Effect of substance use on premature mortality among severely hypertensive African Americans.

Low-income African Americans residing in impoverished neighborhoods confront myriad barriers to adhering to antihypertensive regimens. Substance use may thwart medication adherence and lifestyle modification efforts, which has implications for excess cardiovascular disease mortality. The Inner-City Hypertension and Body Organ Damage (ICHABOD) Study was a longitudinal cohort study that evaluated causes of mortality among African Americans who lived in urban areas, had severe, poorly controlled hypertension, and were admitted to a local hospital between 1999-2001 and 2002-2004. The authors employed Cox proportional hazards models to assess mortality associated with illicit substance use, including use of heroin and cocaine, as well as by use of tobacco and alcohol. Among192 participants with poorly controlled hypertension, 30% were active illicit substance users (specifically, 22.7% heroin users, 19.8% were cocaine users, and 30.7% were both cocaine and heroin users). The mean age among substance non-users was 52.3 years versus 48.7 years among those reporting current use. Mortality over 7.6 years of follow-up was 52.5% among substance users and 33.8% among nonusers (p-value, 0.01). After adjusting for potential confounders, the hazard ratio (HR) for cocaine use was 2.52 (95% confidence interval (CI) 1.38-4.59), while the HR for heroin use was 2.47 (95% CI 1.42-4.28) and the HR for both was 2.75 (95% CI 1.60-4.73). Substance use was associated with increased mortality among urban black Americans with poorly controlled hypertension. These data suggest the need for targeted interventions to support African Americans who have poorly controlled hypertension and use illicit substances, as a means of reducing excess mortality.

Effects of carbohydrate quality and amount on plasma lactate: results from the OmniCarb trial.

INTRODUCTION: Plasma lactate is a marker of non-oxidative glucose metabolism associated with progression to diabetes. We examined the effect of carbohydrate quality (glycemic index (GI)) and amount (%kcal) on plasma lactate. We hypothesized that low GI (≤45 (g)) versus high (≥65 (G)) and low %kcal from carbohydrate (40% kcal (c)) versus high (58% kcal (C)) each would reduce lactate levels. RESEARCH DESIGN AND METHODS: We measured lactate in OmniCarb, a randomized, cross-over trial of four diets in overweight/obese adults without diabetes or cardiovascular disease (N=163). The four diets were high carbohydrate+high GI (CG, reference), high carbohydrate+low GI (Cg), low carbohydrate+high GI (cG), and low carbohydrate+low GI (cg). Participants (N=163) consumed each of the four diets over a 5-week period, separated by 2-week washout periods. Plasma lactate levels were measured at baseline, during which the participants consumed their own diets, and after each 5-week period. RESULTS: Baseline plasma lactate was 1.2 mmol/L. In the setting of high carbohydrate amount, reducing GI lowered plasma lactate non-significantly by 0.08 mmol/L (Cg vs CG: 95% CI -0.16 to 0.00; p=0.06). In the setting of high GI, reducing carbohydrate amount lowered plasma lactate by 0.10 mmol/L (cG vs CG: 95% CI -0.19 to -0.02; p=0.02). The combined effect of reducing GI and carbohydrate proportion in the diet (cg vs CG) was similar (cg vs CG: -0.08; 95% CI -0.16 to 0.00; p=0.04). All four diets reduced plasma lactate compared with baseline. CONCLUSIONS: Compared with a diet with high GI and high carbohydrate amount, diets with low GI and/or low carbohydrate amount reduced plasma lactate. Whether this change in lactate leads to long-term change in glucose metabolism needs to be examined. TRIAL REGISTRATION NUMBER: NCT00608049.

Mitochondrial DNA copy number and diabetes: the Atherosclerosis Risk in Communities (ARIC) study.

