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Background: Traditional cardiovascular risk factors and the underlying genetic risk of elevated blood pressure (BP) determine an individual’s composite risk of developing adverse cardiovascular events. We sought to evaluate the relative contributions of the traditional cardiovascular risk factors to the development of adverse cardiovascular events in the context of varying BP genetic risk profiles. Methods: Genome-wide polygenic risk score (PRS) was computed using multiancestry genome-wide association estimates among US adults who underwent whole-genome sequencing in the Trans-Omics for Precision program. Individuals were stratified into high, intermediate, and low genetic risk groups (>80th, 20–80th, and Results: Among 21 897 US adults (median age: 56 years; 56.0% women; 35.8% non-White race/ethnicity), 1 SD increase in the SBP PRS, computed using 1.08 million variants, was associated with SBP (β: 4.39 [95% CI, 4.13–4.65]) and hypertension (odds ratio, 1.50 [95% CI, 1.46–1.55]), respectively. This association was robustly seen across racial/ethnic groups. Each SD increase in SBP PRS was associated with a higher risk of the incident CVD (multivariable-adjusted hazards ratio, 1.07 [95% CI, 1.04–1.10]) after controlling for ACC/AHA Pooled Cohort Equations risk scores. Among individuals with a high SBP PRS, low atherosclerotic CVD risk was associated with a 58% lower hazard for incident CVD (multivariable-adjusted hazards ratio, 0.42 [95% CI, 0.36–0.50]) compared to those with high atherosclerotic CVD risk. A similar pattern was noted in intermediate and low genetic risk groups. Conclusions: In a multiancestry cohort of >21 000 US adults, genome-wide SBP PRS was associated with BP traits and adverse cardiovascular events. Adequate control of modifiable cardiovascular risk factors may reduce the predisposition to adverse cardiovascular events among those with a high SBP PRS.

Background Dual antiplatelet therapy after percutaneous coronary intervention reduces myocardial infarctions but increases bleeding. The risk of bleeding may be higher among Black patients for unknown reasons. Bleeding risk scores have not been validated among Black patients. We assessed the difference in bleeding risk between Black and White patients along with the performance of the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy, Patterns of Nonadherence to Antiplatelet Regimens in Stented Patients, and Academic Research Consortium for High Bleeding Risk scores among both groups. Methods and Results This was a single‐center prospective study of patients who underwent percutaneous coronary intervention (2014–2019) and were followed for 1 year. The outcome was postdischarge Bleeding Academic Research Consortium 2 to 5 bleeding. Incidence rates were reported. Cox proportional hazards models measured the effect of self‐reported Black race on bleeding and determined the predictors of bleeding among 19 a priori variables. The 3 risk scores were assessed among Black and White patients separately using the Harrell concordance index. Of 1529 included patients, 342 (22.4%) self‐reported as being Black race. Unadjusted bleeding rates were 22.7 per 100 person‐years among Black patients versus 16.3 among White patients (hazard ratio, 1.41 [95% CI, 1.00–2.00], P =0.052). Predictors of bleeding were age, glomerular filtration rate 2 , prior bleeding, ticagrelor or prasugrel use, and anticoagulant use. Among Black and White patients, respectively, the C‐indexes were the following: 0.644 versus 0.600 for Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy ( P P =0.003 and P P =0.006 and P Conclusions The risk of dual antiplatelet therapy–associated postdischarge Bleeding Academic Research Consortium 2 to 5 bleeding was not significantly different between self‐reported Black and White patients. Bleeding risk scores performed similarly among both groups.

Background Corin enzyme contributes to the processing of inactive natriuretic peptides to bioactive hormones. In Black individuals, Corin gene variants (rs111253292 [Q568P] and rs75770792 [T555I]) have been previously reported to have a modest association with blood pressure (BP) and hypertension. Methods and Results We evaluated the association of Corin genotype with BP traits, prevalent hypertension, and incident hypertension among self‐identified 11 322 Black Americans in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study and the JHS (Jackson Heart Study) using multivariable‐adjusted regression modeling. Multivariable‐adjusted genotype‐stratified differences in NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and BNP (B‐type natriuretic peptide) levels were assessed. Genotype‐stratified NPPA and NPPB expression differences in healthy organ donor left atrial and left ventricular heart tissue (N=15) were also examined. The rs111253292 genotype was not associated with systolic BP (β±SE, 0.42±0.58; −1.24±0.82), diastolic BP (0.51±0.33; −0.41±0.46), mean arterial pressure (0.48±0.38; −0.68±0.51), and prevalent hypertension (odds ratio [OR], 0.93 [95% CI, 0.80–1.09]; OR, 0.79 [95% CI, 0.61–1.01]) in both REGARDS and JHS, respectively. The rs75770792 genotype was not associated with systolic BP (0.48±0.58; −1.26±0.81), diastolic BP (0.52±0.33; −0.33±0.45), mean arterial pressure (0.50±0.38; −0.63±0.50), and prevalent hypertension (OR, 1.02 [95% CI, 0.84–1.23]; OR, 0.87 [95% CI, 0.67–1.13]) in both cohorts, respectively. The Corin genotype was also not associated with incident hypertension (OR, 1.35 [95% CI, 0.94–1.93]; OR, 0.95 [95% CI, 0.64–1.39]) in the study cohorts. The NT‐proBNP levels in REGARDS and BNP levels in JHS were similar between the Corin genotype groups. In heart tissue, the NPPA and NPPB expression was similar between the genotype groups. Conclusions Corin gene variants observed more commonly in Black individuals are not associated with differences in NP expression, circulating NP levels, and BP or hypertension as previously reported in candidate gene studies. Understanding the genetic determinants of complex cardiovascular traits in underrepresented populations requires further evaluation.

Previous studies do not widely support hyperuricemia as a risk factor for stroke and other cardiovascular diseases. We assessed the relationship between hyperuricemia and ischemic stroke (≈900 cases) using a large data set from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). We employed a case-cohort design (incident stroke cases and randomly selected cohort participants) and weighted Cox-proportional hazard models to estimate the association of serum urate level ≥6.8 mg/dL (ie, hyperuricemia) and 6.0 to

Background Individual blood cell count abnormalities have been associated with cardiovascular disease and increased mortality. In this study, we defined a “cytopenia phenotype,” reflecting bone marrow hypoproliferation, to determine if peripheral blood cytopenia is associated with increased cardiovascular disease and mortality risk. Methods and Results Study participants were derived from a biracial observational cohort study, REGARDS (Reasons for Geographic and Racial Differences in Stroke), that enrolled 30 239 Black and White participants aged ≥45 years between 2003 and 2007. Median follow up was ≈9 years. The current study included 19 864 participants from REGARDS study (37.9% men, 40% Black participants) who have complete blood count available at study enrollment. We defined a cytopenia phenotype based on age‐, sex‐, and race‐adjusted lowest fifth percentile of blood counts. Multivariable Cox proportional hazards models estimated the hazard ratios (HR) and 95% CI of cytopenia for mortality and incident cardiovascular disease in adjusted models. Mean age of the study participants was 64 years (SD:9.7). The prevalence of cytopenia was 1.9% (n=378). Cytopenia was associated with increased risk of all‐cause mortality (HR, 1.73; 95% CI, 1.34–2.22) and cardiovascular disease mortality (HR, 1.56; 95% CI, 1.11–2.29). Cytopenia was associated with stroke risk in Black but not White participants (HR, 1.96 versus 0.86; P ‐interaction for race=0.08) and was not associated with coronary heart disease risk. Conclusions We defined a cytopenia phenotype with clinical implications for mortality and stroke risk in a large biracial and geographically diverse population. Whether generated through somatic mutations or decreased organ function, cytopenia was associated with mortality risk and was a race‐specific risk factor for stroke.

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the β-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways ( KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2 ) with large effect size (−3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.

