Publications by authors named "Solomon K Musani"

108 Publications

Kidney Function and Aortic Stiffness, Pulsatility, and Endothelial Function in African Americans: The Jackson Heart Study.

Kidney Med 2021 Sep-Oct;3(5):702-711.e1. Epub 2021 Jul 14.

Department of Medicine, University of Mississippi Medical Center, Jackson, MS.

Rationale & Objective: The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans.

Study Design: Cross-sectional cohort analysis of data from the Jackson Heart Study.

Settings & Patients: 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry.

Predictors: Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m.

Outcomes: Prevalent albuminuria, urinary albumin-creatinine ratio.

Analytical Approach: 2-sample test for continuous variables and χ test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable.

Results: Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD;  = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11];  < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65];  = 0.001).

Limitations: Cross-sectional analyses cannot inform causality.

Conclusions: Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans.
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http://dx.doi.org/10.1016/j.xkme.2021.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515070PMC
July 2021

Insulin resistance, metabolic syndrome, and blood pressure progression among Blacks: the Jackson Heart Study.

J Hypertens 2021 11;39(11):2200-2209

Division of Endocrinology, Diabetes & Metabolism, Department of Medicine.

Objective: There is a paucity of data on the relations of insulin resistance with incident blood pressure (BP) changes among Blacks. We investigated the associations of insulin resistance and metabolic syndrome (MetS) with BP progression in a community-based sample of African Americans.

Methods: We analyzed 1064 participants without hypertension at baseline (2000-2004) who attended at least one follow-up visit in 2005-2008 or 2009-2013. Four insulin resistance indices [fasting insulin, insulin-to-glucose ratio (IGR), homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI)] and MetS (excluding hypertension in the definition) were assessed at baseline. Robust Poisson regression was used to generate risk ratios (RRs) and 95% confidence intervals (CI) for BP progression and incident hypertension.

Results: Over a median of 7 years, 69.6% progressed to a higher BP category and 62.7% developed hypertension. After multivariable adjustment, participants in the highest quartile of HOMA-IR had higher risks of BP progression [RR 1.25 (95% CI 1.09-1.43), Ptrend = 0.004] and hypertension [RR 1.35 (95% CI 1.16-1.58), Ptrend < 0.001] compared with those in the lowest quartile. A similar positive association of insulin resistance with BP outcomes was noted with insulin resistance assessed using IGR, fasting insulin, and QUICKI. MetS was associated with increased risks of BP progression [RR 1.15 (95% CI 1.02-1.30), P = 0.02] and incident hypertension [RR 1.23 [95% CI 1.08-1.41], P = 0.002]. These associations were present across baseline BP categories.

Conclusion: Our findings support the notion that higher insulin resistance levels are associated with greater risks of BP progression and incident hypertension among Blacks.
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http://dx.doi.org/10.1097/HJH.0000000000002920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500911PMC
November 2021

Plasma Adiponectin And Blood Pressure Progression in African Americans: The Jackson Heart Study.

Am J Hypertens 2021 Jun 24. Epub 2021 Jun 24.

Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: Little is known on the association of plasma adiponectin with blood pressure (BP) changes in African Americans (AAs). We evaluated the associations between plasma adiponectin and BP progression among AAs.

Methods: We analyzed data from 1184 participants without hypertension at baseline (2000-2004) with ≥1 follow-up visits in the Jackson Heart Study. We used robust Poisson regression to generate risk ratios (RR) for BP progression (an increase by ≥1 BP stage) and incident hypertension.

Results: Over a median of 7 years, 71 % progressed to higher BP stage and 65% developed hypertension. We found evidence of interaction by sex (P-interaction=0.088). Compared to those in the lowest quartile (Q1), male participants in the highest adiponectin quartile (Q4) had reduced risks of BP progression (Risk Ratio [RR] 0.76 [95% CI 0.60-0.96]) and incident hypertension (RR 0.74 [95% CI 0.56-0.97]). After accounting for body mass index, this relation persisted among obese men (RR for the highest (vs. lowest) adiponectin quartile: 0.59 (95% CI 0.36-0.97) for incident hypertension, and 0.69 (95% CI 0.45-1.06) for BP progression). Among women, adiponectin was not associated with BP outcomes (RR [95% CI] for Q4 vs Q1: 1.03 [0.86-1.23], and 1.01[0.83-1.23] for BP progression and incident hypertension respectively). Our findings were consistent across both the ACC/AHA and JNC-7 BP categories.

