Rare coding variants in RCN3 are associated with blood pressure.

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10- 7). CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.

Team Science: American Heart Association's Hypertension Strategically Focused Research Network Experience.

In 2015, the American Heart Association awarded 4-year funding for a Strategically Focused Research Network focused on hypertension composed of 4 Centers: Cincinnati Children's Hospital, Medical College of Wisconsin, University of Alabama at Birmingham, and University of Iowa. Each center proposed 3 integrated (basic, clinical, and population science) projects around a single area of focus relevant to hypertension. Along with scientific progress, the American Heart Association put a significant emphasis on training of next-generation hypertension researchers by sponsoring 3 postdoctoral fellows per center over 4 years. With the center projects being spread across the continuum of basic, clinical, and population sciences, postdoctoral fellows were expected to garner experience in various types of research methodologies. The American Heart Association also provided a number of leadership development opportunities for fellows and investigators in these centers. In addition, collaboration was highly encouraged among the centers (both within and outside the network) with the American Heart Association providing multiple opportunities for meeting and expanding associations. The area of focus for the Cincinnati Children's Hospital Center was hypertension and target organ damage in children utilizing ambulatory blood pressure measurements. The Medical College of Wisconsin Center focused on epigenetic modifications and their role in pathogenesis of hypertension using human and animal studies. The University of Alabama at Birmingham Center's areas of research were diurnal blood pressure patterns and clock genes. The University of Iowa Center evaluated copeptin as a possible early biomarker for preeclampsia and vascular endothelial function during pregnancy. In this review, challenges faced and successes achieved by the investigators of each of the centers are presented.

Differences in ambulatory care fragmentation by race.

BACKGROUND: More fragmented ambulatory care (i.e., care spread across many providers without a dominant provider) has been associated with more subsequent healthcare utilization (such as more tests, procedures, emergency department visits, and hospitalizations) than less fragmented ambulatory care. It is not known if race and socioeconomic status are associated with fragmented ambulatory care. METHODS: We conducted a longitudinal analysis of data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, using the REGARDS baseline visit plus the first year of follow-up. We included participants ≥65 years old, who had linked fee-for-service Medicare claims, and ≥ 4 ambulatory visits in the first year of follow-up. We used Tobit regression to determine the associations between race, annual household income, and educational attainment at baseline and fragmentation score in the subsequent year (as measured with the reversed Bice-Boxerman Index). Covariates included other demographic characteristics, medical conditions, medication use, health behaviors, and psychosocial variables. Additional analyses categorized visits by the type of provider (primary care vs. specialist). RESULTS: The study participants (N = 6799) had an average age of 73.0 years, 53% were female, and 30% were black. Nearly half had low annual household income (<$35,000) and 41% had a high school education or less. Overall, participants had a median of 10 ambulatory visits to 4 providers in the 12 months following their baseline study visit. Participants in the highest quintile of fragmentation scores had a median of 11 visits to 7 providers. Black race was associated with an absolute adjusted 3% lower fragmentation score compared to white race (95% confidence interval (2% lower to 4% lower; p < 0.001). This difference was explained by blacks seeing fewer specialists than whites. Income and education were not independent predictors of fragmentation scores. CONCLUSIONS: Among Medicare beneficiaries, blacks had less fragmented ambulatory care than whites, due to lower utilization of specialty care. Future research is needed to determine the effect of fragmented care on health outcomes for blacks and whites.

Number of Social Determinants of Health and Fatal and Nonfatal Incident Coronary Heart Disease in the REGARDS Study.

