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Multi-omic analysis of stroke recurrence in African Americans from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial.
Davis Armstrong, NM, Spragley, KJ, Chen, WM, Hsu, FC, Brewer, MS, Horn, PJ, Williams, SR, Sale, MM, Worrall, BB, Keene, KL
PloS one. 2021;(3):e0247257
Abstract
African Americans endure a nearly two-fold greater risk of suffering a stroke and are 2-3 times more likely to die from stroke compared to those of European ancestry. African Americans also have a greater risk of recurrent stroke and vascular events, which are deadlier and more disabling than incident stroke. Stroke is a multifactorial disease with both heritable and environmental risk factors. We conducted an integrative, multi-omic study on 922 plasma metabolites, 473,864 DNA methylation loci, and 556 variants from 50 African American participants of the Vitamin Intervention for Stroke Prevention clinical trial to help elucidate biomarkers contributing to recurrent stroke rates in this high risk population. Sixteen metabolites, including cotinine, N-delta-acetylornithine, and sphingomyelin (d17:1/24:1) were identified in t-tests of recurrent stroke outcome or baseline smoking status. Serum tricosanoyl sphingomyelin (d18:1/23:0) levels were significantly associated with recurrent stroke after adjusting for covariates in Cox Proportional Hazards models. Weighted Gene Co-expression Network Analysis identified moderate correlations between sphingolipid markers and clinical traits including days to recurrent stroke. Integrative analyses between genetic variants in sphingolipid pathway genes identified 29 nominal associations with metabolite levels in a one-way analysis of variance, while epigenomic analyses identified xenobiotics, predominately smoking-associated metabolites and pharmaceutical drugs, associated with methylation profiles. Taken together, our results suggest that metabolites, specifically those associated with sphingolipid metabolism, are potential plasma biomarkers for stroke recurrence in African Americans. Furthermore, genetic variation and DNA methylation may play a role in the regulation of these metabolites.
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Lower life satisfaction, active coping and cardiovascular disease risk factors in older African Americans: outcomes of a longitudinal church-based intervention.
Mendez, YP, Ralston, PA, Wickrama, KKAS, Bae, D, Young-Clark, I, Ilich, JZ
Journal of behavioral medicine. 2018;(3):344-356
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Abstract
This study examined lower life satisfaction, active coping and cardiovascular disease risk factors (diastolic and systolic blood pressure, body mass index, and circumferences) in older African Americans over the phases of an 18-month church-based intervention, using a quasi-experimental design. Participants (n = 89) were 45 years of age and older from six churches (three treatment, three comparison) in North Florida. Lower life satisfaction had a persistent unfavorable effect on weight variables. Active coping showed a direct beneficial effect on selected weight variables. However, active coping was adversely associated with blood pressure, and did not moderate the association between lower life satisfaction and cardiovascular risk factors. The intervention had a beneficial moderating influence on the association between lower life satisfaction and weight variables and on the association between active coping and these variables. Yet, this pattern did not hold for the association between active coping and blood pressure. The relationship of lower life satisfaction and selected cardiovascular risk factors and the positive effect of active coping were established, but findings regarding blood pressure suggest further study is needed.
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Incorporating religion and spirituality into the design of community-based physical activity programs for African American women: a qualitative inquiry.
Joseph, RP, Ainsworth, BE, Mathis, L, Hooker, SP, Keller, C
BMC research notes. 2017;(1):506
Abstract
OBJECTIVE Limited research has examined how aspects of religion and spirituality can be incorporated into community-based physical activity programs delivered outside of religious institutions. The purpose of this study was to qualitatively explore how spirituality and religion can be leveraged in the design of community-based physical activity programs for African American women delivered outside of faith-based or faith-placed settings. RESULTS Three focus groups were conducted were conducted with 23 African American women (M age = 37.8 years, M BMI = 39.6 kg m2). Results showed that incorporating aspects of spirituality (i.e., words encouraging connectedness to a higher power, meditation, mind-body activities) into a physical activity program was universally accepted among participants, regardless of religious affiliation. In contrast, including concepts of religion (i.e., bible verses and/or quotes from religious leaders) was controversial and not recommended among women who did not identify with a religious faith. Findings indicate that when developing community-based physical activity interventions that will not be delivered through faith-based or faith-placed settings, researchers should avoid references to specific religious beliefs. Instead, interventions should focus on spirituality and emphasize the mind-body relationship between physical activity and an African American women's inner-being and her connectedness with a higher power. Trial Registration ClinicalTrials.gov NCT02823379. Registered July 1, 2016.