Conclusions: In a large, community-based sample of African Americans, higher adiponectin concentrations were associated with lower risks of BP progression and incident hypertension in men, but no significant association was observed in women.
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http://dx.doi.org/10.1093/ajh/hpab101DOI Listing
June 2021

Electrocardiogram machine learning for detection of cardiovascular disease in African Americans: the Jackson Heart Study.

Eur Heart J Digit Health 2021 Mar 20;2(1):137-151. Epub 2021 Jan 20.

Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, UHN62, Portland, OR 97239, USA.

Aims: Almost half of African American (AA) men and women have cardiovascular disease (CVD). Detection of prevalent CVD in community settings would facilitate secondary prevention of CVD. We sought to develop a tool for automated CVD detection.

Methods And Results: Participants from the Jackson Heart Study (JHS) with analysable electrocardiograms (ECGs) (=3679; age, 6212 years; 36% men) were included. Vectorcardiographic (VCG) metrics QRS, T, and spatial ventricular gradient vectors magnitude and direction, and traditional ECG metrics were measured on 12-lead ECG. Random forests, convolutional neural network (CNN), lasso, adaptive lasso, plugin lasso, elastic net, ridge, and logistic regression models were developed in 80% and validated in 20% samples. We compared models with demographic, clinical, and VCG input (43 predictors) and those after the addition of ECG metrics (695 predictors). Prevalent CVD was diagnosed in 411 out of 3679 participants (11.2%). Machine learning models detected CVD with the area under the receiver operator curve (ROC AUC) 0.690.74. There was no difference in CVD detection accuracy between models with VCG and VCG + ECG input. Models with VCG input were better calibrated than models with ECG input. Plugin-based lasso model consisting of only two predictors (age and peak QRS-T angle) detected CVD with AUC 0.687 [95% confidence interval (CI) 0.6250.749], which was similar (=0.394) to the CNN (0.660; 95% CI 0.5970.722) and better (<0.0001) than random forests (0.512; 95% CI 0.4930.530).

Conclusions: Simple model (age and QRS-T angle) can be used for prevalent CVD detection in limited-resources community settings, which opens an avenue for secondary prevention of CVD in underserved communities.
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http://dx.doi.org/10.1093/ehjdh/ztab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139412PMC
March 2021

Association between MTNR1B polymorphisms and obesity in African American: findings from the Jackson Heart Study.

BMC Med Genomics 2021 05 21;14(1):136. Epub 2021 May 21.

Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA, 30130, USA.

Background: Melatonin is a hormone that is secreted at night by the pineal gland. It exerts its function by binding to the MT and MT receptors, which are encoded by the MTNR1A and MTNR1B genes, respectively. Previous studies reveal that MTNR1B variants are associated with insulin secretion impairments and an increased body mass index (BMI) in individuals of European and Asian ancestries. Obesity is highly prevalent in the US and disproportionately affects African Americans. Here, we hypothesized that common single nucleotide polymorphisms (SNPs) imputed in 1000 Genomes in the MTNR1B gene are associated with adiposity in African American adult men and women and that the association is modified by insomnia.

Methods: We used an additive genetic model to describe the association between the adiposity traits (BMI and waist circumference) and selected MTNR1B variants in 3,029 Jackson Heart Study participants, with an average age of 55.13 ± 12.84 years, and 62% were women. We regressed the adiposity measures on the estimated allelic or genotypic dosage at every selected SNP and adjusted for age, sex, population stratification, and insomnia. Thirty common SNPs, spanning the MTNR1B gene, with a minor allele frequency ≥ 5%, a call rate ≥ 90%, a Hardy-Weinberg equilibrium p value > 10, were available for the analysis.

