Disease In African Americans Research Articles

Seeing in Color: Inclusion and Characterization of Hereditary Eye Disease in African Americans.

Hereditary eye diseases (HEDs) are individually rare but affect millions globally. The era of molecular genetics has ushered major advances in the study of these disorders; however, the inclusivity and population diversity of this research is unknown. Questions on the accuracy and applicability of these findings in diverse populations, especially African American patients, came up consistently during counselling sessions. This also raised the possibility of missed opportunities for broader understanding of these rare diseases. We conducted a literature review to measure the representation of African Americans in genomic research surrounding nine HEDs. A detailed literature search using a predetermined set of search terms for each of nine HED categories was performed across PubMed, Embase, Web of Science, and Scopus focusing on studies published between Jan 1990 and July 2021. Predetermined inclusion criteria were applied to filter the sources. We identified 46 studies clearly reporting HED characterization in African Americans. Analysis of these inclusive studies revealed unique findings demonstrating the known usefulness of including diverse cohorts in genomics research. HED characterization in diverse participants, specifically African Americans, is identified as a knowledge gap area. Genomic research is more applicable to patients when conducted in populations that share their ancestral background. Greater inclusion of African Americans in ophthalmic genetics research is a scientific imperative and a needed step in the pursuit of the best possible patient care for populations of all ancestries. This work reveals gaps in genomic research in African Americans with HEDs.

334 Identification of novel plasma protein biomarkers for diagnosis and prediction of Alzheimer’s disease in African Americans

OBJECTIVES/GOALS: To identify novel panel of plasma protein biomarkers to improve prediction and diagnosis of Alzheimer’s disease (AD) for African Americans (AA), who are at greater risk of developing AD compared to non-Hispanic White individuals but are underrepresented in AD research. METHODS/STUDY POPULATION: Pre-existing plasma samples from 460 AA individuals with clinical diagnoses of AD, cognitively unimpaired (CU), mild cognitive impairment (MCI), or dementia with Lewy bodies (DLB) will undergo untargeted proteomics using the SomaScan assay, where modified single stranded DNA aptamers bind to protein targets which are quantified by DNA microarray. Protein expression levels will be compared between diagnostic groups to identify differentially expressed proteins. Additional clinical, genetic, and lifestyle factors will be compared with protein expression when available. Proteins of interest, identified by differential protein expression analysis results, will be included in receiver operating characteristic analyses to identify the optimal set of proteins for diagnostic classification. RESULTS/ANTICIPATED RESULTS: A pilot experiment utilizing plasma from 40 individuals identified multiple differentially expressed proteins (DEPs) between AD and non-AD groups. Eight proteins were nominated from the differential protein analysis into a receiver operating characteristic (ROC) analysis based on pvalue and previous implication in AD genome wide association studies. Proteins involved in microglial activation, neuronal adhesion, cell proliferation, and innate immunity were nominated. The ROC model achieved 100% classification accuracy of AD and CU groups using age, sex, and the eight nominated proteins. It is expected that there will be more significant associations when utilizing the full cohort of 460 AA and that DEPs between AD, CU, MCI, and DLB will be identified. DISCUSSION/SIGNIFICANCE: The nomination of a novel panel of plasma biomarkers developed from an AA cohort will directly serve the AA community by improving access to an early and accurate diagnosis of AD. Access to improved prediction and diagnosis will likely improve disease management, thus improving patient outcomes and decreasing burden on families and caregivers.

APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.

Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated Na+ import/K+ efflux triggered activation of GPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.

Targeted plasma eQTL and pQTL to identify potential novel biomarkers for Alzheimer’s Disease in African Americans