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Charcot-Marie-Tooth gene, SBF2, associated with taxane-induced peripheral neuropathy in African Americans.
Schneider, BP, Lai, D, Shen, F, Jiang, G, Radovich, M, Li, L, Gardner, L, Miller, KD, O'Neill, A, Sparano, JA, et al
Oncotarget. 2016;(50):82244-82253
Abstract
PURPOSE Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity. EXPERIMENTAL DESIGN Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency <3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN. RESULTS Five genes had a p-value < 10-4 for grade 3-4 TIPN analysis and three genes had a p-value < 10-4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10-6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease. CONCLUSION Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.
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Study design and protocol for moving forward: a weight loss intervention trial for African-American breast cancer survivors.
Stolley, MR, Sharp, LK, Fantuzzi, G, Arroyo, C, Sheean, P, Schiffer, L, Campbell, R, Gerber, B
BMC cancer. 2015;:1018
Abstract
BACKGROUND Breast cancer survival rates are significantly lower among African-American women compared to white women. In addition, African-American women with breast cancer are more likely than white women to die from co-morbid conditions. Obesity is common among African-American women, and it contributes to breast cancer progression and the development and exacerbation of many weight-related conditions. Intervening upon obesity may decrease breast cancer and all-cause mortality among African-American breast cancer survivors. METHODS/DESIGN Moving Forward is a weight loss intervention being evaluated in a randomized trial with a projected sample of 240 African American breast cancer survivors. Outcomes include body mass index, body composition, waist:hip ratio, and behavioral, psychosocial and physiological measures. Survivors are randomized to either a 6-month guided weight loss intervention that involves twice weekly classes and text messaging or a self-guided weight loss intervention based on the same materials offered in the guided program. The guided intervention is being conducted in partnership with the Chicago Park District at park facilities in predominantly African-American neighborhoods in Chicago. Recruitment strategies include direct contact to women identified in hospital cancer registries, as well as community-based efforts. Data collection occurs at baseline, post-intervention (6 months) and at a 12-month follow-up. DISCUSSION This study evaluates a community-based, guided lifestyle intervention designed to improve the health of African-American breast cancer survivors. Few studies have addressed behavioral interventions in this high-risk population. If successful, the intervention may help reduce the risk for breast cancer recurrence, secondary cancers, and co-morbid conditions, as well as improve quality of life. TRIAL REGISTRATION U.S. Clinicaltrials.gov number: NCT02482506, April 2015.
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Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.
Tang, W, Cushman, M, Green, D, Rich, SS, Lange, LA, Yang, Q, Tracy, RP, Tofler, GH, Basu, S, Wilson, JG, et al
American journal of hematology. 2015;(6):534-40
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Abstract
Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII C and VWF Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII C and VWF Ag in both EAs and AAs.
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Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease.
Yu, B, Li, AH, Muzny, D, Veeraraghavan, N, de Vries, PS, Bis, JC, Musani, SK, Alexander, D, Morrison, AC, Franco, OH, et al
Circulation. Cardiovascular genetics. 2015;(2):351-5
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BACKGROUND Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample. METHODS AND RESULTS By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2×10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; P=1.2×10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9×10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium. CONCLUSIONS Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.
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CYP3A4*22 and CYP3A5*3 are associated with increased levels of plasma simvastatin concentrations in the cholesterol and pharmacogenetics study cohort.
