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1.
Health inequity drives disease biology to create disparities in prostate cancer outcomes.
Nelson, WG, Brawley, OW, Isaacs, WB, Platz, EA, Yegnasubramanian, S, Sfanos, KS, Lotan, TL, De Marzo, AM
The Journal of clinical investigation. 2022;(3)
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Abstract
Prostate cancer exerts a greater toll on African American men than on White men of European descent (hereafter referred to as European American men): the disparity in incidence and mortality is greater than that of any other common cancer. The disproportionate impact of prostate cancer on Black men has been attributed to the genetics of African ancestry, to diet and lifestyle risk factors, and to unequal access to quality health care. In this Review, all of these influences are considered in the context of the evolving understanding that chronic or recurrent inflammatory processes drive prostatic carcinogenesis. Studies of inherited susceptibility highlight the contributions of genes involved in prostate cell and tissue repair (BRCA1/2, ATM) and regeneration (HOXB13 and MYC). Social determinants of health appear to accentuate these genetic influences by fueling prostate inflammation and associated cell and genome damage. Molecular characterization of the prostate cancers that arise in Black versus White men further implicates this inflammatory microenvironment in disease behavior. Yet, when Black and White men with similar grade and stage of prostate cancer are treated equally, they exhibit equivalent outcomes. The central role of prostate inflammation in prostate cancer development and progression augments the impact of the social determinants of health on disease pathogenesis. And, when coupled with poorer access to high-quality treatment, these inequities result in a disparate burden of prostate cancer on African American men.
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A Qualitative Study of Stress and Coping to Inform the LEADS Health Promotion Trial for African American Adolescents with Overweight and Obesity.
Quattlebaum, M, Kipp, C, Wilson, DK, Sweeney, A, Loncar, H, Brown, A, Levine, S, Zarrett, N
Nutrients. 2021;(7)
Abstract
The purpose of this study was to conduct in-depth individual interviews with 30 African American adolescents with overweight and obesity and their families (caregiver/adolescent dyads) to gain a better understanding of how to integrate stress and coping essential elements into an existing family-based health promotion program for weight loss. Interview data from 30 African American adolescents with overweight and obesity (Mage = 15.30 ± 2.18; MBMI%-ile = 96.7 ± 3.90) were transcribed and coded for themes using inductive and deductive approaches by two independent coders. Inter-rater reliability was acceptable (r = 0.70-0.80) and discrepancies were resolved to 100% agreement. The themes were guided by the Relapse Prevention Model, which focuses on assessing barriers of overall coping capacity in high stress situations that may undermine health behavior change (physical activity, diet, weight loss). Prominent themes included feeling stressed primarily in response to relationship conflicts within the family and among peers, school responsibilities, and negative emotions (anxiety, depression, anger). A mix of themes emerged related to coping strategies ranging from cognitive reframing and distraction to avoidant coping. Recommendations for future programs include addressing sources of stress and providing supportive resources, as well as embracing broader systems such as neighborhoods and communities. Implications for future intervention studies are discussed.
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Racial disparity in prostate cancer in the African American population with actionable ideas and novel immunotherapies.
Dovey, ZS, Nair, SS, Chakravarty, D, Tewari, AK
Cancer reports (Hoboken, N.J.). 2021;(5):e1340
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Abstract
BACKGROUND African Americans (AAs) in the United States are known to have a higher incidence and mortality for Prostate Cancer (PCa). The drivers of this epidemiological disparity are multifactorial, including socioeconomic factors leading to lifestyle and dietary issues, healthcare access problems, and potentially tumor biology. RECENT FINDINGS Although recent evidence suggests once access is equal, AA men have equal outcomes to Caucasian American (CA) men, differences in PCa incidence remain, and there is much to do to reverse disparities in mortality across the USA. A deeper understanding of these issues, both at the clinical and molecular level, can facilitate improved outcomes in the AA population. This review first discusses PCa oncogenesis in the context of its diverse hallmarks before benchmarking key molecular and genomic differences for PCa in AA men that have emerged in the recent literature. Studies have emphasized the importance of tumor microenvironment that contributes to both the unequal cancer burden and differences in clinical outcome between the races. Management of comorbidities like obesity, hypertension, and diabetes will provide an essential means of reducing prostate cancer incidence in AA men. Although requiring further AA specific research, several new treatment strategies such as immune checkpoint inhibitors used in combination PARP inhibitors and other emerging vaccines, including Sipuleucel-T, have demonstrated some proven efficacy. CONCLUSION Genomic profiling to integrate clinical and genomic data for diagnosis, prognosis, and treatment will allow physicians to plan a "Precision Medicine" approach to AA men. There is a pressing need for further research for risk stratification, which may allow early identification of AA men with higher risk disease based on their unique clinical, genomic, and immunological profiles, which can then be mapped to appropriate clinical trials. Treatment options are outlined, with a concise description of recent work in AA specific populations, detailing several targeted therapies, including immunotherapy. Also, a summary of current clinical trials involving AA men is presented, and it is important that policies are adopted to ensure that AA men are actively recruited. Although it is encouraging that many of these explore the lifestyle and educational initiatives and therapeutic interventions, there is much still work to be done to reduce incidence and mortality in AA men and equalize current racial disparities.