Background Soluble CD 14 ( sCD 14), a circulating pattern recognition receptor, has been suggested as a cardiovascular disease risk factor. Prospective studies evaluating sCD 14 with incident cardiovascular disease events are limited, particularly among racially diverse populations. Methods and Results Between 2003 and 2007, the REGARDS ( Re asons for Geographic and Racial Differences in Stroke) study recruited 30 239 black and white participants across the United States. In a nested case–cohort study, sCD 14 was measured in baseline serum from 548 cases of incident ischemic stroke, 612 cases of incident coronary heart disease ( CHD ), and a cohort random sample (n=1039). Cox models estimated hazards ratios ( HR ) of incident ischemic stroke or CHD per 1 SD higher sCD 14, adjusting for cardiovascular disease risk factors. There was a differential association of sCD 14 with ischemic stroke and CHD risk by race. Among blacks, the adjusted HR of stroke per SD increment of sCD 14 was 1.42 (95% CI : 1.12, 1.80), with no association among whites ( HR 1.02 [95% CI : 0.82, 1.27]). Higher sCD 14 was associated with increased CHD risk in blacks but not whites, and relationships between sCD 14 and CHD were stronger at younger ages. Adjusted for risk factors, the HR of CHD per SD higher sCD 14 among blacks at age 45 years was 2.30 (95% CI : 1.45, 3.65) compared with 1.56 (95% CI : 0.94, 2.57) among whites. At age 65 years, the CHD HR was 1.51 (95% CI : 1.20, 1.91) among blacks and 1.02 (95% CI : 0.80, 1.31) among whites. Conclusions sCD 14 may be a race‐specific stroke and CHD risk marker.

Introduction: APOL1 nephropathy risk variants unique to African- ancestry (AA) populations, have an established role in ESRD and cardiovascular outcomes. Ongoing research efforts are now focused on identifying the potential mechanisms resulting in disease phenotypes. While APOL1 is suggested to alter inflammatory pathways in vivo, few studies have assessed if APOL1 risk variants are associated with inflammatory biomarkers in population studies. Hypothesis: We hypothesized that APOL1 variants are associated with inflammatory biomarkers among AA participants from the REGARDS cohort. Methods: We used baseline data on 10,605 AAs aged ≥45 years from the REGARDS cohort. The primary exposure was the presence of APOL1 genotypes assessed using additive, recessive and dominant genetic models. Inflammatory biomarkers were C-reactive protein [CRP], white blood cell count [WBC], serum albumin [sALB], and platelet count [PLT]. We categorized each biomarker into quartiles with the lowest quartile as a reference category. We also created an indicator variable (1 vs. 0) which assigned 1 point for having at least one of three inflammation biomarkers (CRP, WBC, sALB) in the high category(quartile 4[q4] for CRP and WBC, quartile 1 [q1] for sALB) indicative of an abnormal inflammatory profile(AIP). We examined the association between APOL1 and each inflammatory biomarker using multinomial logistic regression models adjusting for age, sex, prevalent conditions (history of stroke, history of coronary heart disease, hypertension, and dyslipidemia), estimated glomerular filtration rate, and principal component of ancestry. We used logistic regression to examine the association between APOL1 and AIP with similar adjustment for covariates. We further stratified the models by diabetes status. Results: Approximately 58% (6,185/10,605) of individuals had at least one APOL1 risk variant. There were 5,916 individuals with no elevated inflammatory levels while 215 had AIP. Those with AIP were more likely to be female, current smokers, and have diabetes. APOL1 was independently associated with PLT and sALB on adjusted associations under additive models [PLT: Odds ratio [OR] (95% confidence interval [95%CI]) = 1.12(1.00-1.28), sALB: OR (95%CI) =1.19(1.06-1.33), OR represents q4 vs q1]. Additionally, APOL1 was associated with a lower odds of AIP (OR 0.93, 95% CI, 0.87-1.00, additive model). Among those with diabetes (N=3,097), the APOL1 risk genotype was associated with lower odds of AIP under a recessive model (OR 0.73, 95% CI, 0.56-0.96) and an additive model (OR 0.86, 95% CI: 0.75-0.98); the results were not significant among those without diabetes. Conclusion: APOL1 risk genotypes are associated with inflammatory biomarkers in a community-based AA sample. These relationships are strongest among those with diabetes.

Background: Despite concerns about adverse neurocognitive events raised by prior trials, pharmacological PCSK9 (proprotein convertase subtilisin/kexin type-9) inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in lifelong exposure to lower levels of low-density lipoprotein cholesterol can provide information on the potential long-term effects of lower low-density lipoprotein cholesterol on neurocognitive impairment and decline. Methods: We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among black REGARDS study (Reasons for Geographic and Racial Differences in Stroke) participants with (n=241) and without (n=10 454) C697X or Y142X LOF variants. Neurocognitive tests included the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery (Word List Learning, World List Delayed Recall, Semantic Animal Fluency) and Six-Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥1.5 SD below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments or, separately, a score Results: The mean sample age was 64 years (SD, 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% confidence interval [CI], 0.58–2.13) using the CERAD battery and 0.89 (95% CI, 0.61–1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6-year (range, 0.1–9.1) study period ranged between 0.07 (95% CI, −0.06 to 0.20) and −0.07 (95% CI, −0.18 to 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all P >0.10). Odds ratios for neurocognitive impairment per 20 mg/dL low-density lipoprotein cholesterol decrements were 1.02 (95% CI, 0.96–1.08) and 0.99 (95% CI, 0.95–1.02) for the CERAD and SIS definitions of impairment, respectively. Conclusions: These results suggest that lifelong exposure to low PCSK9 levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.

Objective— Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease. Approach and Results— We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, β=0.284, P =3.24×10 –11 ). The rs2022030 effect size was nearly 3× larger among women (β=0.373, P =9.06×10 –13 ) than among men (β=0.135, P =0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women ( P interaction =0.001). Finally, the African ancestral sickle cell variant ( HBB rs334) was significantly associated with higher D-dimer in JHS (β=0.507, P =1.41×10 –14 ), and this association was successfully replicated in 1933 AAs ( P =2.3×10 –5 ). Conclusions— These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs.

High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens. Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based). We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16). Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens. We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

Background: Gout has been associated with a higher risk for coronary heart disease (CHD) and stroke in some but not all prior studies. There are few data available on the risk for incident heart failure associated with gout. Objective: To compare the incidence of heart failure, CHD and stroke among adults with versus without gout. Methods: We used data from 5,499 black and white REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants >65 years of age with Medicare coverage without a history of heart failure, CHD or stroke at baseline in 2003-2007. Gout was defined by (1) ≥1 inpatient claim or ≥2 outpatient or carrier claims on separate days with an ICD-9 diagnosis code for gout (274.x) in Medicare prior to each participant’s baseline study visit, or (2) use of allopurinol, colchicine or probenecid based on a baseline medication inventory. REGARDS study participants were followed through December 31, 2015 for heart failure, CHD, and stroke events, which were adjudicated. Results: Among participants included in the current analysis (mean age 72 years, 45% male, 31% black), 223 (4%) had gout. The incidence of heart failure and CHD was higher, while the incidence of stroke was similar, among participants with versus without gout ( Figure ). After adjustment for sociodemographic and cardiovascular risk factors, hazard ratios comparing participants with versus without gout were 2.41 (95%CI 1.60, 3.64) for heart failure, 1.41 (0.96, 2.07) for CHD and 0.96 (0.58, 1.59) for stroke. There was no statistically significant effect modification by race or gender. In a sensitivity analysis defining gout only based on Medicare diagnosis codes, multivariable-adjusted hazard ratios for heart failure, CHD and stroke associated with gout were 2.25 (95%CI 1.41, 3.59), 1.26 (0.79, 1.99) and 0.83 (0.45, 1.52), respectively. Conclusion: After accounting for sociodemographic and cardiovascular risk factors, gout remains strongly associated with incident heart failure but not with incident CHD or stroke.

