGen-II) with 2 parts: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step PG algorithm (PG-2) (N=504) and (2) a clinical effectiveness comparison of PG-guided with standard dosing in a parallel (nonrandomized) control group (N=1866) within the Intermountain Healthcare system. A rapid method provided same-day CYP2C9 and VKORC1 genotyping. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for the primary end point of percentage of out-of-range international normalized ratios at 1 month and at 3 months and for percentage of time in therapeutic range at 3 months, suggesting that the simpler 1-step PG algorithm may be preferable for clinical application. However, PG guidance (combined cohort) was substantially superior to standard dosing in the parallel control group for these end points (all P<0.001). PG guidance also reduced percentage of international normalized ratios ≥4 and ≤1.5 and serious adverse events. These clinical effectiveness findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-stage PG algorithm provided equivalent results and may be preferable for clinical application.Conclusions—These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application.5Genome-Wide Association Study for Coronary Artery Calcification With Follow-Up in Myocardial InfarctionSummary—Coronary artery calcification, detected by computed tomography, is a noninvasive measure of coronary atherosclerosis and an independent predictor of myocardial infarction. We conducted a genome-wide association study with a discovery sample of nearly 10 000 participants of European original and a replication sample of >6000 participants of European origin. We report strong evidence for genetic variants in 9p21 near the CDKN2B and CDKN2A genes and in 6p24 within the PHACTR1 gene. Additionally, we found evidence for concordance of single-nucleotide polymorphism associations with both coronary artery calcification and some but not all other loci known to be associated with myocardial infarction, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene). These findings reinforce the important role of variation at multiple genes in the pathogenesis of coronary atherosclerosis. Although the functional mechanism of many of these genetic associations remains to be determined, our comprehensive study lays the groundwork for future studies to determine the role of several genes in treatment, prediction, and prevention of coronary atherosclerosis and resulting myocardial infarction and other clinically apparent forms of coronary heart disease.Conclusions—SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with coronary artery calcification and myocardial infarction, and there are suggestive associations with both coronary artery calcification and myocardial infarction of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.6Distinct Epigenomic Features in End-Stage Failing Human HeartsSummary—Molecular research in heart failure points to the hypothesis that a generic cardiac genomic response is activated in the failing myocardium regardless of the original inciting cause. This cardiac genomic stress response is typified by the re-expression of fetal genes, upregulation of fibrosis-related genes, and others. It may also reflect unifying features of a failed myocardium such as fibrosis, altered energy use, vascular rarefaction, cell death, and altered contractility, all of which are features found in the failing myocardium again regardless of the inciting cause. The epigenome refers to “marks” on the genome, including DNA methylation and histone modification. The epigenome regulates the expression of underlying genes, and recent evidence suggests that part of the epigenome may be altered by diet and the environment. In our research, we have examined the genome-wide landscape of the epigenome of healthy and end-stage cardiomyopathic human hearts. We have determined that distinct epigenomic patterns exist in important DNA elements of the human cardiac genome in the failing myocardium. Individually, sites of differential epigenomic patterns may control the expression of specific genes with critical functions in the progression of heart failure. However whether the altered epigenome is simply a consequence in end-stage disease or actually contributes to disease progression remains to be determined. This work now opens an important new avenue of research because the epigenome may represent a drug discovery target for novel heart failure therapy.Conclusions—Distinct epigenomic patterns exist in important DNA elements of the cardiac genome in human end-stage cardiomyopathy. The epigenome may control the expression of local or distal genes with critical functions in myocardial stress response. If epigenomic patterns track with disease progression, assays for the epigenome may be useful for assessing prognosis in heart failure. Further studies are needed to determine whether and how the epigenome contributes to the development of cardiomyopathy.7Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Pathogenic Desmosome Mutations in Index-Patients Predict Outcome of Family Screening: Dutch Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Genotype-Phenotype Follow-Up StudySummary—Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) usually shows an autosomal dominant inheritance pattern, with incomplete penetrance and variable clinical expression. Classically, index patients present between the second and fourth decades of life with right ventricular tachycardia. However, sudden death can occur at adolescence, whereas mutation carriers may remain without signs and symptoms until old age. Previous genotype-phenotype studies involved mainly overt index patients. Data on mainly asymptomatic relatives were scarce. To gain insight into the full spectrum of the disease, 149 ARVD/C index patients and 302 of their relatives were genotypically and phenotypically characterized. DNA analysis comprised sequencing of the desmosomal genes PKP2, DSC2, DSG2, DSP, and JUP and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were identified in 87 of 149 ARVD/C index patients (58%), mainly truncating PKP2 mutations with multiple mutations in 2% of cases. Performing multiplex ligation-dependent probe amplification also appeared to be important; its 2% mutational yield was comparable to the sequencing of DSG2 or DSC2. Identification of mutations in index patients had major consequences for the concurrent relatives. Of the 57 of 282 initially asymptomatic relatives (20%) who showed any sign of ARVD/C, 84% carried a mutation. These 48 mutation carriers had earlier onset of disease signs and symptoms than noncarriers but also a markedly increased risk of arrhythmias and 6-fold risk of ARVD/C diagnosis. Familial cases were identified in 45% of families screened. Prolonged terminal activation duration seemed to be an early marker of ARVD/C; it was observed more often than negative T waves in V1 to V3, especially in mutation-carrying relatives <20 years of age.Conclusions—Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.8Cardiac Structural and Sarcomere Genes Associated With Cardiomyopathy Exhibit Marked Intolerance of Genetic VariationSummary—Recent studies have revealed a high degree of genetic variation in human populations, some of which would be predicted to cause loss of function of the genes encoded. These studies provide a challenge to the careful interpretation of the results from genetic testing and raise concerns about our ability to distinguish between benign and pathogenic variants. We analyzed data from >5000 participants in the National Heart, Lung, and Blood Institute Exome Sequencing Project. To study tolerance of genetic variation in different genes, we derived rates of genetic variation within (1) genes without Mendelian disease association, (2) genes associated with Mendelian disease, and (3) genes associated with inherited cardiomyopathies. We found that genes associated with Mendelian diseases exhibit markedly lower rates of genetic variation. This was even more marked for genes associated with cardiomyopathy. Nonsense variants were extremely rare in most cardiomyopathy genes, suggesting that when such variants are found, they are likely to be pathogenic. We also compared known pathogenic variants in MYH7, MYBPC3, and TNNT2 with those in the population data. We found neither rarity nor nucleotide evolutionary conservation helpful in distinguishing benign from pathogenic variants in these genes. However, the exon distribution of pathogenic and benign variants in MYH7 and TNNT2 was significantly different. Rates of pathogenic variants in population data were higher than would be anticipated, suggesting that a single gene/variant model may not be sufficient to explain many cases of inherited cardiomyopathy. These findings highlight the continued importance of cosegregation and other supporting data in determining variant pathogenicity.Conclusions—Genes associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants with strong evidence for pathogenicity suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the single gene causality model.9TGFβRIIb Mutations Trigger Aortic Aneurysm Pathogenesis by Altering Transforming Growth Factor β2 Signal TransductionSummary—Thoracic aortic aneurysm (TAA) is a common progressive disorder involving gradual dilation of the ascending and/or descending thoracic aorta that is clinically unsuspected until potentially lethal aortic dissection or rupture. TAA is often part of a complex connective tissue syndrome such as Marfan, Loeys-Dietz, and Ehlers-Danlos syndromes, but nonsyndromic TAAs also occur as genetically triggered inherited disorders. Genetically triggered TAAs account for ≈20% of TAAs. Prior analyses of familial TAA in research cohorts have identified disease-causing mutations in genes encoding myosin heavy chain 11 (MYH11), α-smooth muscle actin (ACTA2), and transforming growth β receptors I and II (TGFβRI and TGFβRII). Mutational analyses of these 4 genes were now performed in a cohort of patients routinely presenting to cardiovascular clinics and suspected to have genetically mediated nonsyndromic aortic disease. Nine percent of patients had a mutation in one of the 4 genes analyzed. Three percent of patients had mutations in ACTA2, 3% in MYH11, and 3% in TGFβRII. TGFβRII mutations included ones identified in an alternatively spliced TGFβRII exon, exon 1a, that encodes the TGFβRIIb isoform. These TGFβRII exon 1a mutations occurred in 2% of these TAA patients and suggest that altered TGFβ2 signaling contributes to aneurysm pathogenesis. This study’s findings support the potential value to cardiovascular practitioners of genetic testing with a multigene aortic disease gene panel in the diagnostic workup of TAA patients.Conclusions—We propose that TGFβRIIb expression is a regulatory mechanism for TGFβ2 signal transduction. Dysregulation of the TGFβ2 signaling pathway, as a consequence of TGFβRIIb mutations, results in aortic aneurysm pathogenesis.10Impact of Ancestry and Common Genetic Variants on QT Interval in African AmericansSummary—Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of ventricular fibrillation and sudden cardiac death and a low incidence of atrial fibrillation in African Americans compared with Americans of European ancestry. However, it remains unknown whether such differences result from differences in inherited myocardial electrophysiological properties. Previous studies have shown inconsistent results regarding ethnic differences in electrocardiographic QT interval, a measure of myocardial repolarization time, and a central pathophysiological determinant of arrhythmia known to have a strong genetic component. In the present study, we therefore studied whether African compared with European ancestry inferred from genome-wide genotype data were associated with QT interval in 12 000 African Americans from 7 population-based studies. We observed no difference in duration of QT interval with African compared with European ancestry, arguing against important differences in myocardial repolarization time across these ethnicities. We also performed a genome-wide association study to identify common genetic variants associated