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Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort.
Gettler, K, Levantovsky, R, Moscati, A, Giri, M, Wu, Y, Hsu, NY, Chuang, LS, Sazonovs, A, Venkateswaran, S, Korie, U, et al
Gastroenterology. 2021;(5):1546-1557
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Abstract
BACKGROUND AND AIMS Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology. METHODS PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population. RESULTS Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation. CONCLUSIONS Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.
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Differences in erythrocyte phospholipid membrane long-chain polyunsaturated fatty acids and the prevalence of fatty acid desaturase genotype among African Americans and European Americans.
Rifkin, SB, Shrubsole, MJ, Cai, Q, Smalley, WE, Ness, RM, Swift, LL, Milne, G, Zheng, W, Murff, HJ
Prostaglandins, leukotrienes, and essential fatty acids. 2021;:102216
Abstract
Numerous studies have reported an association between genetic variants in fatty acid desaturases (FADS1 and FADS2) and plasma or erythrocyte long chain polyunsaturated fatty acid (PUFA) levels. Increased levels of n-6 PUFAs have been associated with inflammation and several chronic diseases, including diabetes and cancer. We hypothesized that genetic variants of FADS that more efficiently convert precursor n-6 PUFA to arachidonic acid (AA) may explain the higher burden of chronic diseases observed in African Americans. To test this hypothesis, we measured the level of n-6 and n-3 PUFAs in erythrocyte membrane phospholipids and genotyped the rs174537 FADS variants associated with higher AA conversion among African American and European American populations. We included data from 1,733 individuals who participated in the Tennessee Colorectal Polyp Study, a large colonoscopy-based case-control study. Erythrocyte membrane PUFA percentages were measured using gas chromatography. Generalized linear models were used to estimate association of race and genotype on erythrocyte phospholipid membrane PUFA levels while controlling for self-reported dietary intake. We found that African Americans have higher levels of AA and a higher prevalence of GG allele compared to whites, 81% vs 43%, respectively. Homozygous GG genotype was negatively associated with precursor PUFAs (linoleic [LA], di-homo-γ-linolenic [DGLA]), positively associated with both product PUFA (AA, docosahexaenoic acid [DHA]), product to precursor ratio (AA to DGLA), an indirect measure of FADs efficiency and increased urinary isoprostane F2 (F2-IsoP) and isoprostane F3 (F3-IsoP), markers of oxidative stress. Increased consumption of n-6 PUFA and LA resulting in increased AA and subsequent inflammation may be fueling increased prevalence of chronic diseases especially in African descent.
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Implications of Polymorphisms in the BCKDK and GATA-4 Gene Regions on Stable Warfarin Dose in African Americans.
Bargal, SA, Kight, JN, Augusto de Oliveira, F, Shahin, MH, Langaee, T, Gong, Y, Hamadeh, IS, Cooper-DeHoff, RM, Cavallari, LH
Clinical and translational science. 2021;(2):492-496
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Abstract
VKORC1 and CYP2C9 genotypes explain less variability in warfarin dose requirements in African Americans compared with Europeans. Variants in BCKDK and GATA-4 gene regions, purported to regulate VKORC1 and CYP2C9 expression, have been shown to play an important role in warfarin dose requirements in Europeans and Asians, respectively. We sought to determine whether rs56314408 near BCKDK or GATA-4 rs2645400 influence warfarin dose requirements in 200 African Americans. Unlike the strong linkage disequilibrium (LD) between rs56314408 and VKORC1 rs9923231 in Europeans, they were not in LD in African Americans. No associations were found on univariate analysis. On multivariable analysis, rs56314408 was associated (P = 0.027) with dose in a regression model excluding VKORC1 rs9923231, and GATA-4 rs2645400 was associated (P = 0.032) with dose in a model excluding CYP2C (CYP2C9*2, *3, *5, *6, *8, and *11, CYP2C rs12777823) variants. Neither variant contributed to dose in the model that included both VKORC1 rs9923231 and CYP2C variants. Our results do not support contributions of the studied variants to warfarin dose requirements in African Americans. However, they illustrate the value of studies in African descent populations, who have low LD in their genome, in teasing out genetic variation underlying drug response associations. They also emphasize the importance of confirming associations in persons of African ancestry.
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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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Disparities in cardio metabolic risk between Black and White women with polycystic ovary syndrome: a systematic review and meta-analysis.