INTRODUCTION: Mitochondrial DNA copy number (mtDNA-CN) is a measure of mitochondrial dysfunction and is associated with diabetes in experimental models. To explore the temporality of mitochondrial dysfunction and diabetes, we estimated the prevalent and incident association of mtDNA-CN and diabetes. RESEARCH DESIGN AND METHODS: We assessed the associations of mtDNA-CN measured from buffy coat with prevalent and incident diabetes, stratified by race, in 8954 white and 2444 black participants in the Atherosclerosis Risk in Communities (ARIC) study, an observational cohort study. Follow-up for incident analyses was complete through visit 6, 2016. RESULTS: Mean age at mtDNA-CN measurement was 57 years and 59% were female. Prevalence of diabetes at time of mtDNA-CN measurement was higher in blacks (563/2444, 23%) than whites (855/8954, 10%). The fully adjusted odds of prevalent diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.05 (95% CI 0.74 to 1.49) among black and 1.49 (95% CI 1.20 to 1.85) among white participants. Over a median follow-up time of 19 years (Q1, Q3: 11, 24 years), we observed 617 incident diabetes cases among 1744 black and 2121 cases among 7713 white participants free of diabetes at baseline. The fully adjusted hazard of incident diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.07 (95% CI 0.84 to 1.38) among black and 0.97 (95% CI 0.86 to 1.10) among white participants. CONCLUSIONS: Lower mtDNA-CN in buffy coat was associated with prevalent diabetes in white but not black ARIC participants. Lower mtDNA-CN was not associated with incident diabetes over 20 years of follow-up in whites or blacks.

Overweight/obesity among social network members has an inverse relationship with Baltimore public housing residents' BMI.

The American Heart Association has encouraged networks research focused on cardiovascular disease and its risk factors, such as obesity. However, little network research has focused on minorities or low-income populations. Our objective was to characterize the relationship between body mass index (BMI) with social network overweight/obesity among public housing residents in Baltimore, MD - a predominantly black, low-income group. We conducted a cross-sectional survey of randomly selected public housing residences (8/2014-8/2015). Adults had their height and weight measured and reported their network members' weight statuses using pictograms. Our dependent variable was respondents' BMI, and independent variable was perceived exposure to overweight/obesity in the social network. We also explored network exposure to overweight/obesity among 1) family members and 2) friends. We used multivariable linear regression adjusted for significant covariates. Our sample included 255 adults with mean age of 44.4 years, 85.5% women, 95.7% black, and mean BMI of 33.2 kg/m2. Most network members were overweight/obese (56.1%). For every 1% increase in network exposure to overweight/obesity, individuals' BMI decreased by 0.05 kg/m2 (p = 0.06). As network exposure to overweight/obesity among friends increased, individuals' BMI significantly decreased by 0.06 kg/m2 (p = 0.04). There was no significant relationship between BMI and network exposure to overweight/obesity among family members. In conclusion, among Baltimore public housing residents, a statistically significant, inverse association existed between individuals' BMI and overweight/obesity among friends in their social networks. Our results differ from relationships seen in prior studies of other populations, which may be due to racial and/or contextual differences between studies.

Correction: Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

[This corrects the article DOI: 10.1371/journal.pgen.1006728.].

Perceived Diet and Exercise Behaviors Among Social Network Members With Personal Lifestyle Habits of Public Housing Residents.

Our objective was to characterize the relationship between public housing residents' diet/exercise habits with similar behaviors among their social network. We conducted a cross-sectional survey of randomly selected households in Baltimore, Maryland, from August 2014 to August 2015. Adult heads of household completed questions on diet, exercise, and perceived habits among network members. Our dependent variables were high added sugar intake (≥39.9 teaspoons/day), high fruit/vegetable intake (≥6.1 servings/day), and being physically active (≥moderately activity). Our network exposures were proportion of members perceived to daily consume (1) sugar-sweetened beverages, (2) sweets, (3) fruits, and (4) vegetables, as well as to weekly exercise (1) vigorously or (2) moderately. We used multivariate logistic regression to examine associations between habits with relevant network exposures. Our sample included 266 adults with mean age of 44.5 years, 86.1% women and 95.5% African American. We found a statistically significant association between study participants' high daily intake of added sugar with perceived network exposure to daily sugar-sweetened beverages (odds ratio [OR] = 1.10, 95% confidence interval [CI] [1.02, 1.20]) and daily sweets (OR = 1.10, 95% CI [1.02, 1.20]). Greater network exposure to weekly vigorous exercise was significantly associated with personally being physically active (OR = 1.15, 95% CI [1.04, 1.28]), but not network exposure to weekly moderate exercise. Among public housing residents, associations exist between individuals' and perceived networks' lifestyle habits of high added sugar foods consumption and vigorous exercise, which may hold promise for future social network interventions.