BACKGROUND: Social determinants of health (SDH) are individually associated with incident coronary heart disease (CHD) events. Indices reflecting social deprivation have been developed for population management, but are difficult to operationalize during clinical care. We examined whether a simple count of SDH is associated with fatal incident CHD and nonfatal myocardial infarction (MI). METHODS: We used data from the prospective longitudinal REGARDS cohort study (Reasons for Geographic and Racial Differences in Stroke), a national population-based sample of community-dwelling Black and White adults age ≥45 years recruited from 2003 to 2007. Seven SDH from the 5 Healthy People 2020 domains included social context (Black race, social isolation); education (educational attainment); economic stability (annual household income); neighborhood (living in a zip code with high poverty); and health care (lacking health insurance, living in 1 of the 9 US states with the least public health infrastructure). Outcomes were expert adjudicated fatal incident CHD and nonfatal MI. RESULTS: Of 22 152 participants free of CHD at baseline, 58.8% were women and 42.0% were Black; 20.6% had no SDH, 30.6% had 1, 23.0% had 2, and 25.8% had ≥3. There were 463 fatal incident CHD events and 932 nonfatal MIs over a median of 10.7 years (interquartile range, 6.6 to 12.7). Fewer SDHs were associated with nonfatal MI than with fatal incident CHD. The age-adjusted incidence per 1000 person-years increased with the number of SDH for both fatal incident CHD (0 SDH, 1.30; 1 SDH, 1.44; 2 SDH, 2.05; ≥3 SDH, 2.86) and nonfatal MI (0 SDH, 3.91; 1 SDH, 4.33; ≥2 SDH, 5.44). Compared with those without SDH, crude and fully adjusted hazard ratios for fatal incident CHD among those with ≥3 SDH were 3.00 (95% CI, 2.17 to 4.15) and 1.67 (95% CI, 1.18 to 2.37), respectively; hazard ratios for nonfatal MI among those with ≥2 SDH were 1.57 (95% CI, 1.30 to 1.90) and 1.14 (95% CI, 0.93 to 1.41), respectively. CONCLUSIONS: A greater burden of SDH was associated with a graded increase in risk of incident CHD, with greater magnitude and independent associations for fatal incident CHD. Counting the number of SDHs may be a promising approach that could be incorporated into clinical care to identify individuals at high risk of CHD.

Healthcare Fragmentation and Incident Acute Coronary Heart Disease Events: a Cohort Study.

BACKGROUND: Highly fragmented ambulatory care (i.e., care spread across many providers without a dominant provider) has been associated with excess tests, procedures, emergency department visits, and hospitalizations. Whether fragmented care is associated with worse health outcomes, or whether any association varies with health status, is unclear. OBJECTIVE: To determine whether fragmented care is associated with the risk of incident coronary heart disease (CHD) events, overall and stratified by self-rated general health. DESIGN AND PARTICIPANTS: We conducted a secondary analysis of the nationwide prospective Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study (2003-2016). We included participants who were ≥ 65 years old, had linked Medicare fee-for-service claims, and had no history of CHD (N = 10,556). MAIN MEASURES: We measured fragmentation with the reversed Bice-Boxerman Index. We used Cox proportional hazards models to determine the association between fragmentation as a time-varying exposure and adjudicated incident CHD events in the 3 months following each exposure period. KEY RESULTS: The mean age was 70 years; 57% were women, and 34% were African-American. Over 11.8 years of follow-up, 569 participants had CHD events. Overall, the adjusted hazard ratio (HR) for the association between high fragmentation and incident CHD events was 1.14 (95% confidence interval (CI) 0.92, 1.39). Among those with very good or good self-rated health, high fragmentation was associated with an increased hazard of CHD events (adjusted HR 1.35; 95% CI 1.06, 1.73; p = 0.01). Among those with fair or poor self-rated health, high fragmentation was associated with a trend toward a decreased hazard of CHD events (adjusted HR 0.54; 95% CI 0.29, 1.01; p = 0.052). There was no association among those with excellent self-rated health. CONCLUSION: High fragmentation was associated with an increased independent risk of incident CHD events among those with very good or good self-rated health.

Association Between Patients' Self-Reported Gaps in Care Coordination and Preventable Adverse Outcomes: a Cross-Sectional Survey.