AbstractBackgroundGiven the overlap of symptoms between Alzheimer’s disease (AD) and other dementias, it is essential to develop widely accessible biomarkers that will ensure an accurate diagnosis of AD to enable its proper treatment. African Americans (AA) are twice more likely to develop AD than non‐Hispanic whites (NHW) and yet they remain underrepresented in AD research. The few studies conducted in AA suggest that there are different factors that influence AD in this population; therefore, it is possible that different biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study we are testing the hypothesis that genetic variants that show association with AD‐risk in AA and with plasma levels of transcript and proteins may serve as AD biomarkers which are more accessible and less costly than cerebrospinal fluid or neuroimaging biomarkers.MethodsIn 189 AD cases and 183 cognitively unimpaired (CU) AA participants of the Florida Consortium of African American Alzheimer’s Disease Studies (FCA3DS), we performed targeted DNA sequencing of 10 AD‐associated loci. Genetic variants were tested for association with plasma transcripts and plasma total tau protein levels previously measured in this cohort using a nanoString® custom panel (Reddy J, et al. 2022) and Simoa assays (Deniz K, et al. 2021), respectively. In receiver operating characteristic (ROC) analyses, the most significant expression/protein quantitative trait loci (eQTL/pQTL) were added sequentially to a base model that included only age and sex to identify eQTL/pQTL that improved the accuracy to correctly classify AD cases vs. CU.ResultsOf the 5112 variants identified in the targeted sequencing, 71 were nominally associated (p<0.05) with plasma transcript/protein levels and with AD‐risk. ROC analysis of age, sex, eQTL/pQTL in APOE, ABCA7, AKAP9, EPHA1, SORL1, and TLR4, and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE‐ɛ4 dosage achieved 77.6% area under the curve (AUC) to discriminate AD vs. CU, a 19.9% improvement over a model that only included age and sex.ConclusionsPlasma transcript levels and eQTL/pQTL are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.

Epidemiology and outcomes of non-alcoholic fatty liver disease in African Americans.

1_bxolhs28Kaltura.

Editing of APOL1 mRNA reduces APOL1 expression and activation of innate immunity

The APOL1 gene encodes Apoliprotein L1, an innate immune response protein that confers protection against Trypanosomal diseases and likely other infectious diseases. 1 Thomson R. Genovese G. Canon C. et al. Evolution of the primate trypanolytic factor APOL1. Proc Natl Acad Sci U S A. 2014; 111: E2130-2139 Crossref PubMed Scopus (160) Google Scholar ,2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar The G1 and G2 variants of APOL1, which are enriched in persons of West African ancestry, provide enhanced protection against Trypanosome infection, but persons with APOL1 high risk (HR) genotypes (two risk alleles) have markedly increased risk of progressive CKD. 2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Because most individuals with HR genotypes do not develop kidney disease, it is likely that a “second hit” may be necessary to unmask the HR genotype-associated risk. APOL1 HR genotype is most strongly associated with severe kidney disease occurring in the setting of high interferon levels due to infection (HIV or COVID-19), 3 Kopp J.B. Nelson G.W. Sampath K. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011; 22: 2129-2137 Crossref PubMed Scopus (602) Google Scholar ,4 Kudose S. Batal I. Santoriello D. et al. Kidney Biopsy Findings in Patients with COVID-19. J Am Soc Nephrol. 2020; 31: 1959-1968 Crossref PubMed Scopus (245) Google Scholar lupus nephritis, 5 Freedman B.I. Langefeld C.D. Andringa K.K. et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 2014; 66: 390-396 Crossref PubMed Scopus (203) Google Scholar interferon treatment, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and kidney transplantation. 7 Santoriello D. Husain S.A. De Serres S.A. et al. Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts. Kidney Int. 2018; 94: 1189-1198 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar As APOL1 expression is strongly induced by interferons, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar upregulation of toxic G1 and G2 variants in the setting of high interferon is hypothesized to be an important contributor to kidney injury. Thus, improved understanding of the factors that regulate APOL1 expression may provide new strategies to prevent or treat kidney disease in individuals with HR genotypes.

MeQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans

Identifying genetic variants that are associated with variation in DNA methylation, an analysis commonly referred to as methylation quantitative trait locus (meQTL) mapping, is an important first step towards understanding the genetic architecture underlying epigenetic variation. Most existing meQTL mapping studies have focused on individuals of European ancestry and are underrepresented in other populations, with a particular absence of large studies in populations with African ancestry. We fill this critical knowledge gap by performing a large-scale cis-meQTL mapping study in 961 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We identify a total of 4,565,687 cis-acting meQTLs in 320,965 meCpGs. We find that 45% of meCpGs harbor multiple independent meQTLs, suggesting potential polygenic genetic architecture underlying methylation variation. A large percentage of the cis-meQTLs also colocalize with cis-expression QTLs (eQTLs) in the same population. Importantly, the identified cis-meQTLs explain a substantial proportion (median = 24.6%) of methylation variation. In addition, the cis-meQTL associated CpG sites mediate a substantial proportion (median = 24.9%) of SNP effects underlying gene expression. Overall, our results represent an important step toward revealing the co-regulation of methylation and gene expression, facilitating the functional interpretation of epigenetic and gene regulation underlying common diseases in African Americans.