Introduction: CD14 plays an important role in the innate immune response and promotes inflammation. Soluble CD14 (sCD14) is produced during an acute phase response and following cleavage from immune cell surfaces upon activation. Higher sCD14 may be a risk factor for cardiovascular disease, however prospective studies evaluating sCD14 with incident coronary heart disease (CHD) events are limited. We examined the association of sCD14 levels with incident CHD in black and white REGARDS participants. Methods: REGARDS enrolled 30,239 participants from across the contiguous U.S. in 2003-07. The cohort was 55% female and 41% black by design. In a nested case-cohort study, sCD14 levels were measured by ELISA in 612 participants with incident CHD and 856 in a cohort random sample; all were free of CHD at baseline. Using Cox proportional hazards models we calculated the hazards ratio (HR) of CHD for increasing sCD14, and studied interactions of sCD14 with age, sex, or race. Results: In models adjusted for Framingham risk factors, interaction terms for sCD14-by-race (p-interaction=0.02) and sCD14-by-age (p-interaction=0.02) were statistically significant but not for sCD14-by-sex (p=0.21). Stratified by race and age, each 1-SD higher sCD14 (442 ng/mL) was associated with an increased CHD risk in blacks but not whites (Table). Relationships were stronger in younger than older black participants. SCD14 was not significantly associated with CHD risk among white participants, but there was a trend for stronger relationships at younger ages. Conclusions: Higher sCD14 is associated with risk of CHD in blacks with greater risk at younger ages. These findings suggest sCD14 may be an important CHD risk factor among younger black adults.

Introduction: CD14 is a co-receptor for bacterial lipopolysaccharide and promotes an inflammatory response. CD14 is expressed on the surface of several innate immune cell subpopulations and also circulates in blood as a soluble form (sCD14). Despite its potential role in cardiovascular disease risk, prospective studies evaluating sCD14 with ischemic stroke outcomes are limited, especially among those of non-European ancestry. We examined the associations between sCD14 levels with incident ischemic stroke risk in REGARDS. Methods: REGARDS recruited 30,239 participants across the contiguous U.S. in 2003-07. By design, 55% of participants were female, 41% were black, and 56% lived in the southeast. With 5.8 years follow up, baseline plasma sCD14 was measured by ELISA in 548 incident cases of ischemic stroke and in a stroke-free cohort random sample ( n =1,039). Cox proportional hazards models were used to estimate the hazard ratio (HR) of incident ischemic stroke adjusted for Framingham stroke risk factors. We tested for a sCD14-by-race interaction. Results: Soluble CD14 levels were higher with older age, in women, and lower among blacks. Each 1-standard deviation (SD) higher sCD14 (447 ng/mL) was associated with an increased risk of incident ischemic stroke following adjustment for demographic variables (HR: 1.22; 95% confidence interval (CI): 1.07, 1.40) and stroke risk factors (HR: 1.19; 95% CI: 1.01, 1.40). In analyses stratified by race, the association of sCD14 with stroke was stronger in blacks (HR: 1.42; 95% CI: 1.12, 1.80) and not present in whites (HR: 1.02; 95% CI: 0.82, 1.27) (sCD14 x race interaction p-value = 0.04). Conclusions: These results show that higher sCD14 is associated with risk of ischemic stroke in blacks but not whites, and thus may be a risk factor unique to blacks.

Introduction: The association between hyperuricemia and stroke has been inconsistent especially after adjustment for cardiovascular risk factors. Previous studies were limited in the number of events and did not measure these associations in subgroups. Methods: We used a stratified case-cohort design within the REasons for Geographic and Racial Differences in Stroke study. Clinically adjudicated stroke events (n=903) were defined as focal neurologic deficit lasting >24 hours or non-focal neurological symptoms with brain imaging consistent with stroke. Controls (n=951) were a random stratified sample selected from baseline to ensure representation of high-risk groups. Uric acid was assayed using the baseline sample and categorized into three groups: < 6 (referent), 6-6.8, ≥ 6.8 mg/dl (hyperuricemia). Cox-proportional-hazard-models adjusted for demographic and clinical variables were fit to examine the association between uric acid levels and stroke. We repeated the analysis stratified by race, gender, and age ( Results: Hyperuricemic individuals were more likely to be male and black. Hyperuricemia versus the referent category was significantly associated with stroke after adjustment for race, sex, age, and age*race interaction [model 1 HR(95%CI)= 1.42(1.12-1.80)], and after further adjustment for systolic and diastolic blood pressure [HR (95%CI)= 1.42(1.12-1.80)]. The associations was attenuated after full adjustment [HR (95%CI)= 1.22(0.91-1.63)]. Incremental adjustment by clinical variables suggested nHTN attenuated the association between hyperuricemia and stroke. Results were similar for hyperuricemia within subgroups defined by age, gender and race, except among men Conclusion: We observed a significant association between hyperuricemia and stroke that was partially dependent upon hypertension severity (count of antihypertensive treatment classes). The association was strongest among males aged

Cost-effective identification of novel pharmacogenetic variants remains a pressing need in the field. Using data from the Genetics of Lipid Lowering Drugs and Diet Network, we identified genomic regions of relevance to fenofibrate response in a sample of 173 families. Our approach included a multipoint linkage scan, followed by selection of the families showing evidence of linkage. We identified a strong signal for changes in LDL-cholesterol (LDL-C) on chromosome 7 (peak logarithm of odds score = 4.76) in the full sample (n = 821). The signal for LDL-C response remained even after adjusting for baseline LDL-C. Restricting analyses only to the families contributing to the linkage signal for LDL-C (N = 19), we observed a peak logarithm of odds score of 5.17 for chromosome 7. Two genes under this peak (ABCB4 and CD36) were of biological interest. These results suggest that linked family analyses might be a useful approach to gene discovery in the presence of a complex (e.g. multigenic) phenotype.

Postprandial lipemia (PPL), defined as the series of metabolic events occuring after ingestion of fat, plays a key role in atherogenesis. While the plasma lipid response to meals is extremely variable, the determinants of PPL variation remain poorly understood. Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n=1039), we investigated clinical, genetic, and DNA methylation correlates of prolonged PPL. Participants were administered a standardized high-fat milkshake and blood samples were taken at baseline, 3.5, and 6 hours post-meal. A prolonged PPL response was defined as a binary trait: 1 if plasma triglycerides at 6 hours exceeded the level at 3.5 hours, 0 otherwise. Genome-wide sequence and methylation variation was quantified using next generation sequencing and Illumina 450K methylation array in CD4+ T-cells, respectively. Approximately one third (n=312) of GOLDN participants exhibited a prolonged PPL response to the high-fat challenge. Prolonged PPL was significantly associated with increasing age (P= 1.0x10 -6 ), waist circumference (P= 0.02), fasting glucose (P=0.006), low-density lipoprotein cholesterol (P= 0.04), and fasting triglycerides (P= 1.9x10 -8 ), and inversely associated with high-density lipoprotein cholesterol (P=0.0003). Participants with prolonged PPL were significantly more likely to have prevalent coronary heart disease (P=0.0002) and diabetes mellitus (P= 1.5x10 -5 ). No genetic variants were significantly associated with PPL at the genome-wide level, in either single variant or gene-based tests. However, a DNA methylation variant in the COG5 gene, encoding a component of the oligomeric Golgi complex that has been previously shown to be required for intestinal lipid absorption in a zebrafish model, emerged as the top epigenetic determinant of prolonged PPL response (P= 2.5x10 -7 ) in a mixed effects model adjusting for age (linear and quadratic), sex, study site, smoking, alcohol intake, T-cell purity, and familial relationships. Upon successful replication in independent cohorts and/or functional validation, the COG5 finding can be considered a novel epigenetic target in dyslipidemia, with potential to inform future research efforts and personalized treatment approaches.