Kitzmiller, JP, Luzum, JA, Baldassarre, D, Krauss, RM, Medina, MW
Pharmacogenetics and genomics. 2014;(10):486-91
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Abstract
OBJECTIVE Simvastatin is primarily metabolized by CYP3A4. A combined CYP3A4/5 genotype classification, combining the decrease-of-function CYP3A4*22 and the loss-of-function CYP3A5*3, has recently been reported. We aim to determine whether CYP3A4*22 and CYP3A5*3 alleles are associated with increased plasma concentrations of simvastatin lactone (SV) and simvastatin acid (SVA). This is the first report evaluating associations between in-vivo simvastatin concentrations and CYP3A4*22, alone or in a combined CYP3A4/5 genotype-defined classification. PARTICIPANTS AND METHODS Genotypes and simvastatin concentrations were determined for 830 participants (555 Whites and 275 African-Americans) in the Cholesterol and Pharmacogenomics clinical trial with 40 mg/day simvastatin for 6 weeks. Concentrations were determined in 12-h postdose samples. Associations between simvastatin concentrations and CYP3A4*22 and CYP3A5*3 alleles were tested separately and in a combined CYP3A4/5 genotype-defined classification system. RESULTS In Whites, CYP3A4*22 carriers (n=42) had 14% higher SVA (P=0.04) and 20% higher SV (P=0.06) compared with noncarriers (n=513). CYP3A5*3 allele status was not significantly associated with SV or SVA in Whites. In African-Americans, CYP3A4*22 carriers (n=8) had 170% higher SV (P<0.01) than noncarriers (n=267), but no significant difference was detected for SVA. African-American CYP3A5 nonexpressors (n=28) had 33% higher SV (P=0.02) than CYP3A5 expressors (n=247), but no significant difference was detected for SVA. For both races, SV appeared to decrease across the rank-ordered combined CYP3A4/5 genotype-defined groups (poor, intermediate, and extensive metabolizers); however, similar trends were not observed for SVA. CONCLUSION Genetic variation in CYP3A4 was associated with plasma simvastatin concentrations in self-reported Whites. Genetic variations in CYP3A4 and CYP3A5 were associated with plasma simvastatin concentrations in self-reported African-Americans.
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Common genetic variants associated with resting oxygenation in chronic obstructive pulmonary disease.
McDonald, ML, Cho, MH, Sørheim, IC, Lutz, SM, Castaldi, PJ, Lomas, DA, Coxson, HO, Edwards, LD, MacNee, W, Vestbo, J, et al
American journal of respiratory cell and molecular biology. 2014;(5):678-87
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Abstract
Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10(-5)) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10(-8)). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.
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Influence of CYP2C8*2 on the pharmacokinetics of pioglitazone in healthy African-American volunteers.
Aquilante, CL, Wempe, MF, Spencer, SH, Kosmiski, LA, Predhomme, JA, Sidhom, MS
Pharmacotherapy. 2013;(9):1000-7
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Abstract
STUDY OBJECTIVES To determine the influence of the Cytochrome P450 (CYP) 2C8*2 polymorphism on pioglitazone pharmacokinetics in healthy African-American volunteers. DESIGN Prospective, open-label, single-dose pharmacokinetic study. SETTING University of Colorado Hospital Clinical and Translational Research Center. PARTICIPANTS Healthy African-American volunteers between 21 and 60 years of age were enrolled in the study based on CYP2C8 genotype: CYP2C8*1/*1 (9 participants), CYP2C8*1/*2 (7 participants), and CYP2C8*2/*2 (1 participant). INTERVENTION Participants received a single 15-mg dose of pioglitazone in the fasted state, followed by a 48-hour pharmacokinetic study. MEASUREMENTS AND MAIN RESULTS Plasma concentrations of pioglitazone and its M-III (keto) and M-IV (hydroxy) metabolites were compared between participants with the CYP2C8*1/*1 genotype and CYP2C8*2 carriers. Pioglitazone area under the plasma concentration-time curve (AUC)0-∞ and half-life (t1/2 ) did not differ significantly between CYP2C8*1/*1 and CYP2C8*2 carriers (AUC0-∞ 7331 ± 2846 vs 10431 ± 5090 ng*h/ml, p=0.15, t1/2 7.4 ± 2.7 vs 10.5 ± 4.0 h, p=0.07). M-III and M-IV AUC0-48 also did not differ significantly between genotype groups. However, the M-III:pioglitazone AUC0-48 ratio was significantly lower in CYP2C8*2 carriers than CYP2C8*1 homozygotes (0.70 ± 0.15 vs 1.2 ± 0.37, p=0.006). Similarly, CYP2C8*2 carriers had a significantly lower M-III:M-IV AUC0-48 ratio than participants with the CYP2C8*1/*1 genotype (0.82 ± 0.26 vs 1.22 ± 0.26, p=0.006). CONCLUSION These data suggest that CYP2C8*2 influences pioglitazone pharmacokinetics in vivo, particularly the AUC0-48 ratio of M-III:parent drug, and the AUC0-48 ratio of M-III:M-IV. Larger studies are needed to further investigate the impact of CYP2C8*2 on the pharmacokinetics of CYP2C8 substrates in individuals of African descent.