Results: The allele T of rs76371840 was associated with adiposity (OR = 1.47 [1.13-1.82]; P = 0.0499), and the allele A of rs8192552 showed a significant association with waist circumference (β = 0.023 ± 0.007; P = 0.0077) after correcting for multiple testing. When insomnia was included in the adiposity analysis model, the following four variants became significantly associated with adiposity: rs6483208; rs4388843; rs4601728; and rs12804291.

Conclusions: Our data indicate that polymorphisms in the MTNR1B gene are associated with obesity traits in African Americans. To the best of our knowledge, this is the first study to explore the effect of insomnia on the association between the circadian MTNR1B genetic variants and metabolic traits in an African American sample population. We observed that insomnia affected the association between the MTNR1B variants and adiposity.
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http://dx.doi.org/10.1186/s12920-021-00983-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138980PMC
May 2021

Epidemiology of Heart Failure Stages in Middle-Aged Black People in the Community: Prevalence and Prognosis in the Atherosclerosis Risk in Communities Study.

J Am Heart Assoc 2021 05 21;10(9):e016524. Epub 2021 Apr 21.

Department of Medicine University of Mississippi Medical Center Jackson MS.

Background Black individuals have a higher burden of risk factors for heart failure (HF) and subclinical left ventricular remodeling. Methods and Results We evaluated 1871 Black participants in the Atherosclerosis Risk in Communities Study cohort who attended a routine examination (1993-1996, median age 58 years) when they underwent echocardiography. We estimated the prevalences of 4 HF stages: (1) : no risk factors; (2) : presence of HF risk factors (hypertension, diabetes mellitus, obesity, smoking, dyslipidemia, coronary artery disease without clinical myocardial infarction), no cardiac structural/functional abnormality; (3) : presence of prior myocardial infarction, systolic dysfunction, left ventricular hypertrophy, regional wall motion abnormality, or left ventricular enlargement; and (4) : prevalent HF. We assessed the incidence of clinical HF, atherosclerotic cardiovascular disease events, and all-cause mortality on follow-up according to HF stage. The prevalence of HF Stages 0, A, B, and C/D were 3.8%, 20.6%, 67.0%, and 8.6%, respectively, at baseline. On follow-up (median 19.0 years), 309 participants developed overt HF, 390 incurred new-onset cardiovascular disease events, and 651 individuals died. Incidence rates per 1000 person-years for overt HF, cardiovascular disease events, and death, respectively, were Stage 0, 2.4, 0.8, and 7.6; Stage A, 7.4, 9.7, and 13.5; Stage B 13.6, 15.9, and 22.0. Stage B HF was associated with a 1.5- to 2-fold increased adjusted risk of HF, cardiovascular disease events and death compared with Stages 0/A. Conclusions In our large community-based sample of Black individuals, we observed a strikingly high prevalence of Stage B HF in middle age that was a marker of high cardiovascular morbidity and mortality.
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http://dx.doi.org/10.1161/JAHA.120.016524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200743PMC
May 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517040PMC
April 2021

Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.

Hum Mol Genet 2021 Jul;30(15):1443-1456

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.
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http://dx.doi.org/10.1093/hmg/ddab096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283205PMC
July 2021

Metabolic Dyslipidemia and Cardiovascular Outcomes in Type 2 Diabetes Mellitus: Findings From the Look AHEAD Study.

J Am Heart Assoc 2021 04 17;10(7):e016947. Epub 2021 Mar 17.

Division of Endocrinology, Diabetes & Metabolism Department of Medicine Johns Hopkins School of Medicine Baltimore MD.

