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.].

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.

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.

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.

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.

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.

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.

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.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension: the Atherosclerosis Risk in Communities cohort study.

OBJECTIVE: To quantify the role of diuretic use in gout development in an adult population with hypertension. METHODS: The Atherosclerosis Risk in Communities study, a prospective population-based cohort from 4 US communities, consisted of 4 visits over a 9-year period. Participants were included in this analysis if they answered a query about gout, were free of gout at baseline, and had hypertension (defined as taking medication to treat hypertension or having blood pressure of ≥140/90 mm Hg). Trained interviewers recorded use of antihypertensive drugs. Incident gout was defined as self-reported onset of gout after baseline. Using a time-dependent Cox proportional hazards model, we estimated hazard ratios (HRs; with 95% confidence intervals [95% CIs]) for incident gout by time-varying diuretic use, both adjusted for confounders and tested for mediation by serum urate level. RESULTS: There were 5,789 participants with hypertension; 37% were treated with a diuretic. Use of any diuretic (HR 1.48 [95% CI 1.11, 1.98]), a thiazide diuretic (HR 1.44 [95% CI 1.00, 2.10]), or a loop diuretic (HR 2.31 [95% CI 1.36, 3.91]) was associated with incident gout as compared with not using any diuretic, not using a thiazide diuretic, or not using a loop diuretic, respectively. After adjusting for serum urate level, the association between diuretic use and gout was null. Use of antihypertensive medication other than diuretic agents was associated with decreased gout risk (adjusted HR 0.64 [95% CI 0.49, 0.86]) compared to untreated hypertension. The longitudinal change in serum urate levels was 0.72 mg/dl (95% CI 0.57, 0.87) higher in those who began treatment with a diuretic than in those who did not (P<0.001). CONCLUSION: Thiazide and loop diuretics were associated with increased gout risk, an association mediated by a change in serum urate levels.

The robustness of generalized estimating equations for association tests in extended family data.

Variance components analysis (VCA), the traditional method for handling correlations within families in genetic association studies, is computationally intensive for genome-wide analyses, and the computational burden of VCA increases with family size and the number of genetic markers. Alternative approaches that do not require the computation of familial correlations are preferable, provided that they do not inflate type I error or decrease power. We performed a simulation study to evaluate practical alternatives to VCA that use regression with generalized estimating equations (GEE) in extended family data. We compared the properties of linear regression with GEE applied to an entire extended family structure (GEE-EXT) and GEE applied to nuclear family structures split from these extended families (GEE-SPL) to variance components likelihood-based methods (FastAssoc). GEE-EXT was evaluated with and without robust variance estimators to estimate the standard errors. We observed similar average type I error rates from GEE-EXT and FastAssoc compared to GEE-SPL. Type I error rates for the GEE-EXT method with a robust variance estimator were marginally higher than the nominal rate when the minor allele frequency (MAF) was <0.1, but were close to the nominal rate when the MAF was ≥0.2. All methods gave consistent effect estimates and had similar power. In summary, the GEE framework with the robust variance estimator, the computationally fastest and least data management-intensive approach, appears to work well in extended families and thus provides a reasonable alternative to full variance components approaches for extended pedigrees in a genome-wide association study setting.

Insurance status, not race, is associated with mortality after an acute cardiovascular event in Maryland.

BACKGROUND: It is unclear how lack of health insurance or otherwise being underinsured contributes to observed racial disparities in health outcomes related to cardiovascular disease. OBJECTIVE: To determine the relative risk of death associated with insurance and race after hospital admission for an acute cardiovascular event. DESIGN: Prospective cohort study in three hospitals in Maryland representing different demographics between 1993 and 2007. PATIENTS: Patients with an incident admission who were either white or black, and had either private insurance, state-based insurance or were uninsured. 4,908 patients were diagnosed with acute myocardial infarction, 6,759 with coronary atherosclerosis, and 1,293 with stroke. MAIN MEASURES: Demographic and clinical patient-level data were collected from an administrative billing database and neighborhood household income was collected from the 2000 US Census. The outcome of all-cause mortality was collected from the Social Security Death Master File. KEY RESULTS: In an analysis adjusted for race, disease severity, location, neighborhood household income among other confounders, being underinsured was associated with an increased risk of death after myocardial infarction (relative hazard, 1.31 [95 % CI: 1.09, 1.59]), coronary atherosclerosis (relative hazard, 1.50 [95 % CI: 1.26, 1.80]) or stroke (relative hazard, 1.25 [95 % CI: 0.91, 1.72]). Black race was not associated with an increased risk of death after myocardial infarction (relative hazard, 1.03 [95 % CI: 0.85, 1.24]), or after stroke (relative hazard, 1.18 [95 % CI: 0.86, 1.61]) and was associated with a decreased risk of death after coronary atherosclerosis (relative hazard, 0.82 [95 % CI: 0.69, 0.98]). CONCLUSIONS: Race was not associated with an increased risk of death, before or after adjustment. Being underinsured was strongly associated with death among those admitted with myocardial infarction, or a coronary atherosclerosis event. Our results support growing evidence implicating insurance status and socioeconomic factors as important drivers of health disparities, and potentially racial disparities.