BACKGROUND: Whether patients' reports of gaps in care coordination reflect clinically significant problems is unclear. OBJECTIVE: To determine any association between patient-reported gaps in care coordination and patient-reported preventable adverse outcomes. DESIGN AND PARTICIPANTS: We administered a cross-sectional survey on experiences with healthcare to participants in the national Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who were ≥ 65 years old. Of the 15,817 participants in REGARDS at the time of our survey (August 2017-November 2018), 11,138 completed the survey. We restricted the sample to participants who reported ≥ 2 ambulatory visits and ≥ 2 ambulatory providers in the past year (N = 7568). MAIN MEASURES: We considered 7 gaps in ambulatory care coordination, elicited with previously validated questions. We considered 4 outcomes: (1) a test that was repeated because the doctor did not have the result of the first test, (2) a drug-drug interaction that occurred due to multiple prescribers, (3) an emergency department visit that could have been prevented by better communication among providers, and (4) a hospital admission that could have been prevented by better communication among providers. We used logistic regression to determine the association between ≥ 1 gap in care coordination and ≥ 1 preventable outcome, adjusting for potential confounders. KEY RESULTS: The average age of the sample was 77.0 years; 55% were female, and 34% were African-American. More than one-third of participants (38.1%) reported ≥ 1 gap in care coordination and nearly one-tenth (9.8%) reported ≥ 1 preventable outcome. Having ≥ 1 gap in care coordination was associated with an increased odds of ≥ 1 preventable outcome (adjusted odds ratio 1.55; 95% confidence interval 1.33, 1.81). CONCLUSIONS: Participants' reports of gaps in care coordination were associated with an increased odds of preventable adverse outcomes. Future interventions should leverage patients' observations to detect and resolve gaps in care coordination.

Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data.

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.

Racial disparities in the prevalence and control of hypertension among a cohort of HIV-infected patients in the southeastern United States.

BACKGROUND: African Americans are disproportionately affected by both HIV and hypertension. Failure to modify risk factors for cardiovascular disease and chronic kidney disease such as hypertension among HIV-infected patients may attenuate the benefits conferred by combination antiretroviral therapy. In the general population, African Americans with hypertension are less likely to have controlled blood pressure than whites. However, racial differences in blood pressure control among HIV-infected patients are not well studied. METHODS: We conducted a cross-sectional study evaluating racial differences in hypertension prevalence, treatment, and control among 1,664 patients attending the University of Alabama at Birmingham HIV Clinic in 2013. Multivariable analyses were performed to calculate prevalence ratios (PR) with 95% confidence intervals (CI) as the measure of association between race and hypertension prevalence and control while adjusting for other covariates. RESULTS: The mean age of patients was 47 years, 77% were male and 54% African-American. The prevalence of hypertension was higher among African Americans compared with whites (49% vs. 43%; p = 0.02). Among those with hypertension, 91% of African Americans and 93% of whites were treated (p = 0.43). Among those treated, 50% of African Americans versus 60% of whites had controlled blood pressure (systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg) (p = 0.007). After multivariable adjustment for potential confounders, prevalence of hypertension was higher among African Americans compared to whites (PR 1.25; 95% CI 1.12-1.39) and prevalence of BP control was lower (PR 0.80; 95% CI 0.69-0.93). CONCLUSIONS: Despite comparable levels of hypertension treatment, African Americans in our HIV cohort were less likely to achieve blood pressure control. This may place them at increased risk for adverse outcomes that disproportionately impact HIV-infected patients, such as cardiovascular disease and chronic kidney disease, and thus attenuate the benefits conferred by combination antiretroviral therapy.

Treatment-Resistant Hypertension and Outcomes Based on Randomized Treatment Group in ALLHAT.

