Publications by authors named "Hemant K Tiwari"

150 Publications

Risk Factor Characterization of Ischemic Stroke Subtypes Among West Africans.

Stroke 2021 Sep 30:STROKEAHA120032072. Epub 2021 Sep 30.

Federal Medical Centre Umuahia, , Nigeria (K.U., I.I.C., U.O., O.O., K.A.O.).

Background And Purpose: To identify the qualitative and quantitative contributions of conventional risk factors for occurrence of ischemic stroke and its key pathophysiologic subtypes among West Africans.

Methods: The SIREN (Stroke Investigative Research and Educational Network) is a multicenter, case-control study involving 15 sites in Ghana and Nigeria. Cases include adults aged ≥18 years with ischemic stroke who were etiologically subtyped using the A-S-C-O-D classification into atherosclerosis, small-vessel occlusion, cardiac pathology, other causes, and dissection. Controls were age- and gender-matched stroke-free adults. Detailed evaluations for vascular, lifestyle, and psychosocial factors were performed. We used conditional logistic regression to estimate adjusted odds ratios with 95% CI.

Results: There were 2431 ischemic stroke case and stroke-free control pairs with respective mean ages of 62.2±14.0 versus 60.9±13.7 years. There were 1024 (42.1%) small vessel occlusions, 427 (17.6%) large-artery atherosclerosis, 258 (10.6%) cardio-embolic, 3 (0.1%) carotid dissections, and 719 (29.6%) undetermined/other causes. The adjusted odds ratio (95% CI) for the 8 dominant risk factors for ischemic stroke were hypertension, 10.34 (6.91-15.45); dyslipidemia, 5.16 (3.78-7.03); diabetes, 3.44 (2.60-4.56); low green vegetable consumption, 1.89 (1.45-2.46); red meat consumption, 1.89 (1.45-2.46); cardiac disease, 1.88 (1.22-2.90); monthly income $100 or more, 1.72 (1.24-2.39); and psychosocial stress, 1.62 (1.18-2.21). Hypertension, dyslipidemia, diabetes were confluent factors shared by small-vessel, large-vessel and cardio-embolic subtypes. Stroke cases and stroke-free controls had a mean of 5.3±1.5 versus 3.2±1.0 adverse cardio-metabolic risk factors respectively (<0.0001).

Conclusions: Traditional vascular risk factors demonstrate important differential effect sizes with pathophysiologic, clinical and preventative implications on the occurrence of ischemic stroke among indigenous West Africans.
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http://dx.doi.org/10.1161/STROKEAHA.120.032072DOI Listing
September 2021

Genomic Characterization and Therapeutic Targeting of HPV Undetected Cervical Carcinomas.

Cancers (Basel) 2021 Sep 10;13(18). Epub 2021 Sep 10.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Cervical cancer tumors with undetectable HPV (HPV) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPV tumors to date (HPV = 35, HPV = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV and HPV tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPV cancer cell lines. Patients with HPV CC tumors had worse progression-free and overall survival outcomes compared to HPV patients. , , , , , , and were identified as significantly mutated genes (SMGs) enriched in HPV tumors, with converging functional roles in cell cycle progression. In vitro HPV, but not HPV, cancer cell lines with wild type were sensitive to palbociclib monotherapy. These results indicate that HPV status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments. We suggest primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPV CC patients.
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http://dx.doi.org/10.3390/cancers13184551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467954PMC
September 2021

Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease.

J Cachexia Sarcopenia Muscle 2021 Sep 15. Epub 2021 Sep 15.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach.

Methods: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data.

Results: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling.

Conclusions: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.
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http://dx.doi.org/10.1002/jcsm.12782DOI Listing
September 2021

A Novel Afrocentric Stroke Risk Assessment Score: Models from the Siren Study.

J Stroke Cerebrovasc Dis 2021 Oct 28;30(10):106003. Epub 2021 Jul 28.

Medical University of South Carolina, SC, USA.

Background: Stroke risk can be quantified using risk factors whose effect sizes vary by geography and race. No stroke risk assessment tool exists to estimate aggregate stroke risk for indigenous African.