with electrocardiographic QT interval in 13 000 blacks from 10 cohorts and observed association with QT interval for several loci previously identified as genetic determinants of QT interval in individuals of European ancestry, including SNPs at genetic loci harboring the genes NOS1AP, ATP1B1, KCNQ1, KCNH2, LITAF, and PLN.Conclusions—We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.11Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease RiskSummary—Carotid intima-media thickness, determined by high-resolution ultrasound techniques, is a well-established marker of subclinical atherosclerosis that has been shown to predict incident coronary and cerebrovascular events and is frequently used in both academic research and clinical trials. Genetic association studies of carotid intima-media thickness in individuals free of manifest cardiovascular disease may identify genes involved in early phases of disease, which may be less readily discernible in studies of late-stage disease. In the present study, we performed a genetic association analysis of carotid intima-media thickness in 3430 participants of the pan-European population-based IMPROVE study, who have undergone uniquely extensive ultrasound examinations of the carotid tree. We used a custom genotyping array (the Illumina CardioMetabochip), which interrogates genomic regions identified by previous genome-wide association studies of metabolic and cardiovascular disease. In the second stage, we conducted replication studies and subsequently tested 1 locus for association with coronary artery disease risk and with mRNA expression of nearby genes in vascular tissue biobanks. We thus identified a locus on chromosome 16, containing the BCAR1, CFDP1, and TMEM170A genes, as a novel genetic determinant of carotid intima-media thickness and coronary artery disease risk. Of these genes, BCAR1 has the most plausible role in atherogenesis based on current literature, whereas TMEM170A, which was highlighted by the biobank expression analysis, is an intriguing lead because its biological function is not known. Thus, this study has identified a novel genetic locus of importance for atherosclerosis-related disease, indicating specific genes that merit further research, results of which may become of future clinical use.Conclusions—This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of carotid intima - media thickness and coronary artery disease risk in individuals of European descent.12Low Prevalence of Mutations in Known Loci for Autosomal Dominant Hypercholesterolemia in a Multiethnic Patient CohortSummary—Patients with autosomal dominant hypercholesterolemia (ADH) present with very high low-density lipoprotein-cholesterol levels accompanied by tendon xanthomas and premature coronary heart disease. Worldwide, several countries have undertaken systematic screening efforts to identify patients with mutations in the genes known to cause ADH, and disease-causing mutations have been found in up to 95% of ADH patients. However, most of these screening studies have been performed in Europe or in Japan and are from relatively homogenous populations with regard to ethnicity and race. As a result, there is a paucity of data in subjects of African origin and other minorities. Therefore, we examined the molecular basis of ADH in a multiethnic patient cohort from a large, urban US city (Dallas, TX). We identified 91 unrelated ADH patients and screened them for mutations in the known genes: low-density lipoprotein-cholesterol receptor, apolipoprotein B-100, and proprotein convertase subtilisin-like kexin type 9. Sixty ADH patients did not have mutations in any of these genes (unexplained ADH). A higher proportion of blacks (77%) than either non-Hispanic whites (57%) or Hispanics (53%) had unexplained ADH. Compared with patients with low-density lipoprotein receptor variants, those with unexplained ADH had lower levels of low-density lipoprotein-cholesterol (292±47 mg/dL versus 239±42 mg/dL, respectively; P<0.0001) and higher levels of high-density lipoprotein-cholesterol (45±12 mg/dL versus 54±13 mg/dL, respectively, P=0.003). Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as blacks.Conclusions—Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as blacks.13Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives: Results From the Pharmacogenomic Evaluation of Antihypertensive Responses StudySummary—Hypertension is the most common chronic disease for which medications are prescribed, and controlling blood pressure (BP) is important in reducing long-term mortality and morbidity. Response rates to monotherapy with any given antihypertensive drug are only ≈50%, and those who fail to response to 1 drug class are more likely to respond to a drug with an alternate mechanism. Current selection of initial antihypertensive therapy is essentially by trial and error. The difficulty in determining the most appropriate antihypertensive drug for a specific patient likely contributes to the fact that less than half of the hypertensive patients in the United States (and worldwide) currently have their BP controlled. Pharmacogenomics offers the clinical promise of individualization of therapy based on a person’s genetic makeup. Through genome-wide association studies, 39 genetic polymorphisms have been associated with BP or hypertension in white individuals to date. However, whether these genetic markers are also associated with BP response to commonly used antihypertensives is unclear. In this study, we assessed the association of these genetic markers with BP responses after 9 weeks of monotherapy in white patients with essential hypertension who were randomized to a β-blocker (atenolol) or a thiazide diuretic (hydrochlorothiazide) in a randomized clinical trial. Six of these markers were nominally associated with BP response to either atenolol or hydrochlorothiazide when evaluated individually. However, these markers were much more strongly associated with the BP response to the antihypertensives when considered collectively. These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scorin

Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives

Background— To date, 39 single nucleotide polymorphisms (SNPs) have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites. Our hypothesis is that the loci/SNPs associated with BP/hypertension are also associated with BP response to antihypertensive drugs. Methods and Results— We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics Responses of Antihypertensive Responses study. Linear regression analysis was performed on whites for each SNP in an additive model adjusting for baseline BP, age, sex, and principal components for ancestry. Genetic scores were constructed to include SNPs with nominal associations, and empirical P values were determined by permutation test. Genotypes of 37 loci were obtained from Illumina 50K cardiovascular or Omni1M genome-wide association study chips. In whites, no SNPs reached Bonferroni-corrected α of 0.0014, 6 reached nominal significance ( P &lt;0.05), and 3 were associated with atenolol BP response at P &lt;0.01. The genetic score of the atenolol BP-lowering alleles was associated with response to atenolol ( P =3.3×10 –6 for systolic BP; P =1.6×10 –6 for diastolic BP). The genetic score of the hydrochlorothiazide BP-lowering alleles was associated with response to hydrochlorothiazide ( P =0.0006 for systolic BP; P =0.0003 for diastolic BP). Both risk score P values were &lt;0.01 based on the empirical distribution from the permutation test. Conclusions— These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring. Clinical Trial Registration Information— clinicaltrials.gov ; Identifier: NCT00246519.

Systems-level approaches reveal conservation of trans-regulated genes in the rat and genetic determinants of blood pressure in humans

Human genome-wide association studies (GWAS) of hypertension identified only few susceptibility loci with large effect that were replicated across populations. The vast majority of genes detected by GWAS has small effect and the regulatory mechanisms through which these genetic variants cause disease remain mostly unclear. Here, we used comparative genomics between human and an established rat model of hypertension to explore the transcriptional mechanisms mediating the effect of genes identified in 15 hypertension GWAS. Time series analysis of radiotelemetric blood pressure (BP) was performed to assess 11 parameters of BP variation in recombinant inbred strains derived from the spontaneously hypertensive rat. BP data were integrated with ∼27 000 expression quantative trait loci (eQTLs) mapped across seven tissues, detecting >8000 significant associations between eQTL genes and BP variation in the rat. We then compiled a large catalogue of human genes from GWAS of hypertension and identified a subset of 2292 rat-human orthologous genes. Expression levels for 795 (34%) of these genes correlated with BP variation across rat tissues: 51 genes were cis-regulated, whereas 459 were trans-regulated and enriched for 'calcium signalling pathway' (P = 9.6 × 10(-6)) and 'ion channel' genes (P = 3.5 × 10(-7)), which are important determinants of hypertension. We identified 158 clusters of trans-eQTLs, annotated the underlying 'master regulator' genes and found significant over-representation in the human hypertension gene set (enrichment P = 5 × 10(-4)). We showed extensive conservation of trans-regulated genes and their master regulators between rat and human hypertension. These findings reveal that small-effect genes associated with hypertension by human GWAS are likely to exert their action through coordinate regulation of pathogenic pathways.