Introduction: Life’s Simple 7 (LS7) comprises seven health factors and behaviors promoted by the American Heart Association to reduce cardiovascular morbidity and mortality. Despite compelling evidence of inverse association between LS7 adherence and a variety of adverse health outcomes, the epigenetic sequelae of healthy lifestyle have not been comprehensively characterized and may offer valuable insights into the underlying biological mechanisms. Hypothesis: We hypothesized that LS7 adherence is associated with an epigenetic signature that is consistent with the deceleration of the aging process. Methods: Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n=853), we have estimated cross-sectional associations between epigenome-wide DNA methylation at 487,432 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells and the number of achieved LS7 goals as measured by study staff (blood pressure, body mass index, total cholesterol, and fasting glucose) or reported by the participant (diet, smoking, physical activity). The associations were tested using linear mixed models adjusted for age, sex, study site, technical artifacts (fixed effects), and family relatedness (random effect). Additionally, we tested associations between LS7 compliance and age acceleration, estimated from DNA methylation data and chronological age using two complementary validated algorithms (1: Horvath and 2: Hannum). These linear mixed models adjusted for chronological age, sex, study site, CD4+ T-cell subtype estimates (fixed effects), and family relatedness (random effect). Epigenome-wide association results were considered statistically significant if they fell under the Bonferroni corrected threshold (alpha=0.05/487,432= 1.03x10 -7 ). Results: Methylation of an intronic CpG site in CPT1A , cg00574958, was positively associated with the number of achieved LS7 goals at the epigenome-wide significance level (beta= 0.008, SE= 0.001, P= 4.7x10 -8 ). CPT1A encodes a key enzyme in the beta-oxidation process and has previously been linked to fasting triglycerides, body mass index, and adiponectin levels. Age acceleration was associated with LS7 adherence under the Hannum algorithm (beta=-0.01, SE= 0.006, P= 0.02) but not the Horvath algorithm (beta=-0.005, SE= 0.004, P= 0.18). Conclusions: Achievement of LS7 goals was significantly associated with methylation variation in CPT1A , a critical lipid metabolism gene, and was associated with age deceleration in the Hannum but not the Horvath models. Following independent replication, future studies should consider interrogating CPT1A methylation in relation to cardiovascular morbidity and mortality in a prospective setting.

Background— PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy. Methods and Results— These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel–Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32–39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11–16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28–0.92) in blacks and 0.82 (95% CI, 0.63–1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48–1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80–1.41 in whites). Conclusions— PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.

BackgroundLocal ancestry in relation to clinical cardiovascular events (CVEs) among African Americans can provide insight into their genetic susceptibility to the disease.Methods and ResultsWe examined local European ancestry (LEA) association withCVEsamong 3000 African Americans from the Atherosclerosis Risk in Communities Study (ARIC). We estimatedLEAusingLocalAncestry Inference in adMixedPopulations usingLinkageDisequilibrium (LAMP‐LD) and examined its association with myocardial infarction, stroke, coronary heart disease and its composite and cardiovascular disease composite using logistic regression. Genome‐wide significance was achieved by 121LEAregions in relation tomyocardial infarctionand 2 in relation to the cardiovascular disease composite. TheLEAregion downstream of 4q32.1 was significantly associated with 2 times higher odds of myocardial infarction (P=1.45×10−6). TheLEAregion upstream of 6q11.1 was associated with 0.37 times lower odds of fatal coronary heart disease (P=7.34×10−4), whereas theLEAregion downstream of 21q21.1 was associated with 1.55 times higher odds of composite coronary heart disease (P=3.45×10−4). Association ofLEAwith stroke was observed in the region upstream of 6p22.3 with a 1.57 times higher odds of stroke (P=9.69×10−4). Likewise, theLEAregion on 4q32.3 was associated with a 1.53 times higher odds of composite cardiovascular disease (P=3.04×10−4). We also found 20 of theLEAregions at previously significant cardiovascular disease single‐nucleotide polymorphisms to be associated withCVEin our study.ConclusionsFuture studies are needed to replicate and/or determine the causal variants driving our associations and explore clinical applications for those consistently associated withCVEs.

Background— Local ancestry may contribute to the disproportionate burden of subclinical and clinical cardiovascular disease among admixed African Americans compared with other populations, suggesting a rationale for admixture mapping. Methods and Results— We estimated local European ancestry (LEA) using Local Ancestry inference in adMixed Populations using Linkage Disequilibrium method (LAMP-LD) and evaluated the association with common carotid artery intima–media thickness (cCIMT) using multivariable linear regression analysis among 1554 African Americans from MESA (Multi-Ethnic Study of Atherosclerosis). We conducted secondary analysis to examine the significant cCIMT–LEA associations with clinical cardiovascular disease events. We observed genome-wide significance in relation to cCIMT association with the SERGEF gene (secretion-regulating guanine nucleotide exchange factor; β=0.0137; P =2.98×10 − 4 ), also associated with higher odds of stroke (odds ratio=1.71; P =0.02). Several regions, in particular CADPS gene (Ca 2+ -dependent secretion activator 1) region identified in MESA, were also replicated in the ARIC cohort (Atherosclerosis Risk in Communities). We observed other cCIMT–LEA regions associated with other clinical events, most notably the regions harboring CKMT2 gene (creatine kinase, mitochondrial 2) and RASGRF2 gene (Ras protein–specific guanine nucleotide–releasing factor 2) with all clinical events except stroke, the LRRC3B gene (leucine-rich repeat containing 3B) with myocardial infarction, the PRMT3 gene (protein arginine methyltransferase 3) with stroke, and the LHFPL2 gene (lipoma high mobility group protein I-C fusion partner-like 2) with hard and all coronary heart disease. Conclusions— We identified several novel LEA regions, in addition to previously identified genetic variations, associated with cCIMT and cardiovascular disease events among African Americans.

Background: Calculated ‘epigenetic age,’ a novel biomarker based on DNA methylation levels of 353 CpGs, has been demonstrated to accurately predict chronological age across a broad spectrum of tissues and cell types. Recently epigenetic age acceleration or older epigenetic age in comparison to chronological age has been robustly associated with all-cause mortality independent of chronological age in multiple human cohorts. However, accelerated epigenetic aging has not been associated with lipids levels, including postprandial lipid levels which are linked to prothrombotic and proinflammatory processes that may precipitate aging. In the current study we aimed to evaluate the association between epigenetic age acceleration and lipid levels. Methods: We used the Horvath DNA methylation age calculator to estimate epigenetic age in 988 Caucasian participants from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) using Illumina Infinium HumanMethylation450 BeadChip array data derived from CD4+ T-cell DNA. GOLDN participants did not take lipid lowering drugs for at least four weeks prior to enrollment and underwent a standardized high fat meal challenge after fasting for at least 8 hours followed by timed blood draws at 3.5 and 6 hours following the meal. Epigenetic age acceleration was calculated as the residual from regressing methylation age on chronological age. We used linear mixed models to examine the association of age acceleration quartiles with fasting and postrandial (3.5 and 6 hour time points) low density lipoprotein (LDL), high density lipoprotein (HDL) and triglyceride (TG) levels after adjusting for age, study site, sex, fasting lipid level (if applicable), deconvolution estimated T-cell type percentages and a random effect of family relationship. Results: The correlation between calculated methylation age and chronological age was 0.91. The difference between methylation age and chronological age (methylation age - chronological age) was on average -5.8 (5.9), -0.5 (4.7), 2.9 (4.3), and 7.8 (5.0) years for the first through fourth quartiles of age acceleration, respectively. After adjustment for covariates neither fasting nor postprandial lipids were associated with age acceleration quartile. Conclusions: Evidence from the current study suggests lipid levels in the fasting and postprandial state are not related to accelerated epigenetic aging, however given the association between epigenetic age acceleration and mortality observed in previous studies the relationship of other metabolic parameters with age acceleration may be worthy of investigation.