Abstract MP19: An eGFR Polygenic Score Predicts Chronic Kidney Disease in African Americans

Chronic kidney disease (CKD) is a risk factor for cardiovascular disease and early death. Genetic factors contribute to CKD, and recently, polygenic scores (PGS) have been developed to quantify risk for complex diseases, such as CKD. However, African ancestry populations are underrepresented in both CKD genetic studies and PGS development overall; moreover, European-ancestry derived PGSs demonstrate diminished predictive performance in African ancestry populations. This study aimed to develop a PGS for CKD using genotype and phenotype data from African American (AA) participants of observational cohort studies. We obtained score weights from a meta-analysis of genome-wide association studies (GWAS) for estimated glomerular filtration rate (eGFR) in the Million Veteran Program (MVP) and Reasons for Geographical and Racial Differences in Stroke (REGARDS) Study (total n~66,000). We then optimized the PGS in a cohort of AAs from the Hypertension Genetic Epidemiology Network (HyperGEN) Study (n~1,900) using the PRS-CS software and evaluated the predictive performance of the PGS at multiple global shrinkage parameters. We further adjusted the PGS for APOL1 risk status. In HyperGEN, the eGFR-based PGS was significantly associated with the odds of prevalent CKD—defined as baseline eGFR <60 mL/min/1.73m 2 — in logistic regression models adjusted for age, sex, and population structure. Further, accounting for APOL1 risk status—a putative variant for CKD unique to those of sub-Saharan African descent—improved the score’s accuracy, with the APOL1 -adjusted PGS explaining 1.9% (1.1% without APOL1 ) of the variance in CKD and an area under the curve (AUC) of 58.9% [95% CI: 53.0%-64.9%] (without APOL1 , 58.2% [95% CI: 52.3%-64.1%]). Sensitivity analyses and validation in external cohorts, as well as comparisons to previously published PGS, are ongoing. In this study, we developed a PGS that was significantly associated with CKD with improved predictive accuracy in AAs over previously published PGS.

A narrative review of neuro-ophthalmologic disease in African Americans and Hispanics with multiple sclerosis.

Multiple sclerosis (MS) is the most common non-traumatic cause of disability in young people, with vision loss in the disease representing the second largest contributor to disability. In particular, African-American patients with MS are noted to have lower vision than their Caucasian counterparts. In this review, we examine the disparities in eye diseases in the MS population with our gaps in knowledge and discuss the underlying nature of pathological disparities.

Population‐based Discovery and Ethnically Mixed Mendelian Randomization Validation Identifies Telmisartan as a Candidate Drug for Alzheimer’s Disease in African Americans

AbstractBackgroundElevated incidences of Alzheimer’s disease (AD) and disease progression may be associated with African American (AA)‐specific disease comorbidities, such as hypertension, diabetes, and chronic kidney disease. Treatments and management of these comorbidities — such as antihypertensive angiotensin‐II receptor blockers (ARBs) — may reduce risk of AD in AA people, while conferring additional beneficial effects on renal function and diabetes control.MethodWe conducted a race‐specific pharmacoepidemiologic study to investigate the association between telmisartan (an ARB having PPAR‐gamma (PPARG) agonistic properties and beneficial anti‐diabetic effects) use and AD using Cox analysis, Kaplan‐Meier analysis, and propensity score‐matched log‐rank test. We further conducted ethnically mixed Mendelian randomization analysis to identify likely causal relationships between telmisartan use and AD in AA people. All models were adjusted for age, sex, underlying health, and comorbidities.ResultIn Cox analyses of ARB users in insurance claim data, telmisartan use was significantly associated with reduced risks of AD in AA people (Hazard ratio [HR] = 0.77, P‐value = 0.002), but was not associated with AD reduction in non‐Hispanic White Americans (HR = 0.97, P‐value = 0.411). Compared to lisinopril (an angiotensin‐converting‐enzyme inhibitor) use, telmisartan use was associated with stronger reduced risk of AD in AA people (HR = 0.68, P‐value < 0.001). In all sensitivity and secondary analyses, telmisartan use was associated with stronger protective effects (including AD and dementia) in AA people. Using ethnically mixed Mendelian randomization analysis from large genome‐wide association studies (over 2 million individuals) across AD, hypertension, and diabetes, we demonstrated that telmisartan has greater beneficial effect on AD in AA people compared to European populations.ConclusionWe identified that telmisartan is a candidate drug for potential prevention and treatment of AD in AA people, but not in non‐Hispanic White Americans. Our findings indicate that early comorbidity management (hypertension, diabetes, and kidney dysfunction) by telmisartan will significantly reduce AD incidence for aged individuals, in particular for aged AA people. The association between telmisartan use and decreased incidence of AD in AAs will require a randomized controlled trial with an ethnically diverse population to establish causality and explore therapeutic outcomes.