Background Metabolic dyslipidemia (high triglyceride) and low high-density lipoprotein cholesterol (HDL-C) is highly prevalent in type 2 diabetes mellitus (T2DM). The extent to which diabetes mellitus-related abnormalities in the triglyceride-HDL-C profile associates with cardiovascular disease (CVD) risk is incompletely understood. We evaluated the associations of triglyceride and HDL-C status with CVD outcomes in individuals with T2DM. Methods and Results We analyzed data from 4199 overweight/obese adults with T2DM free of CVD with available data on triglyceride and HDL-C at baseline (2001-2004) in the Look AHEAD (Action for Health in Diabetes) study. We used Cox proportional models to estimate hazard ratios (HRs) and 95% CIs of: (1) composite CVD outcome (myocardial infarction, stroke, hospitalization for angina, and/or death from cardiovascular causes); (2) coronary artery disease events; and (3) cerebrovascular accidents (stroke). Of the 4199 participants, 62% (n=2600) were women, with a mean age of 58 years (SD, 7), and 40% (n=1659) had metabolic dyslipidemia at baseline. Over a median follow-up of 9.5 years (interquartile range, 8.7-10.3), 500 participants experienced the composite CVD outcome, 396 experienced coronary artery disease events, and 100 experienced stroke. Low HDL-C was associated with higher hazards of the composite CVD outcome (HR, 1.36; 95% CI, 1.12-1.64 [=0.002]) and coronary artery disease events (HR, 1.46; 95% CI, 1.18-1.81 [=0.001]) but not stroke (HR, 1.38; 95% CI, 0.90-2.11 [=0.140]). Compared with patients with normal triglyceride and normal HDL, participants with metabolic dyslipidemia had higher risks of the composite CVD outcome (HR, 1.30; 95% CI, 1.03-1.63 [=0.025]) and coronary artery disease events (HR, 1.48; 95% CI, 1.14-1.93 [=0.003]) but not stroke (HR, 1.23; 95% CI, 0.74-2.05 [=0.420]). Conclusions In a large sample of overweight/obese individuals with T2DM, metabolic dyslipidemia was associated with higher risks of CVD outcomes. Our findings highlight the necessity to account for metabolic dyslipidemia in CVD risk stratification among patients with T2DM. Registration URL: https://www.lookaheadtrial.org; Unique identifier: NCT00017953.
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http://dx.doi.org/10.1161/JAHA.120.016947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174364PMC
April 2021

Plasma Leptin and Blood Pressure Progression in Blacks: The Jackson Heart Study.

Hypertension 2021 04 1;77(4):1069-1075. Epub 2021 Mar 1.

From the Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD (R.S.A., S.H.G., J.B.E.-T.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16174DOI Listing
April 2021

Malaria is a cause of iron deficiency in African children.

Nat Med 2021 04 22;27(4):653-658. Epub 2021 Feb 22.

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.
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http://dx.doi.org/10.1038/s41591-021-01238-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610676PMC
April 2021

Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.

EBioMedicine 2021 Jan 6;63:103157. Epub 2021 Jan 6.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
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http://dx.doi.org/10.1016/j.ebiom.2020.103157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804602PMC
January 2021

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

Plasma adipokines and glycaemic progression among African Americans: Findings from the Jackson Heart Study.

Diabet Med 2021 May 25;38(5):e14465. Epub 2020 Dec 25.

Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Aim: To evaluate the association between plasma biomarkers including leptin, adiponectin, adiponectin-to-leptin ratio and high-sensitivity C-reactive protein (hsCRP) with risk of glycaemic progression and incident dysglycaemia (pre-diabetes or diabetes) in a community-based sample of African American (AAs).

Methods: We analysed data from 3223 participants without type 2 diabetes at baseline (2000-2004) who attended ≥1 follow-up visit. Poisson regression was used to generate risk ratios (RRs) for glycaemic progression and incident dysglycaemia.

Results: Over a median of 7 years, 46.4% developed glycaemic progression (n=1495). After adjusting for demographic and lifestyle variables, the RRs (95% CI) for glycaemic progression comparing highest (Q4) to lowest (Q1) quartiles were 1.30 (1.10-1.54), 0.74 (0.65-0.84), 0.70 (0.62-0.80) and 1.22 (1.07-1.38) for leptin, adiponectin, adiponectin-leptin ratio and hsCRP, respectively. Upon additional adjustment for BMI, the corresponding RRs (95% CIs) were 1.15 (0.94-1.42), 0.76 (0.67-0.86), 0.72 (0.62-0.84) and 1.14 (0.99-1.31) respectively. Among participants with normal glycaemia, the RRs (95% CIs) for incident pre-diabetes in Q4 vs Q1 were 1.37 (1.13-1.67), 0.73 (0.63-0.85), 0.70 (0.59-0.82) and 1.28 (1.10-1.48) for leptin, adiponectin, adiponectin-leptin ratio and hsCRP, respectively; equivalent RRs for incident diabetes were 5.15 (2.63-10.10), 0.36 (0.20-0.68), 0.21 (0.12-0.38) and 3.04 (1.70-5.44), respectively.