Background: Animal model studies reported robust associations between fructose intake, a known determinant of metabolic health across species, and DNA methylation/ gene expression patterns. To date, these associations have not been comprehensively investigated in humans. Methods: Using DNA methylation data on ~470,000 cytosine-phosphate-guanine (CpG) sites in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n=991) quantified in CD4+ T-cells, we have interrogated the cross-sectional relationships between fructose intake (ascertained using a validated food frequency questionnaire) and epigenome-wide methylation. We fit linear mixed models adjusted for age, sex, study site, technical covariates (fixed effects) and family relatedness (random effect). We have supplemented the methylation analyses with a transcriptome-wide scan on 98 unrelated GOLDN participants with available RNASeq data in whole blood. For the RNASeq data analysis, we used negative binomial models of read counts as a function of fructose intake, adjusted for age, sex, study site, technical covariates (including differential white blood cell counts). Results and Conclusions: The top loci differentially methylated with respect to fructose intake mapped to SNED1 (regression coefficient +/- SE= 0.002 +/- 0.0005, P=5x10-6) and FARSB (regression coefficient +/- SE= 0.002 +/- 0.0004, P=5x10-6) on chromosome 2. SNED1 is an insulin responsive transcription factor that has previously been shown to be downregulated in the setting of metabolic syndrome. FARSB encodes an aminoacyl-tRNA synethetase implicated in cell growth. Additionally, two genes reached transcriptome-wide significance in the RNASeq analysis: MTATP8P1 (P=1x10-7) and PDXDC1 (P=6x10-7). Sequence variation in PDXDC1 (pyridoxal-dependent decarboxylase isoform) has previously been linked to lipid metabolism, while MTATP8P1 is a pseudogene for a mitochondrially encoded ATP synthase. Upon future replication and functional validation, our preliminary findings offer promising insights into the link between fructose intake and metabolic health.

Few data exist on whether healthy lifestyle factors are associated with better prognosis among individuals with apparent treatment-resistant hypertension, a high-risk phenotype of hypertension. The purpose of this study was to assess the association of healthy lifestyle factors with cardiovascular events, all-cause mortality, and cardiovascular mortality among individuals with apparent treatment-resistant hypertension. We studied participants (n=2043) from the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with apparent treatment-resistant hypertension (blood pressure ≥140/90 mm Hg despite the use of 3 antihypertensive medication classes or the use of ≥4 classes of antihypertensive medication regardless of blood pressure control). Six healthy lifestyle factors adapted from guidelines for the management of hypertension (normal waist circumference, physical activity ≥4 times/week, nonsmoking, moderate alcohol consumption, high Dietary Approaches to Stop Hypertension diet score, and low sodium-to-potassium intake ratio) were examined. A greater number of healthy lifestyle factors were associated with lower risk for cardiovascular events (n=360) during a mean follow-up of 4.5 years. Multivariable-adjusted hazard ratios [HR (95% confidence interval)] for cardiovascular events comparing individuals with 2, 3, and 4 to 6 versus 0 to 1 healthy lifestyle factors were 0.91 (0.68–1.21), 0.80 (0.57–1.14), and 0.63 (0.41–0.95), respectively ( P -trend=0.020). Physical activity and nonsmoking were individual healthy lifestyle factors significantly associated with lower risk for cardiovascular events. Similar associations were observed between healthy lifestyle factors and risk for all-cause and cardiovascular mortality. In conclusion, healthy lifestyle factors, particularly physical activity and nonsmoking, are associated with a lower risk for cardiovascular events and mortality among individuals with apparent treatment-resistant hypertension.

Background— Genetic research regarding blood lipids has largely focused on DNA sequence variation; few studies have explored epigenetic effects. Genome-wide surveys of DNA methylation may uncover epigenetic factors influencing lipid metabolism. Methods and Results— To identify whether differential methylation of cytosine-(phosphate)-guanine dinucleotides (CpGs) correlated with lipid phenotypes, we isolated DNA from CD4+ T cells and quantified the proportion of sample methylation at >450 000 CpGs by using the Illumina Infinium HumanMethylation450 Beadchip in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled the percentage of methylation at individual CpGs as a function of fasting very-low-density lipoprotein cholesterol and triglycerides (TGs) by using mixed linear regression adjusted for age, sex, study site, cell purity, and family structure. Four CpGs (cg00574958, cg17058475, cg01082498, and cg09737197) in intron 1 of carnitine palmitoyltransferase 1A ( CPT1A ) were strongly associated with very-low low-density lipoprotein cholesterol ( P =1.8×10 –21 to 1.6×10 –8 ) and TG ( P =1.6×10 –26 to 1.5×10 –9 ). Array findings were validated by bisulfite sequencing. We performed quantitative polymerase chain reaction experiments demonstrating that methylation of the top CpG (cg00574958) was correlated with CPT1A expression. The association of cg00574958 with TG and CPT1A expression were replicated in the Framingham Heart Study ( P =4.1×10 –14 and 3.1×10 –13 , respectively). DNA methylation at CPT1A cg00574958 explained 11.6% and 5.5% of the variation in TG in the discovery and replication cohorts, respectively. Conclusions— This genome-wide epigenomic study identified CPT1A methylation as strongly and robustly associated with fasting very-low low-density lipoprotein cholesterol and TG. Identifying novel epigenetic contributions to lipid traits may inform future efforts to identify new treatment targets and biomarkers of disease risk.

Atherosclerosis is consistently higher among the HIV-positive patients, with or without treatment, than among the HIV-negative population. Risk factors linked to atherosclerotic cardiovascular disease in HIV infection are both traditional and HIV specific although the underlying mechanisms are not fully delineated. Three key sequential biological processes are postulated to accelerate progression of atherosclerosis in the context of HIV: (1) inflammation, (2) transformation of monocytes to macrophages and then foam cells, and (3) apoptosis of foam cells leading to plaque development through Ca 2+ -dependent endoplasmic reticulum stress. These proatherogenic mechanisms are further affected when HIV interacts with the genes involved in various phases within this network.

Background— Albuminuria is a marker of endothelial dysfunction and has been associated with adverse cardiovascular outcomes. The reasons for this association are unclear but may be attributable to the relationship between endothelial dysfunction and intrinsic myocardial dysfunction. Methods and Results— In the Hypertension Genetic Epidemiology Network (HyperGEN) Study, a population- and family-based study of hypertension, we examined the relationship between urine albumin-to-creatinine ratio (UACR) and cardiac mechanics (n=1894, all of whom had normal left ventricular ejection fraction and wall motion). We performed speckle-tracking echocardiographic analysis to quantify global longitudinal, circumferential, and radial strain, and early diastolic (e′) tissue velocities. We used E/e′ ratio as a marker of increased left ventricular filling pressures. We used multivariable-adjusted linear mixed effect models to determine independent associations between UACR and cardiac mechanics. The mean age was 50±14 years, 59% were female, and 46% were black. Comorbidities were increasingly prevalent among higher UACR quartiles. Albuminuria was associated with global longitudinal strain, global circumferential strain, global radial strain, e′ velocity, and E/e′ ratio on unadjusted analyses. After adjustment for covariates, UACR was independently associated with lower absolute global longitudinal strain (multivariable-adjusted mean global longitudinal strain [95% confidence interval] for UACR Quartile 1 = 15.3 [15.0–15.5]% versus UACR Q4 = 14.6 [14.3–14.9]%, P for trend P =0.003). The association between UACR and global longitudinal strain was present even in participants with UACR < 30 mg/g ( P Conclusions— Albuminuria, even at low levels, is associated with adverse cardiac mechanics and higher E/e′ ratio.