Methods to estimate underlying blood pressure: The Atherosclerosis Risk in Communities (ARIC) Study.

Antihypertensive medications complicate studies of blood pressure (BP) natural history; BP if untreated ("underlying BP") needs to be estimated. Our objectives were to compare validity of five missing data imputation methods to estimate underlying BP and longitudinal associations of underlying BP and age. We simulated BP treatment in untreated hypertensive participants from Atherosclerosis Risk in Communities (ARIC) in visits 1-5 (1987-2013) using matched treated hypertensive participants. The underlying BP was imputed: #1, set as missing; #2, add 10 mmHg for systolic, 5 mmHg for diastolic; #3, add medication class-specific constant; #4, truncated normal regression; and #5, truncated normal regression including prior visit data. Longitudinal associations were estimated using linear mixed models of imputed underlying BP for simulated treated and measured BP for untreated participants. Method 3 was the best-performing for systolic BP; lowest relative bias (5.3% for intercept at age 50, 0% for age coefficient) and average deviation from expected (0.04 to -1.79). Method 2 performed best for diastolic BP; lowest relative bias (0.6% intercept at age 50, 33.3% age <60, 9.1% age 60+) and average deviation (-1.25 to -1.68). Methods 4 and 5 were comparable or slightly inferior. In conclusion, constant addition methods yielded valid and precise underlying BP and longitudinal associations.

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.

We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the participants, 193 individuals developed CKD (estimated glomerular filtration rate under 60 ml/min/1.73m2) between cohort examinations 6 (1995-1998) and 8 (2005-2008, mean follow-up 9.7 years). They were age- and sex-matched to 193 control individuals free of CKD. A total of 154 urinary metabolites were measured using mass spectrometry, and the association between metabolites and CKD was examined using logistic regression. Next, we tested the genetic associations of each metabolite with an Illumina exome chip. Urinary glycine and histidine were associated with a lower risk of incident CKD with an odds ratio of 0.59 (95% confidence interval [CI] 0.43-0.80) and 0.65 (0.50-0.85) respectively, per one standard deviation increase in metabolite concentration. Follow-up in the Atherosclerosis Risk in Communities cohort confirmed the association of urinary glycine with CKD. In exome chip analyses, 36 single nucleotide polymorphisms at 30 loci were significantly associated with 31 metabolites. We surveyed exome chip findings for associations with known renal function loci such as rs8101881 in SLC7A9 coding for an amino acid transporter, which has been associated with a lower risk of CKD. We found this polymorphism was significantly associated with higher levels of lysine and NG-monomethyl-L-arginine (NMMA). Increased urinary lysine and NMMA were associated with a lower risk of CKD (0.73 [0.50-0.90] and 0.66 [0.53-0.83], respectively) in the univariate model. Thus, low urinary glycine and histidine are associated with incident CKD. Furthermore, genomic association of urinary metabolomics identified lysine and NMMA as being linked with CKD and provided additional evidence for the association of SLC7A9 with kidney disease.

Power Analysis and Sample Size Determination in Metabolic Phenotyping.

Estimation of statistical power and sample size is a key aspect of experimental design. However, in metabolic phenotyping, there is currently no accepted approach for these tasks, in large part due to the unknown nature of the expected effect. In such hypothesis free science, neither the number or class of important analytes nor the effect size are known a priori. We introduce a new approach, based on multivariate simulation, which deals effectively with the highly correlated structure and high-dimensionality of metabolic phenotyping data. First, a large data set is simulated based on the characteristics of a pilot study investigating a given biomedical issue. An effect of a given size, corresponding either to a discrete (classification) or continuous (regression) outcome is then added. Different sample sizes are modeled by randomly selecting data sets of various sizes from the simulated data. We investigate different methods for effect detection, including univariate and multivariate techniques. Our framework allows us to investigate the complex relationship between sample size, power, and effect size for real multivariate data sets. For instance, we demonstrate for an example pilot data set that certain features achieve a power of 0.8 for a sample size of 20 samples or that a cross-validated predictivity QY(2) of 0.8 is reached with an effect size of 0.2 and 200 samples. We exemplify the approach for both nuclear magnetic resonance and liquid chromatography-mass spectrometry data from humans and the model organism C. elegans.