Conclusions: In this large community-based cohort of AAs, our results suggest that high plasma leptin and hsCRP, as well as low adiponectin and adiponectin-to-leptin ratio, are associated with higher risks of glycaemic progression. The findings point to the potential utility of these biomarkers in predicting and preventing glycaemic progression in this high-risk population.
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http://dx.doi.org/10.1111/dme.14465DOI Listing
May 2021

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

J Clin Endocrinol Metab 2021 01;106(2):372-387

Brigham and Women's Hospital, Havard University, Boston, MA, USA.

Context: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation.

Objective: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease.

Design: Genetics of Obesity-associated Liver Disease Consortium.

Setting: Population-based.

Main Outcome: Computed tomography measured liver attenuation.

Results: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate.

Conclusions: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.
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http://dx.doi.org/10.1210/clinem/dgaa855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823249PMC
January 2021

Evaluating the precision of EBF1 SNP x stress interaction association: sex, race, and age differences in a big harmonized data set of 28,026 participants.

Transl Psychiatry 2020 10 20;10(1):351. Epub 2020 Oct 20.

Behavioral Medicine Research Center, Duke University School of Medicine, Durham, NC, USA.

In prior work, we identified a novel gene-by-stress association of EBF1's common variation (SNP rs4704963) with obesity (i.e., hip, waist) in Whites, which was further strengthened through multiple replications using our synthetic stress measure. We now extend this prior work in a precision medicine framework to find the risk group using harmonized data from 28,026 participants by evaluating the following: (a) EBF1 SNPxSTRESS interaction in Blacks; (b) 3-way interaction of EBF1 SNPxSTRESS with sex, race, and age; and (c) a race and sex-specific path linking EBF1 and stress to obesity to fasting glucose to the development of cardiometabolic disease risk. Our findings provided additional confirmation that genetic variation in EBF1 may contribute to stress-induced human obesity, including in Blacks (P = 0.022) that mainly resulted from race-specific stress due to "racism/discrimination" (P = 0.036) and "not meeting basic needs" (P = 0.053). The EBF1 gene-by-stress interaction differed significantly (P = 1.01e-03) depending on the sex of participants in Whites. Race and age also showed tentative associations (Ps = 0.103, 0.093, respectively) with this interaction. There was a significant and substantially larger path linking EBF1 and stress to obesity to fasting glucose to type 2 diabetes for the EBF1 minor allele group (coefficient = 0.28, P = 0.009, 95% CI = 0.07-0.49) compared with the same path for the EBF1 major allele homozygotes in White females and also a similar pattern of the path in Black females. Underscoring the race-specific key life-stress indicators (e.g., racism/discrimination) and also the utility of our synthetic stress, we identified the potential risk group of EBF1 and stress-induced human obesity and cardiometabolic disease.
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http://dx.doi.org/10.1038/s41398-020-01028-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572375PMC
October 2020

Clinical Associations of Vascular Stiffness, Microvascular Dysfunction, and Prevalent Cardiovascular Disease in a Black Cohort: The Jackson Heart Study.

J Am Heart Assoc 2020 09 2;9(18):e017018. Epub 2020 Sep 2.

Department of Medicine Division of Cardiovascular Diseases University of Mississippi Medical Center Jackson MS.