Objectives: To develop Afrocentric risk-scoring models for stroke occurrence.

Materials And Methods: We evaluated 3533 radiologically confirmed West African stroke cases paired 1:1 with age-, and sex-matched stroke-free controls in the SIREN study. The 7,066 subjects were randomly split into a training and testing set at the ratio of 85:15. Conditional logistic regression models were constructed by including 17 putative factors linked to stroke occurrence using the training set. Significant risk factors were assigned constant and standardized statistical weights based on regression coefficients (β) to develop an additive risk scoring system on a scale of 0-100%. Using the testing set, Receiver Operating Characteristics (ROC) curves were constructed to obtain a total score to serve as cut-off to discriminate between cases and controls. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) at this cut-off.

Results: For stroke occurrence, we identified 15 traditional vascular factors. Cohen's kappa for validity was maximal at a total risk score of 56% using both statistical weighting approaches to risk quantification and in both datasets. The risk score had a predictive accuracy of 76% (95%CI: 74-79%), sensitivity of 80.3%, specificity of 63.0%, PPV of 68.5% and NPV of 76.2% in the test dataset. For ischemic strokes, 12 risk factors had predictive accuracy of 78% (95%CI: 74-81%). For hemorrhagic strokes, 7 factors had a predictive accuracy of 79% (95%CI: 73-84%).

Conclusions: The SIREN models quantify aggregate stroke risk in indigenous West Africans with good accuracy. Prospective studies are needed to validate this instrument for stroke prevention.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511059PMC
October 2021

Influence of age on links between major modifiable risk factors and stroke occurrence in West Africa.

J Neurol Sci 2021 09 9;428:117573. Epub 2021 Jul 9.

College of Medicine, University of Ibadan, Nigeria. Electronic address:

Background The burden of stroke in Africa is high. Understanding how age associates with major modifiable stroke risk factors could inform tailored demographic stroke prevention strategies. Purpose To quantify the magnitude and direction of the effect sizes of key modifiable stroke risk factors according to three age groups: <50 years (young), 50-65 years (middle age) and > 65 years (elderly) in West Africa. Methods This was a case-control study involving 15 sites in Ghana and Nigeria. Cases included adults aged ≥18 years with CT/MRI scan-typed stroke. Controls were age-and gender-matched stroke-free adults. Detailed evaluations for vascular, lifestyle and psychosocial factors were performed. We estimated adjusted odds ratios (aOR) using conditional logistic regression and population attributable risk (PAR) with 95% Confidence Interval of vascular risk factors by age groups. Results Among 3553 stroke cases, 813 (22.9%) were young, 1441 (40.6%) were middle-aged and 1299 (36.6%) were elderly. Among the 5 co-shared risk factors, dyslipidemia with PAR and aOR (95%CI) of 62.20% (52.82-71.58) and 4.13 (2.64-6.46) was highest among the young age group; hypertension with PAR of 94.31% (91.82-96.80) and aOR of 28.93 (15.10-55.44) was highest among the middle-age group. Diabetes with PAR of 32.29%(27.52-37.05) and aOR of 3.49 (2.56-4.75); meat consumption with PAR of 42.34%(32.33-52.35) and aOR of 2.40 (1.76, 3.26); and non-consumption of green vegetables, PAR of 16.81%(12.02-21.60) and aOR of 2.23 (1.60-3.12) were highest among the elderly age group. However confidence intervals of risk estimates overlapped across age groups. Additionally, among the young age group cigarette smoking, psychosocial stress and cardiac disease were independently associated with stroke. Furthermore, education, stress, physical inactivity and salt intake were associated with stroke in the middle-age group while cardiac disease was associated with stroke in the elderly age group. Conclusion There is a differential influence of age on the associations of major risk factors with stroke in this West African cohort. Targeting modifiable factors predominant within an age group may be more effective as a stroke prevention strategy.
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http://dx.doi.org/10.1016/j.jns.2021.117573DOI Listing
September 2021

A novel Mendelian randomization method with binary risk factor and outcome.