ASHP-Association of Black Health-System Pharmacists Joint Leadership Award.

Angela Massey Hill, PharmD, CPh, RPh, is the 2022 recipient of the ASHP–Association of Black Health-System Pharmacists (ABHP) Joint Leadership Award. The award was established in 2009 to recognize people whose exceptional leadership has helped reduce racial and ethnic disparities in healthcare. Hill is associate dean and professor of pharmacy at the University of South Florida (USF) Health Taneja College of Pharmacy in Tampa. Her clinical work focuses primarily on neuropsychiatric conditions and gerontology. She has worked throughout her career to improve the care of people with dementia and to educate patients, clinicians, and caregivers about dementia and other memory disorders. She practices as a clinician at Reliance Medical Centers, where she provides medication therapy management and works with the organization’s Brain Health Awareness Program. She is also a consultant for the USF Neuroscience Byrd Alzheimer’s Institute. Hill was the 2004 recipient of a research endowment from Delta Sigma Theta Inc. for the investigation of biomarkers associated with Alzheimer’s disease in African Americans. The award launched and continues to drive her research agenda.

Population-based discovery and Mendelian randomization analysis identify telmisartan as a candidate medicine for Alzheimer's disease in African Americans.

African Americans (AAs) and European Americans (EAs) differ in Alzheimer's disease (AD) prevalence, risk factors, and symptomatic presentation and AAs are less likely to enroll in AD clinical trials. We conducted race-conscious pharmacoepidemiologic studies of 5.62 million older individuals (age ≥60) to investigate the association of telmisartan exposure and AD outcome using Cox analysis, Kaplan-Meier analysis, and log-rank test. We performed Mendelian randomization (MR) analysis of large ethnically diverse genetic data to test likely causal relationships between telmisartan's target and AD. We identified that moderate/high telmisartan exposure was significantly associated with a reduced incidence of AD in the AAs compared to low/no telmisartan exposure (hazard ratio [HR] = 0.77, 95% CI: 0.65-0.91, p-value = 0.0022), but not in the non-Hispanic EAs (HR = 0.97, 95% CI: 0.89-1.05, p-value = 0.4110). Sensitivity and sex-/age-stratified patient subgroup analyses identified that telmisartan's medication possession ratio (MPR) and average hypertension daily dosage were significantly associated with a stronger reduction in the incidence of both AD and dementia in AAs. Using MR analysis from large genome-wide association studies (GWAS) (over 2 million individuals) across AD, hypertension, and diabetes, we further identified AA-specific beneficial effects of telmisartan for AD. Randomized controlled trials with ethnically diverse patient cohorts are warranted to establish causality and therapeutic outcomes of telmisartan and AD. Telmisartan is associated with lower risk of Alzheimer's disease (AD) in African Americans (AAs). Telmisartan is the only angiotensin II receptor blockers having PPAR-γ agonistic properties with beneficial anti-diabetic and renal function effects, which mitigate AD risk in AAs. Mendelian randomization (MR) analysis demonstrates the specificity of telmisartan's protective mechanism to AAs.

Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism.