Background Measures of vascular dysfunction are related to adverse cardiovascular disease (CVD) outcomes in non-Hispanic, White populations; however, data from Black individuals are limited. We aimed to investigate the associations between novel hemodynamic measures and prevalent CVD in a sample of Black individuals. Methods and Results Among older Black participants of the Jackson Heart Study, we assessed noninvasive vascular hemodynamic measures using arterial tonometry and Doppler ultrasound. We assessed 5 measures of aortic stiffness and wave reflection (carotid-femoral pulse wave velocity, pulse wave velocity ratio, forward pressure wave amplitude, central pulse pressure, and augmentation index), and 2 measures of microvascular function (baseline and hyperemic brachial flow velocity). Using multivariable logistic regression models, we examined the relations between vascular hemodynamic measures and prevalent CVD. In models adjusted for traditional CVD risk factors, higher carotid-femoral pulse wave velocity (odds ratio [OR],1.25; 95% CI, 1.01-1.55; =0.04), lower augmentation index (OR, 0.84; 95% CI, 0.70-0.99; =0.05), and lower hyperemic brachial flow velocity (OR, 0.77; 95% CI, 0.65-0.90; =0.001) were associated with higher odds of CVD. After further adjustment for hypertension treatment, lower augmentation index (OR, 0.84; 95% CI, 0.70-0.99; =0.04) and hyperemic brachial flow velocity (OR, 0.79; 95% CI, 0.67-0.94; =0.006), but not carotid-femoral pulse wave velocity (OR, 1.23; 95% CI, 0.99-1.051; =0.06), were associated with higher odds of CVD. Conclusions In a sample of older Black individuals, more severe microvascular damage and aortic stiffness were associated with prevalent CVD. Further research on hemodynamic mechanisms that contribute to cardiovascular risk among older Black individuals is merited.
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http://dx.doi.org/10.1161/JAHA.120.017018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726980PMC
September 2020

Experiences of Discrimination Are Associated With Worse Metabolic Syndrome Severity Among African Americans in the Jackson Heart Study.

Ann Behav Med 2021 03;55(3):266-279

Department of Health Outcomes and Biomedical Informatics, University of Florida, Gainesville, FL, USA.

Background: Metabolic syndrome (MetS) is a risk factor for the development of cardiovascular disease and type 2 diabetes. Although the development of MetS is attributed to known lifestyle factors, perceived discrimination may also contribute to MetS development and severity.

Purpose: We examined the associations of perceived discrimination with MetS severity among African American adults at baseline and 8-year follow-up.

Methods: Three thousand eight hundred and seventy participants (mean age 53.8 ± 13.0; 63.1% female) without diabetes and no missing MetS severity scores at baseline were included. Each self-reported measure of discrimination at baseline (everyday, lifetime, and burden of lifetime) was classified into tertiles (low, medium, high). After adjustment for demographics and MetS risk factors, associations of discrimination were examined with a sex- and race/ethnicity-specific MetS severity Z-score. We employed a mixed model approach that allowed for the assessment of an overall association between reported discrimination at baseline and MetS severity, and for the possible change over time.

Results: Sex and age differences were observed in experiences with discrimination, such that men reported higher levels of all aspects of discrimination relative to women. Everyday discrimination decreased with age, whereas lifetime discrimination increased with age (p < .05). Independent of lifestyle and demographic factors, everyday and lifetime discrimination were significantly associated with MetS severity (p = .003 and p = .017, respectively) and the associations remained constant over the 8 years (i.e., no interaction with time).

Conclusions: Our results suggest that, in a large community-based sample of African Americans, discrimination is a salient psychosocial risk factor for severity of MetS.
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http://dx.doi.org/10.1093/abm/kaaa050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980767PMC
March 2021

Risk of Ischemic Stroke Increases Over the Spectrum of Metabolic Syndrome Severity.

Stroke 2020 08 19;51(8):2548-2552. Epub 2020 Jun 19.

Department of Health Outcomes and Biomedical Informatics, University of Florida, Gainesville (S.L.F., M.L.G.).

Background And Purpose: Ischemic stroke is associated with the metabolic syndrome (MetS) as diagnosed using dichotomous criteria; however, these criteria exhibit racial/ethnic discrepancies. Our goal was to assess whether ischemic stroke risk extended over the spectrum of worsening MetS severity using a sex- and race/ethnicity-specific MetS-severity score.

Methods: We used Cox-proportional hazards models to assess the relationship between baseline MetS- score and incident ischemic stroke among participants of the Atherosclerosis Risk in Communities study and Jackson Heart Study who were free from diabetes, coronary heart disease or stroke at baseline, evaluating 13 141 white and black individuals with mean follow-up of 18.6 years.