Access to Care, Treatment Ambivalence, Medication Nonadherence, and Long-Term Mortality Among Severely Hypertensive African Americans: A Prospective Cohort Study.

African Americans living in poor neighborhoods bear a high burden of illness and early mortality. Nonadherence may contribute to this burden. In a prospective cohort study of urban African Americans with poorly controlled hypertension, mortality was 47.6% over a median follow-up of 6.1 years. Patients with pill-taking nonadherence were more likely to die (hazard ratio, 1.80; 95% confidence interval [CI], 1.18-2.76) after adjustment for potential confounders. With regard to factors related to nonadherence, poor access to care such as difficulty paying for medications was associated with prescription refill nonadherence (odds ratio [OR], 4.12; 95% CI, 1.88-9.03). Pill-taking nonadherence was not associated with poor access to care; however, it was associated with factors related to treatment ambivalence including lower hypertension knowledge (OR, 2.97; 95% CI, 1.39-6.32), side effects (OR, 3.44; 95% CI, 1.47-8.03), forgetfulness (OR, 3.62; 95% CI, 1.78-7.34), and feeling that the medications do not help (OR, 2.78; 95% CI, 1.09-7.09). These data suggest that greater access to care is a necessary but insufficient remedy to the disparities experienced by urban African Americans with hypertension. To achieve its full promise, health reform must also address treatment ambivalence.

Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension.

Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple-even distinct-traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10(-8)) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10(-7)) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes.

Plasma lactate and incident hypertension in the atherosclerosis risk in communities study.

BACKGROUND: Recent evidence suggests that insufficient oxidative capacity or mitochondrial dysfunction may play a causal role in the development of high blood pressure. However, this hypothesis has not been tested in the general population. We hypothesized that lactate, a measure of oxidative capacity, would be positively associated with incident hypertension even after accounting for traditional hypertension risk factors. METHODS: Plasma lactate was measured in 5,554 participants from the Atherosclerosis Risk in Communities (ARIC) Study with no subclinical or diagnosed hypertension at baseline (1996-1998). Incident hypertension was defined by self-report or hypertension medication use. Analyses were performed with Cox proportional hazards models. RESULTS: The mean age was 61.9 years, and the mean lactate was 0.8 mmol/L. During a median follow-up period of 11.9 years (range = 26.9 days to 13.4 years), there were 3,849 new cases of hypertension. The fourth quartile of lactate (compared with the first quartile) was associated with an elevated risk of hypertension (hazard ratio (HR) = 1.18; 95% confidence interval (CI) = 1.07-1.31) even after adjustment for traditional risk factors, including baseline systolic and diastolic blood pressure. This association was stronger when the population was restricted to participants with normal blood pressure (<120mm Hg/<80mm Hg; HR = 1.42; 95% CI = 1.23-1.63). In strata of sex, the association was strong in women vs. null in men (P interaction = 0.01). CONCLUSIONS: Plasma lactate is associated with incident hypertension in women, especially with a normal blood pressure (<120mm Hg/<80mm Hg). Future studies should elucidate the mechanisms underlying these observations.

Factors associated with appointment non-adherence among African-Americans with severe, poorly controlled hypertension.