The Thr92Ala-Dio2 polymorphism has been associated with reduced cognition in 2-month-old male mice and increased risk for cognitive impairment and Alzheimer’s disease in African Americans. This has been attributed to reduced thyroid hormone (TH) signaling and endoplasmic reticulum (ER) stress in the brain. Here we studied the Thr92Ala-Dio2 mouse model and saw that older male mice (7–8-month-old) exhibited a more severe cognition impairment, which extended to different aspects of declarative and working memories. A similar phenotype was observed in 4–5-month-old female mice. There were no structural alterations in the prefrontal cortex (PFC) and hippocampus of the Thr92Ala-Dio2 mouse. Nonetheless, in both male and female PFC, there was an enrichment in genes associated with TH-dependent processes, ER stress, and Golgi apparatus, while in the hippocampus there was additional enrichment in genes associated with inflammation and apoptosis. Reduced TH signaling remains a key mechanism of disease given that short-term treatment with L-T3 rescued the cognitive phenotype observed in males and females. We conclude that in mice, age is an additional risk factor for cognitive impairment associated with the Thr92Ala-Dio2 polymorphism. In addition to reduced TH signaling, ER-stress, and involvement of the Golgi apparatus, hippocampal inflammation and apoptosis were identified as potentially important mechanisms of a disease.

Number of Educational Sessions Attended Was Not Associated With Weight Loss or Blood Pressure Changes in African Americans Enrolled in Weight Matters

ObjectivesProgram evaluation is an important step in understanding factors that strengthen the quality of the program and improve outcomes for future interventions. Program participation, as defined by number of educational sessions attended, was investigated for its association with weight and blood pressure changes in African Americans that enrolled in Weight Matters.MethodsWeight Matters, a community-based chronic disease intervention targeting African Americans enrolled 499 participants (88.6% female, 51.5 ± 12.7 years, BMI: 36.7 ± 8.0) aimed at reducing risk factors of prevalent chronic disease in African Americans. The intervention consisted of bi-weekly educational sessions focusing on health, fitness, and nutrition during an 18-week period with scheduled follow ups and post-intervention at 12 months. During these follow up study visits, data, including weight and blood pressure (BP), was collected.Results57% of participants attended all educational sessions (10). ANOVA was used to compare the attendance of educational sessions by participant weight loss and BP changes. There was no significant difference in the amount of educational sessions attended in the participants that lowered their BP at post intervention compared to those that had no change or raised (F(3,219) = 0.431, p = 0.73). Similarly, there were no differences observed in the number of attended sessions between participants that achieved normal BP values compared to those with elevated BP or hypertension at post-intervention (F(3,298) = 1.41, p = 0.24) or 12-months (p = 0.63). There was no difference in the number of attended sessions in participants that had ³ 5% weight loss compared to those with < 5% weight loss or gained weight at post-intervention (F(2,276) = 0.187, p = 0.83) or 12 months (p = 0.39).ConclusionsFindings suggest that attendance to educational sessions was not associated with changes in blood pressure or weight loss at post intervention and 12-month post. There were limitations to this study as there was a high dropout rate (40%) of participants that did not complete the program. In addition, some class sizes were determined to be too large and may have contributed to an ineffective knowledge transfer.Funding SourcesThis project was supported by funding from the Centers for Medicare & Medicaid Services (CMS) (DHHS Grant # 1102017000118).