Kazemi, M, Kim, JY, Parry, SA, Azziz, R, Lujan, ME
American journal of obstetrics and gynecology. 2021;(5):428-444.e8
Abstract
OBJECTIVE We conducted a systematic review and meta-analysis to summarize and quantitatively pool evidence on cardiometabolic health disparities between Black and White women with polycystic ovary syndrome in the United States in response to the call for further delineation of these disparities in the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. DATA SOURCES Databases of MEDLINE, Web of Science, and Scopus were searched initially through March 05, 2020, and confirmed on September 11, 2020. STUDY ELIGIBILITY CRITERIA Observational studies documenting cardiometabolic risk profile (glucoregulatory, lipid profile, anthropometric, and blood pressure status) in Black and White women with polycystic ovary syndrome were included. Studies on children (<17 years old) and pregnant or menopausal-aged women (>50 years) were excluded. The primary outcome was fasting glucose. Furthermore, data on major cardiovascular events (stroke, coronary heart disease, heart failure) and mortality rate (cardiovascular death, total mortality) were evaluated. METHODS Data were pooled by random-effects models and expressed as mean differences and 95% confidence intervals. Studies were weighted based on the inverse of the variance. Heterogeneity was evaluated by Cochran Q and I2 statistics. Study methodologic quality was assessed by the Newcastle-Ottawa scale. RESULTS A total of 11 studies (N=2851 [652 Black and 2199 White]) evaluated cardiometabolic risk profile and all had high quality (Newcastle-Ottawa scale score of ≥8). No studies reported on cardiovascular events and mortality rate. Black women had comparable fasting glucose (-0.61 [-1.69 to 2.92] mg/dL; I2=62.5%), yet exhibited increased fasting insulin (6.76 [4.97-8.56] μIU/mL; I2=59.0%); homeostatic model assessment of insulin resistance (1.47 [0.86-2.08]; I2=83.2%); systolic blood pressure (3.32 [0.34-6.30] mm Hg; I2=52.0%); and decreased triglyceride (-32.56 [-54.69 to -10.42] mg/dL; I2=68.0%) compared with White women (all, P≤.03). Groups exhibited comparable total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and diastolic blood pressure (all, P≥.06). CONCLUSIONS Black women with polycystic ovary syndrome have a greater tendency for an adverse cardiometabolic risk profile (increased insulin, homeostatic model assessment of insulin resistance, and systolic blood pressure) despite lower triglycerides than White women. Our observations support the consideration of these disparities for diagnostic, monitoring, and management practices in Black women and for future guideline recommendations. Given the heterogeneity among studies, future research should address the relative contributions of biologic, environmental, socioeconomic, and healthcare factors to the observed disparities. Furthermore, longitudinal research is required to address patient-pressing complications, including cardiovascular events and mortality rate in Black women with polycystic ovary syndrome as a high-risk yet understudied population.
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Prevalence of Overweight and Obesity Among African American Children and Adolescents: Risk Factors, Health Outcomes, and Prevention/Intervention Strategies.
Sutherland, ME
Journal of racial and ethnic health disparities. 2021;(5):1281-1292
Abstract
This paper examines the biological, psychosocial, cultural, and obesogenic environmental factors that might account for the high prevalence rates of overweight and obesity among African American young children (aged 2-11) and adolescents (aged 12-19). Research findings are discussed on the practices associated with the development of childhood obesity including maternal overweight and obesity, physiological predisposition, infant feeding practices, breastfeeding, rapid infant weight gain, sleep disruption, low nutrition diets, physical inactivity, and sedentary behavior. The psychological correlates of overweight and obesity are discussed. Consistent with the obesogenic arguments, this paper examines the development of childhood obesity as a function of socioeconomic disadvantages, social inequities, urban environmental contingencies, and media food product messages. The potential deleterious health consequences of overweight and obesity are discussed. There is an examination of the structural-level and individual-level prevention/intervention strategies necessary for sustainable declines in childhood overweight and obesity.
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Comparative effectiveness of a standard behavioral and physical activity enhanced behavioral weight loss intervention in Black women.
Blackman Carr, LT, Samuel-Hodge, CD, Ward, DS, Evenson, KR, Bangdiwala, SI, Tate, DF
Women & health. 2020;(6):676-691
Abstract
Black women typically lose small amounts of weight in behavioral weight loss interventions, partially due to low engagement in physical activity. Culturally relevant enhancement of the physical activity component may improve weight loss. This study compared the effectiveness of a culturally-relevant, physical activity-enhanced behavioral weight loss intervention to a standard behavioral weight loss intervention in Black women (n = 85) over 6 months. The study was conducted in two cohorts from March 2016 to February 2017 at the University of North Carolina at Chapel Hill. Participants had an average age of 48.30 ± 11.02 years with an average body mass index of 36.46 ± 4.50 kg/m2. Standard and enhanced groups' weight change (-2.83 kg and -2.08 kg, respectively) and change in physical activity (43.93 min/ week and 15.29 min/week, respectively) did not differ between groups. Significantly more standard group participants lost 5% of baseline weight compared to enhanced group participants. This study produced typical weight loss results in Black women. Behavioral weight loss treatment remains moderately effective for Black women. Strategies to increase attendance and self-monitoring, and the inclusion of cultural contexts to weight-related behaviors are needed to improve outcomes.