Abstract 189: Analysis of Hypertension Associated Genetic Variants in Stroke Cases and Controls

BACKGROUND: Recent genome-wide association studies (GWAS) have identified a number of novel SNPs associated with blood pressure and hypertension-related traits although studies were very large (approaching 80K participants) and effect sizes were modest with per allele effect sizes as small variants as a single millimeter of mercury difference in blood pressure. However, because hypertension is the most potent modifiable risk factor for ischemic stroke, lowering blood pressure by a few mm Hg can translate into measurable decrease in stroke risk. METHODS: We investigated 22 hypertension (HTN) associated SNPs in a case-control analysis of ischemic stroke in multiple stroke studies including the Siblings With Ischemic Stroke Study (SWISS), the Ischemic Stroke Genetics Study (ISGS), the Bio-Repository of DNA in Stroke (BRAINS), the Vitamin Intervention for Stroke Prevention (VISP) trial, and the Women's Health Initiative (WHI). SWISS/ISGS/BRAINS were analyzed together and included subtype information. Genotyping was funded through the individual studies, the Genomics and Randomized Trials Network (GARNET) consortium, and the SHARe (SNP Health Association Resource). All studies had both raw and imputed GWAS data. Analyses included the following phenotypes: all ischemic stroke, stroke subtypes, and age-at-stroke-onset and were stratified by race. Analyses were minimally adjusted for age, sex and principal components 1 &amp; 2. Alpha was set at 0.05. RESULTS: Eleven of the SNPs from the HTN GWAS were associated with ischemic stroke in European ancestry from one or more of the study populations. Two SNPs on chromosome 12 and one on chromosome 21 were associated in multiple European ancestry cohorts. No SNP was associated in all studies. A SNP previously associated with HTN in African ancestry populations was associated with stroke in African-Americans. Analysis of subtypes found associations with small vessel disease and cardioembolic stroke but not large artery disease. The case-only age-at-stroke-onset analysis also found associations for the two SNPs on chromosome 12. CONCLUSION: These data suggest that candidate SNPs from a HTN GWAS may be associated with ischemic stroke and warrant further investigation. Racial differences were observed. Replication in populations from the other SiGN (Stroke Genetics Network), GENEVA (Gene Environment Association Studies) consortium, and the ISGC (International Stroke Genetics Consortium) studies are underway.

Genome-wide association studies of hypertension: Achievements, difficulties and strategies

Genome-wide association studies of hypertension: Achievements, difficulties and strategies

Genome-Wide Association Studies of Hypertension: Have They Been Fruitful?

Over the last two decades candidate gene association studies and genome-wide linkage scans have met with little success in characterizing risk variants for hypertension. Several factors could be responsible for the relative lack of success, although our understanding of the genetics has evolved to support the belief that there are multiple common risk variants, which are associated with hypertension with modest effect sizes. Genome-wide association studies (GWAS) have successfully identified risk loci for several complex polygenic disease states. Until recently, the productivity of GWAS with respect to identifying risk loci for hypertension was limited. In this paper we describe the recent success of GWAS of hypertension in identifying over a dozen loci associated with essential hypertension. We will review these findings, and place these results in the context of the future potential of pharmocogenetics of hypertension.

Genome-Wide Association Studies of Hypertension: Light at the End of the Tunnel

Despite its significant genetic component, the study of hypertension by genome-wide association presents more challenges than other common complex diseases. Its high prevalence, heterogeneity, and somewhat unclear definition are the challenges that need to be overcome on one hand. On the other hand, there are issues of small effect sizes and pleiotropism that are not specific to hypertension alone but nonetheless magnify the problems of genetic dissection when coupled with phenotypic misclassification. We discuss issues of study design and summarise published genome-wide association studies (GWASs) of hypertension and blood pressure. With careful study design and analysis success is possible, as demonstrated by the recent large-scale studies. Following these, there is still further scope to advance the field through high fidelity phenotyping and deep sequencing.