Genet Epidemiol 2021 Jul 16;45(5):549-560. Epub 2021 May 16.

Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Background: Mendelian randomization (MR) applies instrumental variable (IV) methods to observational data using a genetic variant as an IV. Several Monte-Carlo studies investigate the performance of MR methods with binary outcomes, but few consider them in conjunction with binary risk factors.

Objective: To develop a novel MR estimator for scenarios with a binary risk factor and outcome; and compare to existing MR estimators via simulations and real data analysis.

Methods: A bivariate Bernoulli distribution is adapted to the IV setting. Empirical bias and asymptotic coverage probabilities are estimated via simulations. The proposed method is compared to the Wald method, two-stage predictor substitution (2SPS), two-stage residual inclusion (2SRI), and the generalized method of moments (GMM). An analysis is performed using existing data from the CLEAR study to estimate the potential causal effect of smoking on rheumatoid arthritis risk in African Americans.

Results: Bias was low for the proposed method and comparable to 2SPS. The Wald method was often biased towards the null. Coverage was adequate for the proposed method, 2SPS, and 2SRI. Coverage for the Wald and GMM methods was poor in several scenarios. The causal effect of ever smoking on rheumatoid arthritis risk was not statistically significant using a variety of genetic instruments.

Conclusions: Simulations suggest the proposed MR method is sound with binary risk factors and outcomes, and comparable to 2SPS and 2SRI in terms of bias. The proposed method also provides more natural framework for hypothesis testing compared to 2SPS or 2SRI, which require ad-hoc variance adjustments.
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http://dx.doi.org/10.1002/gepi.22387DOI Listing
July 2021

Predicting the Probability of Chlamydia Reinfection in African American Women Using Immunologic and Genetic Determinants in a Bayesian Model.

Sex Transm Dis 2021 Nov;48(11):813-818

Biostatistics, University of Alabama at Birmingham, Birmingham, AL.

Background: African Americans have the highest rates of Chlamydia trachomatis (CT) infection in the United States and also high reinfection rates. The primary objective of this study was to develop a Bayesian model to predict the probability of CT reinfection in African American women using immunogenetic data.

Methods: We analyzed data from a cohort of CT-infected African American women enrolled at the time they returned to a clinic in Birmingham, AL, for the treatment of a positive routine CT test result. We modeled the probability of CT reinfection within 6 months after treatment using logistic regression in a Bayesian framework. Predictors of interest were presence or absence of an HLA-DQB1*06 allele and CT-specific CD4+ IFN-γ response, both of which we had previously reported were independently associated with CT reinfection risk.

Results: Among 99 participants evaluated, the probability of reinfection for those with a CT-specific CD4+ IFN-γ response and no HLA-DQB1*06 alleles was 14.1% (95% credible interval [CI], 3.0%-45.0%), whereas the probability of reinfection for those without a CT-specific CD4+ IFN-γ response and at least one HLA-DQB1*06 allele was 61.5% (95% CI, 23.1%-89.7%).

Conclusions: Our model demonstrated that presence or absence of an HLA-DQB1*06 allele and CT-specific CD4+ IFN-γ response can have an impact on the predictive probability of CT reinfection in African American women.
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http://dx.doi.org/10.1097/OLQ.0000000000001468DOI Listing
November 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 May;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
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http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify , , and of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population.

Front Genet 2021 19;12:588452. Epub 2021 Feb 19.

College of Public Health, University of Kentucky, Lexington, KY, United States.