Apparent treatment-resistant hypertension is defined as systolic/diastolic BP ≥ 140/90 mmHg with concurrent use of three or more antihypertensive medication classes or use of four or more antihypertensive medication classes regardless of BP level.The prevalence of apparent treatment-resistant hypertension among Reasons for Geographic and Racial Differences in Stroke study participants treated for hypertension (n=10,700) was determined by level of estimated GFR and albumin-to-creatinine ratio, and correlates of apparent treatment-resistant hypertension among those participants with CKD were evaluated. CKD was defined as an albumin-to-creatinine ratio ≥ 30 mg/g or estimated GFR60 ml/min per 1.73 m(2).The prevalence of apparent treatment-resistant hypertension was 15.8%, 24.9%, and 33.4% for those participants with estimated GFR ≥ 60, 45-59, and45 ml/min per 1.73 m(2), respectively, and 12.1%, 20.8%, 27.7%, and 48.3% for albumin-to-creatinine ratio10, 10-29, 30-299, and ≥ 300 mg/g, respectively. The multivariable-adjusted prevalence ratios (95% confidence intervals) for apparent treatment-resistant hypertension were 1.25 (1.11 to 1.41) and 1.20 (1.04 to 1.37) for estimated GFR levels of 45-59 and45 ml/min per 1.73 m(2), respectively, versus ≥ 60 ml/min per 1.73 m(2) and 1.54 (1.39 to 1.71), 1.76 (1.57 to 1.97), and 2.44 (2.12 to 2.81) for albumin-to-creatinine ratio levels of 10-29, 30-299, and ≥ 300 mg/g, respectively, versus albumin-to-creatinine ratio10 mg/g. After multivariable adjustment, men, black race, larger waist circumference, diabetes, history of myocardial infarction or stroke, statin use, and lower estimated GFR and higher albumin-to-creatinine ratio levels were associated with apparent treatment-resistant hypertension among individuals with CKD.This study highlights the high prevalence of apparent treatment-resistant hypertension among individuals with CKD.

Background— Central obesity, defined by increased waist circumference or waist:hip ratio (WHR), is associated with increased cardiovascular events, including heart failure. However, the pathophysiological link between central obesity and adverse cardiovascular outcomes remains poorly understood. We hypothesized that central obesity and larger WHR are independently associated with worse cardiac mechanics (reduced left ventricular strain and systolic [s′] and early diastolic [e′] tissue velocities). Methods and Results— We performed speckle-tracking analysis of echocardiograms from participants in the Hypertension Genetic Epidemiology Network (HyperGEN) study, a population- and family-based epidemiological study (n=2181). Multiple indices of systolic and diastolic cardiac mechanics were measured. We evaluated the association between central obesity and cardiac mechanics using multivariable-adjusted linear mixed-effects models to account for relatedness among participants. The mean age of the cohort was 51±14 years, 58% were women, and 47% were black. Mean body mass index was 30.8±7.1 kg/m 2 , waist circumference was 102±17 cm, WHR was 0.91±0.08, and 80% had central obesity based on waist circumference and WHR criteria. After adjusting for multiple potential confounders (including age, sex, race, physical activity, body mass index, heart rate, smoking status, systolic blood pressure, fasting glucose, total cholesterol, antihypertensive medication use, glomerular filtration rate, left ventricular mass index, wall motion abnormalities, and ejection fraction), central obesity and WHR remained associated with worse global longitudinal strain, early diastolic strain rate, s′ velocity, and e′ velocity ( P Conclusions— In this cross-sectional study of participants with multiple comorbidities, central obesity was found to be associated with adverse cardiac mechanics.

Thiazide diuretics (TD) lead to hypokalemia and angiotensin-converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) lead to hyperkalemia more frequently than other antihypertensives. Inter-individual variation in serum potassium on antihypertensive treatments exist and we hypothesized genetic markers may modify the association of treatment class with serum potassium levels. We separately evaluated interactions of SNP-by-TD as well as SNP-by-ACE /ARB on serum potassium levels among users of antihypertensive medication (anti-HTN). Our study included 7 European-ancestry cohorts (EA, N = 1673 TD exposed; N=1262 ACE /ARB exposed; N=1998 reference, users of other anti-HTN) and 4 African-American ancestry cohorts (AA, N = 482 TD exposed; N =411 ACE/ARB exposed; N=1182 users of other anti-HTN). Models were adjusted for age, sex, BMI, potassium supplementation, and ancestry at the cohort level. We filtered results based on an estimated degrees of freedom filter that incorporated SNP imputation quality, minor allele frequency (MAF), and the number of exposed participants. We performed race-stratified fixed effects inverse variance weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates. ACE /ARB data uncovered eleven significant (P

Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation.Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-α)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect.Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10 and rs12722605, P=5×10). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10, 5×10, 6×10, and 7×10, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10).We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.

Genetic studies may help explain abnormalities of fat distribution in HIV-infected patients treated with antiretroviral therapy (ARV).Subcutaneous adipose tissue (SAT) volume measured by MRI in the leg, the lower trunk, the upper trunk, and the arm was examined in 192 HIV-infected White men, ARV-treated from the Fat Redistribution and Metabolic Change in HIV infection study. Single-nucleotide polymorphisms were assayed using the Illumina Human CNV370-quad beadchip. Multivariate and univariate genome-wide association analyses of the four SAT depots were implemented in PLINK software adjusted for age and ARV duration. Functional annotation analysis using Ingenuity Systems Pathway Analysis tool was carried out for markers with P lower than 10(-3) near known genes identified by multivariate analysis.Loci (rs10504906, rs13267998, rs921231) in or near the anion exchanger solute carrier family 26, member 7 isoform a (SLC26A7) were strongly associated with the upper trunk and the arm SAT (9.8×10(-7) ≤P7.8×10(-6)). Loci (rs193139, rs7523050, rs1761621) in and near a gene-rich region including G-protein-signaling modulator 2 (GPSM2) and syntaxin-binding protein 3 (STXBP3) were significantly associated with the lower body SAT depots (9.9×10(-7) ≤P9.5×10(-6)). GPSM2 is associated with cell division and cancer whereas STXBP3 is associated with glucose metabolism in adipoctyes. Ingenuity Systems Pathway Analysis identified atherosclerosis, mitochondrial function, and T-cell-mediated apoptosis as processes related to SAT volume in HIV-infected individuals (P5×10(-3)).Our results are limited by the small sample size and replication is needed; however, this genomic scan uncovered new genes associated with metabolism and inflammatory pathways that may affect SAT volume in ARV-treated HIV-infected patients.

Several clinical studies report increased risk of diabetes mellitus (DM) with pharmacologic treatment for hypertension (HTN). HTN genes may modify glycemic response to antihypertensive treatment. The current study examined the association of 24 single nucleotide polymorphisms (SNPs) in 11 HTN candidate genes with fasting glucose measured at 2, 4, and 6 years after treatment initiation. The study sample included participants free of diabetes at baseline in the Genetics of Hypertension Associated Treatment (GenHAT) study (N=9,309). GenHAT participants were randomized to receive treatment with a diuretic (chlorthalidone), calcium channel blocker (amlodipine), or ACE inhibitor (lisinopril). Mixed models for repeated measures were employed to test for gene and pharmacogenetic associations with fasting glucose during follow-up. Fasting glucose at year 2 increased on average 6.8 mg/dL, 4.8 mg/dL and 3.0 mg/dL from baseline in the chlorthalidone, amlodipine and lisinopril groups, respectively. Carrying the I allele (rs1799752) of the angiotensin-converting enzyme (ACE) I/D polymorphism was associated with lower fasting glucose levels (P=0.02). Additionally, an ACE promoter polymorphism (−262, rs4291) was associated with lower fasting glucose for the model AA/AT vs. TT which remained significant after correction for multiple testing (P=0.001). Finally, a SNP in the α-subunit of the amiloride-sensitive epithelial sodium channel (SCNN1A, rs2228576) modified the association of amlodipine versus chlorthalidone treatment with fasting glucose (P

Introduction: A genetic predisposition to abnormal cardiac mechanics may explain the familial predisposition to heart failure (HF). We hypothesized that indices of cardiac mechanics (speckle-tracking strain parameters and tissue velocities) are heritable traits. Methods: We performed speckle-tracking analysis on echocardiograms and measured global longitudinal, circumferential, and radial strain (GLS, GCS, GRS), early diastolic strain rate, and e’ velocities in the HyperGEN study, a family- and population-based study of hypertension (N=2058 [54% African American (AA)]). Additive genetic heritability estimates for cardiac mechanics were calculated by maximizing the likelihood variance components in SOLAR (ver.6) adjusted for age, sex, race, height, weight, systolic blood pressure (SBP), left ventricular (LV) mass, ejection fraction, reader, image quality, and institution. Results: Mean age was 51±14 years and HF risk factors were common: hypertension (56%), obesity (47%), and diabetes (16%). Clinical and conventional echocardiographic characteristics, including male gender, hypertension, elevated fasting glucose, higher body-mass index, and LV hypertrophy were all significantly associated with increased absolute GLS and septal e’ velocity (P Conclusions: Echocardiographic measures of cardiac mechanics, particularly GLS and e’ velocity, are heritable traits, even after adjustment for clinical and cardiac structural factors (e.g., SBP and LV mass, respectively) that are known to be heritable and associated with cardiac mechanics. These data support the exploration of genetics of cardiac mechanics, which may provide insight into the molecular pathogenesis of LV dysfunction and HF.