Results: We found that risk of ischemic stroke increased consistently with MetS severity, with a hazard ratio of 1.75 (95% CI, 1.35-2.27) for those >75th percentile compared to those <25th percentile. This risk was highest for white females (hazard ratio, 2.63 [CI, 1.70-4.07]) though without significant interaction by sex and race. Relationships between stroke and all the individual components of MetS were only noted for white females, though again without sex-race interactions. Hazard ratio's for systolic blood pressure and stroke were significant among all sex/racial subgroups.

Conclusions: Ischemic stroke risk increased over the spectrum of MetS severity in the absence of baseline diabetes mellitus, further implicating potential etiologic risks from processes underlying MetS. Individuals with elevated MetS severity should be counselled toward lifestyle modification to lower ischemic stroke risk.
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http://dx.doi.org/10.1161/STROKEAHA.120.028944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428063PMC
August 2020

Associations of adiponectin and leptin with brain natriuretic peptide in African Americans: the Jackson Heart Study.

Cardiovasc Endocrinol Metab 2020 Jun 15;9(2):49-55. Epub 2020 May 15.

Indiana University School of Public Health, Bloomington, Indiana.

Brain natriuretic peptide (BNP) is elevated in decompensated systolic and diastolic heart failure. The plasma levels of adipokines, such as adiponectin and leptin, may provide evidence for mechanistic differences in BNP concentrations. African-American-specific associations are limited in the literature. The objective of this study was to evaluate the associations of adiponectin and leptin with BNP among African Americans.

Methods: Linear and logistic regressions were used to test the associations between adiponectin, leptin, and plasma BNP in 3738 participants of the Jackson Heart Study (JHS), a single-site prospective cohort study of African Americans in Jackson, Mississippi.

Results: A direct relationship of adiponectin was observed in multiple multivariate-adjusted linear models: in men ( = 0.41-0.47), and in women ( = 0.32-0.38). Those in the highest quartile of adiponectin expression were twice as likely to have elevated BNP levels after adjustment [odds ratio 2.66 (95% confidence interval, 1.66-4.34)]. An inverse relationship of leptin with BNP was observed ( = -0.15) but attenuated after adjustment for aldosterone, renin, and adiponectin.

Conclusions: Different linear associations of adiponectin and leptin with BNP were observed. Odds of elevated adiponectin were observed with elevated BNP in multivariate-adjusted models. This paradoxical relationship of adiponectin and plasma BNP is possibly explained through adiponectin resistance.
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http://dx.doi.org/10.1097/XCE.0000000000000198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228776PMC
June 2020

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

PLoS One 2020 7;15(5):e0230815. Epub 2020 May 7.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States of America.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205201PMC
August 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 06 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

Ambulatory Blood Pressure Phenotypes in Adults Taking Antihypertensive Medication with and without CKD.

Clin J Am Soc Nephrol 2020 04 26;15(4):501-510. Epub 2020 Mar 26.

Departments of Epidemiology and

Background And Objectives: Recent guidelines recommend out-of-clinic BP measurements.

Design, Setting, Participants, & Measurements: We compared the prevalence of BP phenotypes between 561 black patients, with and without CKD, taking antihypertensive medication who underwent ambulatory BP monitoring at baseline (between 2000 and 2004) in the Jackson Heart Study. CKD was defined as an albumin-to-creatinine ratio ≥30 mg/g or eGFR <60 ml/min per 1.73 m. Sustained controlled BP was defined by BP at goal both inside and outside of the clinic and sustained uncontrolled BP as BP above goal both inside and outside of the clinic. Masked uncontrolled hypertension was defined by controlled clinic-measured BP with uncontrolled out-of-clinic BP.