: Indices of left ventricular (LV) structure and geometry represent useful intermediate phenotypes related to LV hypertrophy (LVH), a predictor of cardiovascular (CV) disease (CVD) outcomes. We conducted an exome-wide association study of LV mass (LVM) adjusted to height, LV internal diastolic dimension (LVIDD), and relative wall thickness (RWT) among 1,364 participants of African ancestry (AAs) in the Hypertension Genetic Epidemiology Network (HyperGEN). Both single-variant and gene-based sequence kernel association tests were performed to examine whether common and rare coding variants contribute to variation in echocardiographic traits in AAs. We then used a data-driven procedure to prioritize and select genes for functional validation using a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model. Three genes [myosin VIIA and Rab interacting protein (), trafficking protein particle complex 11 (), and solute carrier family 27 member 6 ()] were prioritized based on statistical significance, variant functional annotations, gene expression in the hiPSC-CM model, and prior biological evidence and were subsequently knocked down in the hiPSC-CM model. Expression profiling of hypertrophic gene markers in the knockdowns suggested a decrease in hypertrophic expression profiles. knockdowns showed a significant decrease in atrial natriuretic factor () and brain natriuretic peptide () expression. Knockdowns of the heart long chain fatty acid (FA) transporter resulted in downregulated caveolin 3 () expression, which has been linked to hypertrophic phenotypes in animal models. Finally, knockdown was linked to deficient calcium handling. : The three genes are biologically plausible candidates that provide new insight to hypertrophic pathways.
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http://dx.doi.org/10.3389/fgene.2021.588452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933688PMC
February 2021

Epigenome-wide association study identifies DNA methylation sites associated with target organ damage in older African Americans.

Epigenetics 2021 Aug 26;16(8):862-875. Epub 2020 Oct 26.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

Target organ damage (TOD) manifests as vascular injuries in the body organ systems associated with long-standing hypertension. DNA methylation in peripheral blood leukocytes can capture inflammatory processes and gene expression changes underlying TOD. We investigated the association between epigenome-wide DNA methylation and five measures of TOD (estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), relative wall thickness (RWT), and white matter hyperintensity (WMH)) in 961 African Americans from hypertensive sibships. A multivariate (multi-trait) model of eGFR, UACR, LVMI, and RWT identified seven CpGs associated with at least one of the traits (cg21134922, cg04816311 near , cg09155024, cg10254690 near , cg07660512, cg12661888 near , and cg02264946 near ) at FDR q < 0.1. Adjusting for blood pressure, body mass index, and type 2 diabetes attenuated the association for four CpGs. DNA methylation was associated with -gene expression for some CpGs, but no significant mediation by gene expression was detected. Mendelian randomization analyses suggested causality between three CpGs and eGFR (cg04816311, cg10254690, and cg07660512). We also assessed whether the identified CpGs were associated with TOD in 614 African Americans in the Hypertension Genetic Epidemiology Network (HyperGEN) study. Out of three CpGs available for replication, cg04816311 was significantly associated with eGFR (p = 0.0003), LVMI (p = 0.0003), and RWT (p = 0.002). This study found evidence of an association between DNA methylation and TOD in African Americans and highlights the utility of using a multivariate-based model that leverages information across related traits in epigenome-wide association studies.
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http://dx.doi.org/10.1080/15592294.2020.1827717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331005PMC
August 2021

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A.

Am J Clin Nutr 2020 11;112(5):1200-1211

Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.

Background: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown.

Objectives: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases.

Methods: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator.

Results: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with β = 58.4 ± 7.27, P = 8.98 x 10-16 for CHO intake; β = -36.4 ± 5.95, P = 9.96 x 10-10 for FAT intake; and β = 3.30 ± 0.49, P = 1.48 x 10-11 for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases.

Conclusions: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A.Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)-NCT01023750; and the Framingham Heart Study (FHS)-NCT00005121.
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http://dx.doi.org/10.1093/ajcn/nqaa233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657341PMC
November 2020

Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

Nat Genet 2020 09 24;52(9):969-983. Epub 2020 Aug 24.

Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.
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http://dx.doi.org/10.1038/s41588-020-0676-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483769PMC
September 2020

A lipidome-wide association study of the lipoprotein insulin resistance index.

Lipids Health Dis 2020 Jun 25;19(1):153. Epub 2020 Jun 25.

Department of Epidemiology, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL, 35294, USA.

Background: The lipoprotein insulin resistance (LPIR) score was shown to predict insulin resistance (IR) and type 2 diabetes (T2D) in healthy adults. However, the molecular basis underlying the LPIR utility for classification remains unclear.