BACKGROUND: Missed appointments are associated with an increased risk of hospitalization and mortality. Despite its widespread prevalence, little data exists regarding factors related to appointment non-adherence among hypertensive African-Americans. OBJECTIVE: To investigate factors associated with appointment non-adherence among African-Americans with severe, poorly controlled hypertension. DESIGN AND PARTICIPANTS: A cross-sectional survey of 185 African-Americans admitted to an urban medical center in Maryland, with severe, poorly controlled hypertension from 1999-2004. Categorical and continuous variables were compared using chi-square and t-tests. Adjusted multivariable logistic regression was used to assess correlates of appointment non-adherence. MAIN OUTCOME MEASURES: Appointment non-adherence was the primary outcome and was defined as patient-report of missing greater than 3 appointments out of 10 during their lifetime. RESULTS: Twenty percent of participants (n = 37) reported missing more than 30% of their appointments. Patient characteristics independently associated with a higher odds of appointment non-adherence included not finishing high school (Odds ratio [OR]  = 3.23 95% confidence interval [CI] (1.33-7.69), hypertension knowledge ([OR]  = 1.20 95% CI: 1.01-1.42), lack of insurance ([OR]  = 6.02 95% CI: 1.83-19.88), insurance with no medication coverage ([OR]  = 5.08 95% CI: 1.05-24.63), cost of discharge medications ([OR]  = 1.20 95% CI: 1.01-1.42), belief that anti-hypertensive medications do not work ([OR]  = 3.67 95% CI: 1.16-11.7), experience of side effects ([OR]  = 3.63 95% CI: 1.24-10.62), medication non-adherence ([OR]  = 11.31 95% CI: 3.87-33.10). Substance abuse was not associated with appointment non-adherence ([OR]  = 1.05 95% CI: 0.43-2.57). CONCLUSIONS: Appointment non-adherence among African-Americans with poorly controlled hypertension was associated with many markers of inadequate access to healthcare, knowledge, attitudes and beliefs.

Association between intentional injury and long-term survival after trauma.

OBJECTIVE: To determine the risk-adjusted mortality of intentionally injured patients within 7 to 9 years postinjury, compared with unintentionally injured patients. BACKGROUND: Violent injury contributes significantly to trauma mortality in the United States. Homicide is the second leading killer of American youth, aged 15 to 24 years. Long-term survival among intentionally injured patients has not been well studied. It is also unknown whether intentionally injured patients have worse long-term survival compared with unintentionally or accidentally injured patients with equivalent injuries. METHODS: Adult trauma patients admitted for 24 hours or more and discharged alive from the Johns Hopkins Hospital from January 1, 1998, to December 31, 2000, were included. The primary outcome was mortality within 7 to 9 years postinjury. Long-term patient survival was determined using the National Death Index. The association between injury intentionality and mortality was investigated using a Cox proportional hazard regression model, adjusted for confounders such as injury severity and patient race, socioeconomic status, and comorbid conditions. Overall differences in survival between those with intentional versus unintentional injury were also determined by comparing adjusted Kaplan-Meier survival curves. RESULTS: A total of 2062 patients met inclusion criteria. Of these, 56.4% were intentionally injured and 43.6% were unintentionally injured. Compared with unintentionally injured patients, intentionally injured patients were younger and more often male and from a zip code with low median household income. Approximately 15% of all patients had died within 7 to 9 years of follow-up. Older age and presence of comorbidities were associated with this outcome; however, intentional injury was not found to be significantly associated with long-term mortality rates. There was also no significant difference in survival curves between groups; intentionally injured patients were much more likely to die of a subsequent injury, whereas those with unintentional injury commonly died of noninjury causes. CONCLUSIONS: There was no significant difference in mortality between intentionally injured and unintentionally injured patients within 7 to 9 years postinjury. These results confirm the long-term effectiveness of lifesaving trauma care for those with intentional injury. However, given that patients with intentional injuries were more likely to suffer a subsequent violent death, interventions focused on breaking the cycle of violence are needed.

Disparities in diabetes: the nexus of race, poverty, and place.

OBJECTIVES: We sought to determine the role of neighborhood poverty and racial composition on race disparities in diabetes prevalence. METHODS: We used data from the 1999-2004 National Health and Nutrition Examination Survey and 2000 US Census to estimate the impact of individual race and poverty and neighborhood racial composition and poverty concentration on the odds of having diabetes. RESULTS: We found a race-poverty-place gradient for diabetes prevalence for Blacks and poor Whites. The odds of having diabetes were higher for Blacks than for Whites. Individual poverty increased the odds of having diabetes for both Whites and Blacks. Living in a poor neighborhood increased the odds of having diabetes for Blacks and poor Whites. CONCLUSIONS: To address race disparities in diabetes, policymakers should address problems created by concentrated poverty (e.g., lack of access to reasonably priced fruits and vegetables, recreational facilities, and health care services; high crime rates; and greater exposures to environmental toxins). Housing and development policies in urban areas should avoid creating high-poverty neighborhoods.