Modeling the Progression of Hypertensive Kidney Disease in African Americans

Chronic kidney disease (CKD) is associated with the progressive functional loss of nephrons and hypertension (HTN). Several clinical studies demonstrate calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN, but there are few long‐term clinical studies that determine the impact of CCBs in patients with hypertensive CKD. African Americans (AA) have a faster progression to end stage renal disease as compared to the white population which may be partially explained by factors such as salt‐sensitive blood pressure (BP) and greater prevalence of uncontrolled HTN. Observational studies demonstrate BP to be a strong independent risk factor for CKD progression, yet intense BP lowering in AA does not diminish the renal function decline any more than standard therapy. The African American Study of Kidney Disease and Hypertension (AASK) trial suggests AA with proteinuric CKD may have detrimental responses to CCB as compared to an angiotensin converting enzyme (ACE) inhibitor. Therefore, using a large physiological model, we set out to replicate the AASK trial findings and predict the roles of the renin‐angiotensin system, salt intake, and intensive antihypertensive therapy in a virtual population during CCB therapy. Our current mathematical model, HumMod, is a large physiological simulator that is comprised of key systems that play an integral role in BP control such as neural, endocrine, circulatory, and renal systems. All of the parameters (n=335) that control these systems were randomly varied and resulted in over 3,000 unique models that we define as a virtual population. We calibrated this virtual population to patient level data from the AASK trial (BP and glomerular filtration rate [GFR] before and after 3 years of amlodipine). After matching the virtual population to individual level data, the virtual population (n=140) was associated with statistically similar BP and GFR before and after CCB therapy (Figure) as well as similar increases in glomerular damage. Baseline factors such as elevated single nephron GFR and increased tubuloglomerular feedback were correlated with greater declines in renal function and increased glomerulosclerosis after 3 years of CCB. Interestingly, when looking at the models with severe CKD (&lt;35 mL/min), glomerulosclerosis and angiotensin II significantly increased with CCB despite significant falls in mean BP (‐7 ± 7 mmHg). Adding an ACE inhibitor decreased angiotensin II levels and abrogated the increase in glomerulosclerosis while further decreasing BP (‐12 ± 9 mmHg). Decreasing salt intake in addition to the CCB+ACE inhibitor therapy further benefited systemic and glomerular pressures but significantly decreased overall GFR independent of any glomerular damage. Finally, all antihypertensive therapies were associated with significant decreases in left ventricular mass. These data suggest the current clinical markers of renal function such as eGFR may not fully reflect the actual progression of CKD, especially with intensive antihypertensive treatment. Our simulation also supports that angiotensin system inhibitors are renoprotective and cardioprotective when combined with CCB therapy in African American CKD patients.

A Lifestyle Intervention to Delay Early Chronic Kidney Disease in African Americans With Diabetic Kidney Disease: Pre-Post Pilot Study.

BackgroundBehavioral factors, such as lifestyle, have been shown to explain approximately 24% of the excess risk of chronic kidney disease (CKD) among African Americans. However, there are limited intervention studies culturally tailored to African Americans with type 2 diabetes mellitus and CKD.ObjectiveThe main objective of this study was to examine the feasibility and preliminary efficacy of a culturally tailored lifestyle intervention among African Americans with type 2 diabetes mellitus and CKD.MethodsA pre-post design was used to test the feasibility of a lifestyle intervention in 30 African American adults recruited from the Medical University of South Carolina between January 2017 and February 2017. A research nurse delivered the manualized study intervention weekly for 6 weeks. Clinical outcomes (hemoglobin A1c, blood pressure, and estimated glomerular filtration rate [eGFR]) were measured at baseline and postintervention. Disease knowledge, self-care, and behavior outcomes were also measured using validated structured questionnaires at baseline and postintervention. Descriptive statistics and effect sizes were calculated to determine clinically important changes from baseline.ResultsSignificant pre-post mean differences and decreases were observed for hemoglobin A1c (mean 0.75%, 95% CI 0.16-1.34; P=.01), total cholesterol (mean 16.38 mg/dL, 95% CI 5.82-26.94; P=.004), low-density lipoprotein (mean 13.73 mg/dL, 95% CI 3.91-23.54; P=.008), and eGFR (mean 6.73 mL/min/1.73m2, 95% CI 0.97-12.48; P=.02). Significant pre-post mean differences and increases were observed for CKD self-efficacy (mean −11.15, 95% CI −21.55 to −0.75; P=.03), CKD knowledge (mean −2.62, 95% CI −3.98 to −1.25; P<.001), exercise behavior (mean −1.21, 95% CI −1.96 to −0.46; P=.003), and blood sugar testing (mean −2.15, 95% CI −3.47 to −0.83; P=.003).ConclusionsThis study provides preliminary data for a large-scale appropriately powered randomized controlled trial to examine a culturally tailored lifestyle intervention in African Americans with type 2 diabetes mellitus and CKD in order to improve clinical, knowledge, self-care, and behavior outcomes in this population.