Objective: To identify small molecule lipids associated with variation in the LPIR score, a weighted index of lipoproteins measured by nuclear magnetic resonance, in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 980).

Methods: Linear mixed effects models were used to test the association between the LPIR score and 413 lipid species and their principal component analysis-derived groups. Significant associations were tested for replication with homeostatic model assessment-IR (HOMA-IR), a phenotype correlated with the LPIR score (r = 0.48, p <  0.001), in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 590).

Results: In GOLDN, 319 lipids were associated with the LPIR score (false discovery rate-adjusted p-values ranging from 4.59 × 10 to 49.50 × 10). Factors 1 (triglycerides and diglycerides/storage lipids) and 3 (mixed lipids) were positively (β = 0.025, p = 4.52 × 10 and β = 0.021, p = 5.84 × 10, respectively) and factor 2 (phospholipids/non-storage lipids) was inversely (β = - 0.013, p = 2.28 × 10) associated with the LPIR score. These findings were replicated for HOMA-IR in the HAPI Heart Study (β = 0.10, p = 1.21 × 10 for storage, β = - 0.13, p = 3.14 × 10 for non-storage, and β = 0.19, p = 8.40 × 10 for mixed lipids).

Conclusions: Non-storage lipidomics species show a significant inverse association with the LPIR metabolic dysfunction score and present a promising focus for future therapeutic and prevention studies.
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http://dx.doi.org/10.1186/s12944-020-01321-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318473PMC
June 2020

Heme metabolism genes Downregulated in COPD Cachexia.

Respir Res 2020 May 1;21(1):100. Epub 2020 May 1.

Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.

Introduction: Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.

Methods: We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m among women and < 17 kg/m among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.

Results: The prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).

Discussion: Several replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage.
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http://dx.doi.org/10.1186/s12931-020-01336-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193359PMC
May 2020

Salivary AMY1 Copy Number Variation Modifies Age-Related Type 2 Diabetes Risk.

Clin Chem 2020 05;66(5):718-726

USDA Agricultural Research Service, Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.

Background: Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain.

Methods: We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk.

Results: We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR.

Conclusions: We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.
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http://dx.doi.org/10.1093/clinchem/hvaa072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192522PMC
May 2020

Correction to: Association of CMV genomic mutations with symptomatic infection and hearing loss in congenital CMV infection.

BMC Infect Dis 2020 Feb 10;20(1):111. Epub 2020 Feb 10.

Department of Pediatrics, The University of Alabama School of Medicine, CHB 116, 1600 6th Avenue South, Birmingham, AL, USA.

After publication of the original article [1], we were notified that Fig. 3 has "Fig. 1" posted on the top of it and Figs. 4 and 5 have "Genomic Position" in a different spot.
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http://dx.doi.org/10.1186/s12879-020-4766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008528PMC
February 2020

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.

PLoS Genet 2020 01 24;16(1):e1008544. Epub 2020 Jan 24.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.
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http://dx.doi.org/10.1371/journal.pgen.1008544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001991PMC
January 2020

Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension.

Am J Respir Crit Care Med 2020 06;201(11):1407-1415

Department of Medicine, Indiana University, Indianapolis, Indiana.

Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH). Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH. Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis. After covariate adjustment, self-reported Hispanic patients ( = 290) exhibited significantly reduced mortality versus NHW patients ( = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87];  = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01];  = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients ( = 1,524) versus NHW patients ( = 8,829; OR, 0.65 [95% CI, 0.50-0.84];  = 0.001). An inpatient mortality benefit was observed for Native American patients ( = 185; OR, 0.38 [95% CI, 0.15-0.93];  = 0.034). This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.
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http://dx.doi.org/10.1164/rccm.201907-1447OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258627PMC
June 2020

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

PLoS Genet 2019 12 23;15(12):e1008500. Epub 2019 Dec 23.

Genomics Platform, Broad Institute, Cambridge, Massachusetts, United States of America.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.
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http://dx.doi.org/10.1371/journal.pgen.1008500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953885PMC
December 2019

Association of CMV genomic mutations with symptomatic infection and hearing loss in congenital CMV infection.