Background Comorbidities are common in heart failure ( HF ), and the number of comorbidities has been associated with poor outcomes in HF patients. However, little is known about the effect of multiple comorbidities on cardiac mechanics, which could impact the pathogenesis of HF . We sought to determine the relationship between comorbidity burden and adverse cardiac mechanics. Methods and Results We performed speckle‐tracking analysis on echocardiograms from the HyperGEN study (n=2150). Global longitudinal, circumferential, and radial strain, and early diastolic (e') tissue velocities were measured. We evaluated the association between comorbidity number and cardiac mechanics using linear mixed effects models to account for relatedness among subjects. The mean age was 51±14 years, 58% were female, and 47% were African American. Dyslipidemia and hypertension were the most common comorbidities (61% and 58%, respectively). After adjusting for left ventricular ( LV ) mass index, ejection fraction, and several potential confounders, the number of comorbidities remained associated with all indices of cardiac mechanics except global circumferential strain (eg, β=−0.32 [95% CI −0.44, −0.20] per 1‐unit increase in number of comorbidities for global longitudinal strain; β=−0.16 [95% CI −0.20, −0.11] for e' velocity; P ≤0.0001 for both comparisons). Results were similar after excluding participants with abnormal LV geometry ( P Conclusions Higher comorbidity burden is associated with worse cardiac mechanics, even in the presence of normal LV geometry. The deleterious effect of multiple comorbidities on cardiac mechanics may explain both the high comorbidity burden and adverse outcomes in patients who ultimately develop HF .

Background: Patients with apparent treatment-resistant hypertension (aTRH), defined as uncontrolled blood pressure (≥140/90 mmHg) despite use of 3 antihypertensive medications or use of ≥4 medications regardless of blood pressure control, have a higher risk for cardiovascular events compared to hypertensive patients whose blood pressure is controlled with antihypertensive medications. As the incidence of aTRH has been increasing, there is an urgent need toward improving outcomes in this high-risk population. Few data exist regarding whether healthy lifestyle factors, either individually or combined as part of an overall healthy lifestyle, are associated with a better prognosis among individuals with aTRH. The purpose of this study was to assess the association of healthy lifestyle factors with all-cause mortality and secondarily incident cardiovascular events among individuals with aTRH. Methods: We studied participants from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, a unique resource with 2,043 participants with aTRH. Six healthy lifestyle factors (normal waist circumference, physical activity ≥4 times/week, non-smoking, moderate alcohol consumption, high Dietary Approaches to Stop Hypertension (DASH) diet score, and low sodium-to-potassium intake ratio) were examined. Results: A higher number of healthy lifestyle factors was associated with a lower risk for all-cause mortality over a mean follow-up of 5.2 years. Multivariable adjusted hazard ratios [HR (95% CI)] for all-cause mortality comparing individuals with 2, 3, 4, and 5-6 versus 0-1 healthy lifestyle factors were 0.78 (0.60-1.00), 0.70 (0.52-0.95), 0.56 (0.38-0.83) and 0.57 (0.32-1.00), respectively (P-trend=0.001). Physical activity (1-3 days/weeks vs. 0 days/week: HR 0.58; 95% CI 0.46-0.73; ≥ 4 days/week: HR 0.58; 95% CI 0.45-0.75) and, separately, non-smoking (HR 0.53; 95% CI 0.40 -0.70) were individual healthy lifestyle factors each significantly associated with a lower risk for all-cause mortality in a fully adjusted model. The HRs (95% CI) of incident cardiovascular events for 2, 3, and 4-6 versus 0-1 healthy lifestyle factors were 1.07 (0.68-1.67), 0.83 (0.48-1.44), and 0.66 (0.34-1.29), respectively (P-trend=0.150), in a fully adjusted model. Conclusions: In conclusion, healthy lifestyle factors, particularly physical activity and non-smoking, were associated with a lower risk for all-cause mortality among individuals with aTRH, a high-risk subgroup of hypertensive individuals who require multiple medications. These data support the concept that the prognosis among individuals with aTRH may be improved by interventions targeting healthy lifestyle factors. Future randomized controlled trials may be warranted to examine whether lifestyle interventions lower mortality risk among adults with aTRH.

Introduction: Waist-to-hip ratio (WHR) is associated with cardiometabolic disease and its risk factors independent of body-mass-index (BMI). Previous GWAS on WHR adjusting for BMI (WHR’) have identified several SNPs but mainly among European descent populations (EA SNPs). While these SNPs point to general loci of interest, they are not likely the causal variants. Expanding analyses of these loci to other race and ethnic populations can dually assess whether these loci apply to more diverse populations and utilize differences in genetic linkage disequilibrium (LD) patterns to narrow the region containing the causal variant. Objective: To better capture genetic variants of WHR’ in self-identified African Americans (AA) within 14 loci containing previously reported WHR’ EA SNPs. Methods: Up to 14,322 AA participants (aged 20-93 years, 61% female) were included from seven studies. Individuals were genotyped using the Illumina iSelect Metabochip array consisting of nearly 200,000 SNPs enriched to fine map GWAS signals of cardiometabolic traits, including the 14 WHR’ loci. We modeled WHR’ adjusting for age, sex, study site, and the first three ancestry principle components for each study and conducted an inverse variance weighted meta-analysis. Variants reaching a Bonferroni adjusted threshold of P Results: Within the 14 regions, seven loci (in or near TBX15-WARS2, DNM3-PIGC, GRB14, NISCH-STAB1, ADAMTS9, VEGFA, and RSPO3 ) contained a significant AA SNP. In the GRB14 locus, the AA SNP (rs10195252, P =1.93x10 -06 ) was the same as the EA SNP. Among four of the seven loci, the AA SNPs (rs12096179 near TBX15-WARS2, rs2371767 in ADAMTS9 , rs1358990 near VEGFA, and rs9385487 in RSPO3 ) were not independent of the EA SNPs (LD r 2 ≥0.3), but were more significant in AA, possibly narrowing the region containing the functional variant. Two AA SNPs (rs11715796 in NISCH-STAB1 and rs4916251 near DNM3-PIGC ) suggesting independence from the EA SNP (r 2 NISCH-STAB1 had a stronger association after conditioning on the EA SNP, signifying independence. The AA SNP near DNM3-PIGC was less significant after conditioning, indicating it points to the same signal as the EA SNP. We have identified participants from additional cohorts for inclusion in future analyses and will conduct a sex-stratified analysis to further explore WHR’ loci among AA. Conclusions: Examination of 14 previously identified loci for WHR’ in AA individuals revealed one novel signal in NISCH-STAB1 . Five additional non-independent AA SNPs suggested a narrower region containing the WHR’ altering variant based on the LD structure differences between EA and AA. These findings highlight the value in expanding genetic association studies to other race and ethnic populations.