Behavioural health interventions in the Johns Hopkins Community Health Partnership: integrated care as a component of health systems transformation.

Health systems in the USA have received a mandate to improve quality while reining in costs. Several opportunities have been created to stimulate this transformation. This paper describes the design, early implementation and lessons learned for the behavioural components of the John Hopkins Community Health Partnership (J-CHiP) programme. J-CHiP is designed to improve health outcomes and reduce the total healthcare costs of a group of high healthcare use patients who are insured by the government-funded health insurance programmes, Medicaid and Medicare. These patients have a disproportionately high prevalence of depression, other psychiatric conditions, and unhealthy behaviours that could be addressed with behavioural interventions. The J-CHiP behavioural intervention is based on integrated care models, which include embedding mental health professionals into primary sites. A four-session behaviour-based protocol was developed to motivate self-efficacy through illness management skills. In addition to staff embedded in primary care, the programme design includes expedited access to specialist psychiatric services as well as a community outreach component that addresses stigma. The progress and challenges involved with developing this programme over a relatively short period of time are discussed.

Plasma lactate and diabetes risk in 8045 participants of the atherosclerosis risk in communities study.

PURPOSE: Determinants of oxidative capacity, such as fitness and level of adiposity, are strongly associated with type 2 diabetes. Whether decreased oxidative capacity itself is a cause or consequence of insulin resistance and diabetes is unknown. METHODS: We examined the association of plasma lactate, a marker of oxidative capacity, with incident diabetes in 8045 participants from the Atherosclerosis Risk in Communities (ARIC) Study with no history of subclinical or diagnosed diabetes at baseline (1996-1998). Incident diabetes was self-reported during annual telephone calls. RESULTS: During a median follow-up of 12 years, there were 1513 new cases of diabetes. In Cox proportional hazards models, baseline plasma lactate (per 10 mg/dL) was significantly associated with diabetes (hazard ratio, 1.20; 95% confidence interval, 1.01-1.43), even after adjustment for diabetes risk factors, fasting glucose, and insulin. The upper quartile of baseline lactate (≥ 8.1 mg/dL) was also significantly associated with diabetes risk (hazard ratio, 1.20; 95% confidence interval, 1.02-1.41) compared with the lowest quartile (≤ 5.1 mg/dL). Significant associations persisted among persons without insulin resistance (homeostatic model assessment insulin resistance index < 2.6 U) (P-trend < .01). CONCLUSIONS: These findings suggest that low oxidative capacity may precede diabetes. Future studies should evaluate the physiological origins of elevated lactate to better understand its possible role in the pathogenesis of diabetes.

Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

The association of plasma lactate with incident cardiovascular outcomes: the ARIC Study.

We examined the association of plasma lactate at rest, a marker of oxidative capacity, with incident cardiovascular outcomes in 10,006 participants in the Atherosclerosis Risk in Communities (ARIC) Study visit 4 (1996-1998). We used Cox proportional-hazards models to estimate hazard ratios of incident coronary heart disease, stroke, heart failure, and all-cause mortality by quartiles of plasma lactate (Q1, ≤5.3 mg/dL; Q2, 5.4-6.6; Q3, 6.7-8.6; and Q4 ≥8.7). During a median follow-up time of 10.7 years, there were 1,105 coronary heart disease cases, 379 stroke cases, 820 heart failure cases, and 1,408 deaths. A significant graded relation between lactate level and cardiovascular events was observed in the demographically adjusted model (all P for trend < 0.001). After further adjustment for traditional and other potential confounders, the association remained significant for heart failure (Q4 vs. Q1: hazard ratio (HR) = 1.35, 95% confidence interval (CI): 1.07, 1.71) and all-cause mortality (HR = 1.27, 95% CI: 1.07, 1.51) (P for trend < 0.02 for these outcomes) but not for coronary heart disease (HR = 1.02, 95% CI: 0.84, 1.24) and stroke (HR = 1.26, 95% CI: 0.91, 1.75). The results for heart failure were robust across multiple subgroups, after further adjustment for N-terminal pro-B-type natriuretic peptide and after exclusion of participants with incident heart failure within 3 years. The independent associations of plasma lactate with heart failure and all-cause mortality suggest an important role for low resting oxidative capacity.