BACKGROUND: Although hypertension guidelines define treatment-resistant hypertension as blood pressure uncontrolled by ≥3 antihypertensive medications, including a diuretic, it is unknown whether patient prognosis differs when a diuretic is included. METHODS: Participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) were randomly assigned to first-step therapy with chlorthalidone, amlodipine, or lisinopril. At a Year 2 follow-up visit, those with average blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic on ≥3 antihypertensive medications, or blood pressure <140/90 mm Hg on ≥4 antihypertensive medications were identified as having apparent treatment-resistant hypertension. The prevalence of treatment-resistant hypertension and its association with ALLHAT primary (combined fatal coronary heart disease or nonfatal myocardial infarction) and secondary (all-cause mortality, stroke, heart failure, combined coronary heart disease, and combined cardiovascular disease) outcomes were identified for each treatment group. RESULTS: Of participants assigned to chlorthalidone, amlodipine, or lisinopril, 9.6%, 11.4%, and 19.7%, respectively, had treatment-resistant hypertension. During mean follow-up of 2.9 years, primary outcome incidence was similar for those assigned to chlorthalidone compared with amlodipine or lisinopril (amlodipine- vs chlorthalidone-adjusted hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.53-1.39; P = .53; lisinopril- vs chlorthalidone-adjusted HR = 1.06; 95% CI, 0.70-1.60; P = .78). Secondary outcome risks were similar for most comparisons except coronary revascularization, which was higher with amlodipine than with chlorthalidone (HR 1.86; 95% CI, 1.11-3.11; P = .02). An as-treated analysis based on diuretic use produced similar results. CONCLUSIONS: In this study, which titrated medications to a goal, participants assigned to chlorthalidone were less likely to develop treatment-resistant hypertension. However, prognoses in those with treatment-resistant hypertension were similar across treatment groups.

Is Pulse Pressure an Independent Risk Factor for Incident Stroke, REasons for Geographic And Racial Differences in Stroke.

BACKGROUND: Pulse pressure (PP) is a potential risk factor of stroke. The relationship of incident stroke with systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and PP was examined. METHODS: Data were from the REasons for Geographic And Racial Differences in Stroke national cohort study of 30,239 black and white participants aged ≥45 years, enrolled between 2003 and 2007. PP (SBP-DBP) and MAP (MAP = DBP + 1/3*PP) were calculated. Telephone follow-up occurred every six months for self or proxy-reported suspected stroke events, confirmed using expert adjudication. Cox-proportional hazards models examined the association of incident stroke for the different BP measurements with multivariable adjustment for sociodemographic and clinical risk factors including gender and race. RESULTS: Men and women without prevalent stroke at baseline were analyzed (n = 25,462). During follow-up (mean 6.3±2.3 years, maximum 10 years), 916 strokes occurred. Unadjusted PP (hazard ratio [HR] = 1.30; 95% confidence interval [CI] 1.24-1.35), SBP (HR = 1.22; 95% CI 1.18-1.32), MAP (HR = 1.24; 95% CI 1.16-1.32), and DBP (HR = 1.09; 95% CI 1.01-1.17) were associated with stroke risk; however, after adjustment for SBP and other risk factors, the association with PP was attenuated (HR = 0.98; 95% CI 0.90-1.07), whereas SBP persisted as a predictor (HR = 1.14; 95% CI 1.06-1.23). These associations were consistent across age (younger vs. older >70 years) and race (black vs. white). CONCLUSIONS: PP is positively associated with incident stroke, but not independently from SBP; and, there were no significant gender, racial, or regional differences in that association.

Association of race and sex with risk of incident acute coronary heart disease events.