Background: Uncontrolled blood pressure (BP) and use of multiple antihypertensive medication classes are common among persons with a history of stroke, suggesting prevalence of resistant hypertension may be high in this population. In a cohort of persons with hypertension, we sought to determine prevalence of apparent treatment-resistant hypertension (aTRH) among those with a history of stroke and/or TIA. Additionally, demographics and clinical factors associated with aTRH were determined. Methods: This cross-sectional analysis used data from REGARDS, a national, population-based, longitudinal study of 30,239 black and white adults ≥ 45 years, enrolled 2003-2007. Baseline data collection included centralized telephone interview for medical history, including self-report of physician diagnosed stroke or TIA. Analysis was restricted to 14,160 participants with hypertension, defined as SBP ≥ 140 mmHg, DBP ≥ 90 mmHg, or self-reported use of antihypertensive medications. aTRH was defined as: 1) uncontrolled BP (systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg) with concurrent use of ≥ 3 antihypertensive medication classes, or 2) use of ≥ 4 antihypertensive medication classes, regardless of BP level. We used Poisson regression to calculate predictors of aTRH. Results: Among all hypertensive participants, 2,208 (15.6%) had aTRH, however, 433/1,961 (22.1%) with a history of stroke/TIA had aTRH . After adjustment for age, race and sex, participants with history of stroke/TIA were more likely to have aTRH (prevalence ratio [PR] = 1.43; 95% CI: 1.30 - 1.57) although the association was partially mediated by adjustment for risk factors and socio-economic status (PR = 1.15; 95% CI: 1.04 - 1.28). Among stroke/TIA participants, aTRH was more common in blacks (PR = 1.70; 95% CI: 1.43 - 2.02), larger waists (PR = 1.31 per 15 cm; 95% CI: 1.22 - 1.42), diabetes (PR = 1.62; 95% CI: 1.37 - 1.91), albumin-to-creatinine ratio ≥ 30 mg/g (PR = 1.87; 1.59 - 2.20), and history of myocardial infarction (PR = 1.34; 95% CI: 1.12 - 1.59). Conclusions: In this study, over 20% of persons with stroke/TIA had aTRH. As current guidelines recommend BP reduction in these individuals, our results support identification of those who may need more intensive BP monitoring and management.

Hypertension requiring treatment with multiple antihypertensive medications is common among individuals with chronic kidney disease (CKD). Small clinic-based studies have reported a high prevalence of treatment resistant hypertension (TRH) among patients with CKD. However, the prevalence of TRH has not been estimated for people with CKD in population-based studies. We hypothesized that lower estimated glomerular filtration rate (eGFR) and higher albumin-to-creatinine ratio (ACR) would be associated with a higher prevalence of TRH. We determined the prevalence of TRH among REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants (n=30,239) by eGFR and ACR and evaluated clinical and demographic correlates of TRH in those with CKD. Blood pressure was measured twice, pill bottles were inspected, and serum creatinine and an ACR were measured during an in-home study visit. TRH was defined as systolic/diastolic blood pressure ≥140/90 mmHg with concurrent use of ≥3 antihypertensive medication classes or use of ≥4 antihypertensive medication classes. CKD was defined as an ACR ≥30 mg/g or a CKD-EPI equation-derived eGFR 2 . The mean age of the 11,285 REGARDS participants treated for hypertension was 66.0 (SD=9.0) years, 56.9% were women and 48.8% were black. The prevalence of TRH was 14.5%, 23.5%, and 31.2% for those with an eGFR ≥60, 45-59, and 2 , respectively. The prevalence of TRH was 11.3%, 18.8%, 25.5%, and 44.5% for ACR

Apparent treatment resistant hypertension (aTRH) is characterized as uncontrolled hypertension (HTN) with the use of 3 or more antihypertensive medication classes or controlled HTN while treated with 4 or more antihypertensive medication classes. Few data are available on the association of aTRH with cardiovascular disease outcomes in comparison to more easily controlled HTN. We evaluated the risk for stroke, coronary heart disease (CHD) and all-cause mortality among 2,043 participants with aTRH and 9,519 participants with controlled HTN (systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg) treated with < 4 antihypertensive medication classes from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study. aTRH was further categorized as controlled aTRH (≥ 4 antihypertensive medication classes and controlled HTN) and uncontrolled aTRH (≥ 3 antihypertensive medication classes and uncontrolled HTN). Participants with and without aTRH, respectively, were 68±9 and 66±9 years of age, 60.5% (1236 0f 2043) and 46.8% (4455 of 9519) black, and 49.2% (1005 of 2043) and 40.8% (3884 of 9519) male. After adjusting for demographic, clinical and comorbid factors, the hazard ratio (HR) for stroke, CHD, and all-cause mortality associated with aTRH (vs. controlled HTN and < 4 medication classes) was 1.29 (95% CI 0.96-1.73), 1.90 (95% CI 1.40-2.58), and 1.36 (95% CI 1.20-1.55), respectively. Compared to those with controlled hypertension, the multivariable-adjusted HR for stroke, CHD and all-cause mortality was increased for those with uncontrolled aTRH but not those with controlled aTRH (Table 1). Compared to those with controlled aTRH, uncontrolled aTRH was associated with CHD (HR 2.33; 95% CI: 1.21 [[Unable to Display Character: –]] 4.48) but not stroke (HR 1.05; 95% CI: 0.61 [[Unable to Display Character: –]] 1.81) or all-cause mortality (HR 1.15; 95% CI: 0.91 [[Unable to Display Character: –]] 1.45). We conclude achieving blood pressure control within aTRH is paramount to decrease risk for events similarly to other patients with more easily controlled HTN. Table 1. Hazard ratios for stroke, coronary heart disease, and all-cause mortality associated with apparent treatment resistant hypertension (aTRH). *< 4 antihypertensive medication classes Models are adjusted for age, race, gender, and geographic region of residence, waist circumference, smoking status, physical activity, alcohol consumption, C - reactive protein, statin use, Morisky score for medication adherence, total cholesterol, HDL-cholesterol, and hypertension duration, estimated glomerular filtration rate < 60 ml/min/1.73m 2 , albuminuria, and diabetes. Hazard ratios for stroke were also adjusted for history of coronary heart disease. Hazard ratios for coronary heart disease were also adjusted for history of stroke. Hazard ratios for all-cause mortality were also adjusted for history of coronary heart disease and stroke.

The lipid-lowering drug fenofibrate (FF) is best known for its triglyceride (TG)-lowering properties, but it also reduces low-density lipoprotein (LDL), very low density lipoprotein (VLDL) and increases high-density lipoprotein concentrations (HDL). Response to FF varies considerably among individuals and may be under genetic influence. This study seeks to uncover genetic variants that underlie the interindividual response of TG, LDL, and VLDL to FF treatment. Methods: TG, LDL, and VLDL concentrations were measured as part of the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study before and after a 3-week FF treatment (160 mg/day). Genotyping was done using the Affymetrix 6.0 genome-wide array. Lipid response phenotypes were generated using growth curve models adjusted for age, agê2, sex, and center. Associations between single nucleotide polymorphisms (SNPs) and lipid phenotypes were assessed with mixed linear models including kinship correlation structure using the R package LMEKIN . Results: Genotype and TG, LDL, and VLDL response phenotype data were successfully collected from 769, 772, and 752 participants, respectively. The strongest evidence for association (P=3.80*10-7) was observed for LDL on chromosome 10 (133.7Mb) for SNP rs1646693. This lies near SLC35B4, a gene associated with obesity and glucose homeostasis. LDL also showed evidence of association (P=4.33*10-7) with rs6593376 on chromosome 10 (43.8Mb). The strongest evidence of association (P=5.54*10-7) with TG response was also on chromosome 10 (90.2Mb) at rs7917100 within RNLS, previously associated with cardiovascular function, cardiac hypertrophy, ischemia, and hypertension. Suggestive evidence of association (P=2.52*10-6) of rs11196872, with VLDL was also found on chromosome 10 (132Mb). Conclusions: We identified several novel loci suggestively associated with TG, LDL, and VLDL response to fenofibrate treatment.

We appreciate the comments from Dr Puneetpal Singh and colleagues concerning “Apolipoprotein E (APOE) polymorphisms and postprandial triglyceridemia before and after fenofibrate treatment in the GOLDN Study.” APOE serum concentration was not measured in GOLDN. We agree that other variants in APOE may have an effect on triglyceride concentration and response to fenofibrate. Plus, interactions between variants determining e2, e3, and …