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.

Factors affecting the likelihood of presentation to the emergency department of trauma patients after discharge.

STUDY OBJECTIVE: We determine the rate at which trauma patients re-present to the emergency department (ED) after discharge from the hospital and determine whether re-presentation is related to race, insurance, and socioeconomic factors such as neighborhood income level. METHODS: Trauma patients admitted to a Level I trauma center between January 1, 1997, and December 31, 2007, were identified with the hospital's trauma registry. These patients were linked to administrative data to obtain information about re-presentation to the hospital. Neighborhood income was obtained with census block data; multiple imputation was implemented to account for missing income data. Logistic regression analysis was used to determine the predictors of re-presentation. RESULTS: There were 6,675 patients who were included in the study. A total of 886 patients (13.3%) returned to the ED within 30 days of discharge from the hospital. Uninsured patients (odds ratio [OR]=1.64; 95% confidence interval [CI] 1.30 to 2.06) and publicly insured patients (OR=1.60; 95% CI 1.20 to 2.14) were more likely to re-present to the ED than those with commercial insurance. Residing in a neighborhood with a median household income less than $20,000 was associated with a higher odds of re-presentation (OR=1.77; 95% CI 1.37 to 2.29). Only 13.2% of patients who came to the ED were readmitted to the hospital. CONCLUSION: A substantial number of trauma patients return to the ED within 30 days of being discharged, but only a small proportion of these patients required readmission. Re-presentation is associated with being uninsured or underinsured and with lower neighborhood income level.

Associations between genetic variants in the ACE, AGT, AGTR1 and AGTR2 genes and renal function in the Multi-ethnic Study of Atherosclerosis.

BACKGROUND/AIMS: Some studies suggest that polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AGTR1) and angiotensin II type II receptor (AGTR2) genes may contribute to renal function variation. METHODS: Genotyping for single nucleotide polymorphisms (SNPs) in these candidate genes was performed in 2,847 participants from four racial/ethnic groups (African American, Chinese, White and Hispanic) without known cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. SNP and haplotype analyses were performed to determine associations between genotypes and cross-sectional renal function measurements, including urine albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin C. RESULTS: Twenty-four ACE SNPs, 10 AGT SNPs, 15 AGTR1 SNPs and 6 AGTR2 SNPs were typed successfully. After adjusting for ancestry, age and gender, 3 SNPs (AGT M235T, AGT rs2148582 and AGTR1 rs2131127) showed associations with an empiric p value <0.05 with the same phenotype in multiple racial/ethnic groups, suggesting replication. The AGT M235T SNP has been shown previously to be associated with diabetic and hypertensive nephropathy. CONCLUSIONS: These data suggest that genetic polymorphisms in the renin-angiotensin system are associated with renal phenotypes in the general population, but that many associations differ across racial/ethnic groups.

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.

Blood pressure change and risk of hypertension associated with parental hypertension: the Johns Hopkins Precursors Study.

BACKGROUND: Parental hypertension is used to classify hypertension risk in young adults, but the long-term association of parental hypertension with blood pressure (BP) change and risk of hypertension over the adult life span has not been well studied. METHODS: We examined the association of parental hypertension with BP change and hypertension risk from young adulthood through the ninth decade of life in a longitudinal cohort of 1160 male former medical students with 54 years of follow-up. RESULTS: In mixed-effects models using 29 867 BP measurements, mean systolic and diastolic BP readings were significantly higher at baseline among participants with parental hypertension. The rate of annual increase was slightly higher for systolic (0.03 mm Hg, P= .04), but not diastolic, BP in those with parental hypertension. After adjustment for baseline systolic and diastolic BP and time-dependent covariates--body mass index, alcohol consumption, coffee drinking, physical activity, and cigarette smoking--the hazard ratio (95% confidence interval [CI]) of hypertension development was 1.5 (1.2-2.0) for men with maternal hypertension only, 1.8 (1.4-2.4) for men with paternal hypertension only, and 2.4 (1.8-3.2) for men with hypertension in both parents compared with men whose parents never developed hypertension. Early-onset (at age