CONTEXT: It is unknown whether long-standing disparities in incidence of coronary heart disease (CHD) among US blacks and whites persist. OBJECTIVE: To examine incident CHD by black and white race and by sex. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 24,443 participants without CHD at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, who resided in the continental United States and were enrolled between 2003 and 2007 with follow-up through December 31, 2009. MAIN OUTCOME MEASURE: Expert-adjudicated total (fatal and nonfatal) CHD, fatal CHD, and nonfatal CHD (definite or probable myocardial infarction [MI]; very small non-ST-elevation MI [NSTEMI] had peak troponin level <0.5 µg/L). RESULTS: Over a mean (SD) of 4.2 (1.5) years of follow-up, 659 incident CHD events occurred (153 in black men, 138 in black women, 254 in white men, and 114 in white women). Among men, the age-standardized incidence rate per 1000 person-years for total CHD was 9.0 (95% CI, 7.5-10.8) for blacks vs 8.1 (95% CI, 6.9-9.4) for whites; fatal CHD: 4.0 (95% CI, 2.9-5.3) vs 1.9 (95% CI, 1.4-2.6), respectively; and nonfatal CHD: 4.9 (95% CI, 3.8-6.2) vs 6.2 (95% CI, 5.2-7.4). Among women, the age-standardized incidence rate per 1000 person-years for total CHD was 5.0 (95% CI, 4.2-6.1) for blacks vs 3.4 (95% CI, 2.8-4.2) for whites; fatal CHD: 2.0 (95% CI, 1.5-2.7) vs 1.0 (95% CI, 0.7-1.5), respectively; and nonfatal CHD: 2.8 (95% CI, 2.2-3.7) vs 2.2 (95% CI, 1.7-2.9). Age- and region-adjusted hazard ratios for fatal CHD among blacks vs whites was near 2.0 for both men and women and became statistically nonsignificant after multivariable adjustment. The multivariable-adjusted hazard ratio for incident nonfatal CHD for blacks vs whites was 0.68 (95% CI, 0.51-0.91) for men and 0.81 (95% CI, 0.58-1.15) for women. Of the 444 nonfatal CHD events, 139 participants (31.3%) had very small NSTEMIs. CONCLUSIONS: The higher risk of fatal CHD among blacks compared with whites was associated with cardiovascular disease risk factor burden. These relationships may differ by sex.

Prevalence of acidosis and inflammation and their association with low serum albumin in chronic kidney disease.

BACKGROUND: Low serum albumin is a strong risk factor for mortality, but its association with low serum bicarbonate and inflammation in the setting of mild to moderately decreased kidney function is uncertain. METHODS: We analyzed data from 15594 subjects over the age of 20 who participated in the Third National Health and Nutrition Examination Survey (NHANES III). Glomerular filtration rate (GFR) in mL/min/1.73 m2 was estimated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation using appropriately calibrated serum creatinine. RESULTS: The age-adjusted prevalence of hypoalbuminemia (serum albumin <3.8 g/dL) at a GFR of 90, 60, 30, and 15 mL/min/1.73 m2 was 19%, 21%, 38%, and 59%, respectively, while the age-adjusted prevalence of C-reactive protein (CRP) >or= 0.22 mg/dL was 36%, 44%, 69%, and 81%, respectively, both P trend <0.001. Age, female gender, non-Hispanic black compared with non-Hispanic white race, diabetes, hypertension, hepatitis C, urine albumin: creatinine ratio >1 g/g, dietary protein intake, dietary caloric intake, serum bicarbonate, CRP, and GFR category were all significant predictors of hypoalbuminemia on univariate analysis. On simultaneously adjusting for the above variables, hypertension, diabetes, GFR, and dietary protein and caloric intake were no longer significant independent predictors of hypoalbuminemia. The adjusted odds ratio (OR) of serum bicarbonate (by quartile) for hypoalbuminemia was 1.0 for serum bicarbonate >28 mEq/L (reference), 1.25 for 26-28 mEq/L, 1.51 for 23-25 mEq/L, and 1.54 for 1.0 mg/dL. CONCLUSION: Elevated CRP and low serum bicarbonate are independently associated with hypoalbuminemia, explaining much of the high prevalence of hypoalbuminemia in chronic kidney disease.