BMC Infect Dis 2019 Dec 10;19(1):1046. Epub 2019 Dec 10.

Department of Pediatrics, The University of Alabama School of Medicine, CHB 116, 1600 6th Avenue South, Birmingham, AL, USA.

Background: Congenital cytomegalovirus (cCMV) infection is the most common congenital infection and a leading cause of long-term neurological and sensory sequelae, the most common being sensorineural hearing loss (SNHL). Despite extensive research, clinical or laboratory markers to identify CMV infected children with increased risk for disease have not been identified. This study utilizes viral whole-genome next generation-sequencing (NGS) of specimens from congenitally infected infants to explore viral diversity and specific viral variants that may be associated with symptomatic infection and SNHL.

Methods: CMV DNA from urine specimens of 30 infants (17 asymptomatic, 13 symptomatic) was target enriched and next generation sequenced resulting in 93% coverage of the CMV genome allowing analysis of viral diversity.

Results: Variant frequency distribution was compared between children with symptomatic and asymptomatic cCMV and those with (n = 13) and without (n = 17) hearing loss. The CMV genes UL48A, UL88, US19 and US22 were found to have an increase in nucleotide diversity in symptomatic children; while UL57, UL20, UL104, US14, UL115, and UL35 had an increase in diversity in children with hearing loss. An analysis of single variant differences between symptomatic and asymptomatic children found UL55 to have the highest number, while the most variants associated with SNHL were in the RL11 gene family. In asymptomatic infants with SNHL, mutations were observed more frequently in UL33 and UL20.

Conclusion: CMV genomes from infected newborns can be mapped to 93% of the genome at a depth allowing accurate and reproducible analysis of polymorphisms for variant and gene discovery that may be linked to symptomatic and hearing loss outcomes.
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http://dx.doi.org/10.1186/s12879-019-4681-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905059PMC
December 2019

Genetic risk of Spontaneous intracerebral hemorrhage: Systematic review and future directions.

J Neurol Sci 2019 Dec 13;407:116526. Epub 2019 Oct 13.

Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria; Department of Medicine, University of Ibadan, Ibadan, Nigeria. Electronic address:

Background: Although highly heritable, few genes have been linked to spontaneous intracerebral hemorrhage (SICH), which does not currently have any evidence-based disease-modifying therapy. Individuals of African ancestry are especially susceptible to SICH, even more so for indigenous Africans. We systematically reviewed the genetic variants associated with SICH and examined opportunities for rapidly advancing SICH genomic research for precision medicine.

Method: We searched the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Genome Wide Association Study (GWAS) catalog and PubMed for original research articles on genetic variants associated with SICH as of 15 June 2019 using the PRISMA guideline.

Results: Eight hundred and sixty-four articles were identified using pre-specified search criteria, of which 64 met the study inclusion criteria. Among eligible articles, only 9 utilized GWAS approach while the rest were candidate gene studies. Thirty-eight genetic loci were found to be variously associated with the risk of SICH, hematoma volume, functional outcome and mortality, out of which 8 were from GWAS including APOE, CR1, KCNK17, 1q22, CETP, STYK1, COL4A2 and 17p12. None of the studies included indigenous Africans.

Conclusion: Given this limited information on the genetic contributors to SICH, more genomic studies are needed to provide additional insights into the pathophysiology of SICH, and develop targeted preventive and therapeutic strategies. This call for additional investigation of the pathogenesis of SICH is likely to yield more discoveries in the unexplored indigenous African populations which also have a greater predilection.
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http://dx.doi.org/10.1016/j.jns.2019.116526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413646PMC
December 2019

Genome-wide meta-analysis of SNP and antihypertensive medication interactions on left ventricular traits in African Americans.

Mol Genet Genomic Med 2019 10 13;7(10):e00788. Epub 2019 Aug 13.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Background: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography.

Methods: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates.

Results: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population.

Conclusions: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.
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http://dx.doi.org/10.1002/mgg3.788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785453PMC
October 2019

A Systematic Scoping Review of Surgically Manipulated Adipose Tissue and the Regulation of Energetics and Body Fat in Animals.