Results: CKD was associated with a higher multivariable-adjusted prevalence ratio for uncontrolled versus controlled clinic BP (prevalence ratio, 1.44; 95% CI, 1.02 to 2.02) and sustained uncontrolled BP versus sustained controlled BP (prevalence ratio, 1.66; 95% CI, 1.16 to 2.36). There were no statistically significant differences in the prevalence of uncontrolled daytime or nighttime BP, nondipping BP, white-coat effect, and masked uncontrolled hypertension between participants with and without CKD after multivariable adjustment. After multivariable adjustment, reduced eGFR was associated with masked uncontrolled hypertension versus sustained controlled BP (prevalence ratio, 1.42; 95% CI, 1.00 to 2.00), whereas albuminuria was associated with uncontrolled clinic BP (prevalence ratio, 1.76; 95% CI, 1.20 to 2.60) and sustained uncontrolled BP versus sustained controlled BP (prevalence ratio, 2.02; 95% CI, 1.36 to 2.99).

Conclusions: The prevalence of BP phenotypes defined using ambulatory BP monitoring is high among adults with CKD taking antihypertensive medication.
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http://dx.doi.org/10.2215/CJN.08840719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133126PMC
April 2020

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Nat Commun 2019 11 12;10(1):5121. Epub 2019 Nov 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
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http://dx.doi.org/10.1038/s41467-019-12958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851116PMC
November 2019

Kidney Risk Variants and Cardiovascular Disease: An Individual Participant Data Meta-Analysis.

J Am Soc Nephrol 2019 10 5;30(10):2027-2036. Epub 2019 Aug 5.

Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Background: Two coding variants in the apo L1 gene () are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results.

Methods: We conducted a two-stage individual participant data meta-analysis to assess the association of kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts.

Results: Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by genotype. genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index.

Conclusions: In this large, two-stage individual participant data meta-analysis, kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.
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http://dx.doi.org/10.1681/ASN.2019030240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779370PMC
October 2019

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Hum Mol Genet 2019 08;28(15):2615-2633

Icelandic Heart Association, Kopavogur, Iceland.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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http://dx.doi.org/10.1093/hmg/ddz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644157PMC
August 2019

Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.

Nat Genet 2019 04 29;51(4):636-648. Epub 2019 Mar 29.

Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
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http://dx.doi.org/10.1038/s41588-019-0378-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467258PMC
April 2019

Effect of Previous Exposure to Malaria on Blood Pressure in Kilifi, Kenya: A Mendelian Randomization Study.

J Am Heart Assoc 2019 03;8(6):e011771

1 KEMRI-Wellcome Trust Research Programme Kilifi Kenya.

Background Malaria exposure in childhood may contribute to high blood pressure ( BP ) in adults. We used sickle cell trait ( SCT ) and αthalassemia, genetic variants conferring partial protection against malaria, as tools to test this hypothesis. Methods and Results Study sites were Kilifi, Kenya, which has malaria transmission, and Nairobi, Kenya, and Jackson, Mississippi, where there is no malaria transmission. The primary outcome was 24-hour systolic BP. Prevalent hypertension, diagnosed using European Society of Hypertension thresholds was a secondary outcome. We performed regression analyses adjusting for age, sex, and estimated glomerular filtration rate. We studied 1127 participants in Kilifi, 516 in Nairobi, and 651 in Jackson. SCT frequency was 21% in Kilifi, 16% in Nairobi, and 9% in Jackson. SCT was associated with -2.4 (95% CI , -4.7 to -0.2) mm Hg lower 24-hour systolic BP in Kilifi but had no effect in Nairobi/Jackson. The effect of SCT in Kilifi was limited to 30- to 59-year-old participants, among whom it was associated with -6.1 mm Hg ( CI , -10.5 to -1.8) lower 24-hour systolic BP. In pooled analysis allowing interaction by site, the effect of SCT on 24-hour systolic BP in Kilifi was -3.5 mm Hg ( CI , -6.9 to -0.1), increasing to -5.2 mm Hg ( CI , -9.5 to -0.9) when replacing estimated glomerular filtration rate with urine albumin to creatinine ratio as a covariate. In Kilifi, the prevalence ratio for hypertension was 0.86 ( CI , 0.76-0.98) for SCT and 0.89 ( CI , 0.80-0.99) for αthalassemia. Conclusions Lifelong malaria protection is associated with lower BP in Kilifi. Confirmation of this finding at other sites and elucidating the mechanisms involved may yield new preventive and therapeutic targets.
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http://dx.doi.org/10.1161/JAHA.118.011771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475058PMC
March 2019
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