Obesity (Silver Spring) 2019 09 30;27(9):1404-1417. Epub 2019 Jul 30.

Department of Epidemiology and Biostatistics, School of Public Health, Indiana University-Bloomington, Bloomington, Indiana, USA.

Objective: Surgical manipulations of adipose tissue by removal, or partial lipectomy, have demonstrated body fat compensation and recovered body weight, suggesting that the body is able to resist changes to body composition. However, the mechanisms underlying these observations are not well understood. The purpose of this scoping review is to provide an update on what is currently known about the regulation of energetics and body fat after surgical manipulations of adipose tissue in small mammals.

Methods: PubMed and Scopus were searched to identify 64 eligible studies. Outcome measures included body fat, body weight, food intake, and circulating biomarkers.

Results: Surgeries performed included lipectomy (72%) or transplantation (12%) in mice (35%), rats (35%), and other small mammals. Findings suggested that lipectomy did not have consistent long-term effects on reducing body weight and fat because regain occurred within 12 to 14 weeks post surgery. Hence, biological feedback mechanisms act to resist long-term changes of body weight or fat. Furthermore, whether this weight and fat regain occurred because of "passive" and "active" regulation under the "set point" or "settling point" theories cannot fully be discerned because of limitations in study designs and data collected.

Conclusions: The regulation of energetics and body fat are complex and dynamic processes that require further studies of the interplay of genetic, physiological, and behavioral factors.
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http://dx.doi.org/10.1002/oby.22511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707830PMC
September 2019

Echocardiographic Abnormalities and Determinants of 1-Month Outcome of Stroke Among West Africans in the SIREN Study.

J Am Heart Assoc 2019 06 30;8(11):e010814. Epub 2019 May 30.

1 Center for Genomic and Precision Medicine University of Ibadan Ibadan Nigeria.

Background Little is known about the relationship between echocardiographic abnormalities and outcome among patients with acute stroke. We investigated the pattern and association of baseline echocardiographic variables with 1-month disability and mortality among patients with stroke in the SIREN (Stroke Investigative Research and Education Network) study. Methods and Results We enrolled and followed up consecutive 1020 adult patients with acute stroke with baseline transthoracic echocardiography from west Africa. To explore the relationship between echocardiographic variables and 1-month disability (using modified Rankin scale >3) and fatality, regression models were fitted. Relative risks were computed with 95% CIs. The participants comprised 60% men with a mean age of 59.2±14.6 years. Ischemic stroke was associated with smaller aortic root diameter (30.2 versus 32.5, P=0.018) and septal (16.8 versus 19.1, P<0.001) and posterior wall thickness at systole (18.9 versus 21.5, P=0.004). Over 90% of patients with stroke had abnormal left ventricular (LV) geometry with eccentric hypertrophy predominating (56.1%). Of 13 candidate variables investigated, only baseline abnormal LV geometry (concentric hypertrophy) was weakly associated with 1-month disability (unadjusted relative risk, 1.80; 95% CI , 0.97-5.73). Severe LV systolic dysfunction was significantly associated with increased 1-month mortality (unadjusted relative risk, 3.05; 95% CI , 1.36-6.83). Conclusions Nine of 10 patients with acute stroke had abnormal LV geometry and a third had systolic dysfunction. Severe LV systolic dysfunction was significantly associated with 1 month mortality. Larger studies are required to establish the independent effect and unravel predictive accuracy of this association.
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http://dx.doi.org/10.1161/JAHA.118.010814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585359PMC
June 2019

Differential Impact of Risk Factors on Stroke Occurrence Among Men Versus Women in West Africa.

Stroke 2019 04;50(4):820-827

Centre for Genomic and Precision Medicine, University of Ibadan, Nigeria (R.A., A.A., M.O.).

Background and Purpose- The interplay between sex and the dominant risk factors for stroke occurrence in sub-Saharan Africa has not been clearly delineated. We compared the effect sizes of risk factors of stroke by sex among West Africans. Methods- SIREN study (Stroke Investigative Research and Educational Networks) is a case-control study conducted at 15 sites in Ghana and Nigeria. Cases were adults aged >18 years with computerized tomography/magnetic resonance imaging confirmed stroke, and controls were age- and sex-matched stroke-free adults. Comprehensive evaluation for vascular, lifestyle, and psychosocial factors was performed using validated tools. We used conditional logistic regression to estimate odds ratios and reported risk factor specific and composite population attributable risks with 95% CIs. Results- Of the 2118 stroke cases, 1193 (56.3%) were males. The mean±SD age of males was 58.1±13.2 versus 60.15±14.53 years among females. Shared modifiable risk factors for stroke with adjusted odds ratios (95% CI) among females versus males, respectively, were hypertension [29.95 (12.49-71.77) versus 16.1 0(9.19-28.19)], dyslipidemia [2.08 (1.42-3.06) versus 1.83 (1.29-2.59)], diabetes mellitus [3.18 (2.11-4.78) versus 2.19 (1.53-3.15)], stress [2.34 (1.48-3.67) versus 1.61 (1.07-2.43)], and low consumption of green leafy vegetables [2.92 (1.89-4.50) versus 2.00 (1.33-3.00)]. However, salt intake and income were significantly different between males and females. Six modifiable factors had a combined population attributable risk of 99.1% (98.3%-99.6%) among females with 9 factors accounting for 97.2% (94.9%-98.7%) among males. Hemorrhagic stroke was more common among males (36.0%) than among females (27.6%), but stroke was less severe among males than females. Conclusions- Overall, risk factors for stroke occurrence are commonly shared by both sexes in West Africa favoring concerted interventions for stroke prevention in the region.
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http://dx.doi.org/10.1161/STROKEAHA.118.022786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433514PMC
April 2019

An Exome-Wide Sequencing Study of the GOLDN Cohort Reveals Novel Associations of Coding Variants and Fasting Plasma Lipids.

Front Genet 2019 26;10:158. Epub 2019 Feb 26.

School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United States.

Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ) was associated with fasting triglyceride levels ( = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ( = 1.77E-07) and ( = 7.18E-07) and triglycerides, as well as between ( = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved -values of 0.04 (), 0.08 (), and 0.02 (). In GOLDN, gene transcript levels of and were associated with fasting triglycerides ( = 0.07 and = 0.02), highlighting functional relevance of our findings. In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.
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http://dx.doi.org/10.3389/fgene.2019.00158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399202PMC
February 2019

Identification of Gene Variants Associated with Melanocyte Stem Cell Differentiation in Mice Predisposed for Hair Graying.

G3 (Bethesda) 2019 03 7;9(3):817-827. Epub 2019 Mar 7.

Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

Age-related hair graying is caused by malfunction in the regenerative potential of the adult pigmentation system. The retention of hair color over the life of an organism is dependent on the ability of the melanocyte stem cells and their progeny to produce pigment each time a new hair grows. Age-related hair graying is variable in association with genetic background suggesting that quantitative trait loci influencing this trait can be identified. Identification of these quantitative trait loci may lead to the discovery of novel and interesting genes involved in stem cell biology and/or melanogenesis. With this in mind we developed previously a sensitized, mouse modifier screen and discovered that the DBA/1J background is particularly resistant to melanocyte stem cell differentiation in comparison to the C57BL/6J background. Melanocyte stem cell differentiation generally precedes hair graying and is observed in melanocyte stem cells with age. Using quantitative trait loci analysis, we have now identified three quantitative trait loci on mouse chromosomes 7, 13, and X that are associated with DBA/1J-mediated variability in melanocyte stem cell differentiation. Taking advantage of publicly-available mouse sequence and variant data, in silico protein prediction programs, and whole genome gene expression results we describe a short list of potential candidate genes that we anticipate to be involved in melanocyte stem cell biology in mice.
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http://dx.doi.org/10.1534/g3.118.200965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404613PMC
March 2019

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.

Am J Hum Genet 2019 01 27;104(1):112-138. Epub 2018 Dec 27.

School of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323610PMC
January 2019
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