APOL1 G3 Variant Is Associated with Cardiovascular Mortality and Sudden Cardiac Death in Patients Receiving Maintenance Hemodialysis of European Ancestry

Introduction: The G1 and G2 variants in the APOL1 gene convey high risk for the progression of chronic kidney disease in African Americans. The G3 variant in APOL1 is more common in patients of European ancestry (EA); outcomes associated with this variant have not been explored previously in EA patients receiving dialysis. Methods: DNA was collected from approximately half of the patients enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial and genotyped for the G3 variants. We utilized an additive genetic model to test associations of G3 with the EVOLVE adjudicated endpoints of all-cause mortality, cardiovascular mortality, sudden cardiac death (SCD), and heart failure. EA and African ancestry samples were analyzed separately. Validation was done in the Vanderbilt BioVU using ICD codes for cardiovascular events that parallel the adjudicated endpoints in EVOLVE. Results: In EVOLVE, G3 in EA patients was associated with the adjudicated endpoints of cardiovascular mortality and SCD. In a validation cohort from the Vanderbilt BioVU, cardiovascular events and cardiovascular mortality defined by ICD codes showed similar associations in EA participants who had been on dialysis for 2 to <5 years. Discussion/Conclusions: G3 in APOL1 variant was associated with cardiovascular events and cardiovascular mortality in the EA patients receiving dialysis. This suggests that variations in the APOL1 gene that differ in populations of different ancestry may contribute to cardiovascular disease.

Admixture mapping identifies novel regions influencing Alzheimer disease in African Americans.

African Americans (AA) are substantially underrepresented in Alzheimer's disease (AD) genetic studies, yet their admixed genetic ancestry (African and European) provides a unique opportunity to identify novel genetic factors associated with AD related to genetic ancestry. Admixture mapping (AM) provides a more powerful approach than SNP-based genome-wide association studies (GWAS) in admixed populations in part due to the lower multiple testing burden. In this study we used AM to identify regions associated with AD in AA individuals. Our analyses included 10,271 individuals from 17 AD Sequencing Project and AD Genetics Consortium cohorts. We estimated global ancestry (GA) using the GENESIS software. To infer local ancestry (LA), the target AA dataset was combined with appropriate reference-population samples from HGDP reference panel, and LA was estimated using SHAPEIT followed by RFMix. Then, we performed AM using the GENESIS software separately on each cohort. We meta-analyzed the AM results with the random effect approach (RE2). We calculated the significance threshold using STEAM software. Finally, we performed logistic regression of genotype on affection status for variants across the prioritized regions from AM for fine-mapping. The regression model included LA and genotype as main effects and term for their interaction, along with GA, sex and age as covariates, and used permutation-based testing approach for multiple test correction (N=10,000). AM identified two genome-wide significant loci on chromosomes 17p13.2 (pv=2.2 x10-5 ) and 18q21.33 (pv=1.22x10-5 ). 17p13.2 region was identified as a genome-wide significant in two previous studies in non-Hispanic White population. To fine map this region we conducted ancestry-aware regression analysis. LA x genotype interaction model found the MINK1 gene (rs72835013) on the 17p13.2 region significantly associated with AD (pv = 1x10-4 ). Our results confirmed an AD associated region on the chromosome 17p13.2 and showed that the 17p13.2 region increases AD risk in AA individuals with the European LA. This region includes genes previously indicated in AD such as SCIMP through association studies and the MINK1 and SLC25A11 genes through brain expression studies.

Obesity and the Bidirectional Risk of Cancer and Cardiovascular Diseases in African Americans: Disparity vs. Ancestry.

Cardiovascular disease (CVD) and cancer often occur in the same individuals, in part due to the shared risk factors such as obesity. Obesity promotes adipose inflammation, which is pathogenically linked to both cardiovascular disease and cancer. Compared with Caucasians, the prevalence of obesity is significantly higher in African Americans (AA), who exhibit more pronounced inflammation and, in turn, suffer from a higher burden of CVD and cancer-related mortality. The mechanisms that underlie this association among obesity, inflammation, and the bidirectional risk of CVD and cancer, particularly in AA, remain to be determined. Socio-economic disparities such as lack of access to healthy and affordable food may promote obesity and exacerbate hypertension and other CVD risk factors in AA. In turn, the resulting pro-inflammatory milieu contributes to the higher burden of CVD and cancer in AA. Additionally, biological factors that regulate systemic inflammation may be contributory. Mutations in atypical chemokine receptor 1 (ACKR1), otherwise known as the Duffy antigen receptor for chemokines (DARC), confer protection against malaria. Many AAs carry a mutation in the gene encoding this receptor, resulting in loss of its expression. ACKR1 functions as a decoy chemokine receptor, thus dampening chemokine receptor activation and inflammation. Published and preliminary data in humans and mice genetically deficient in ACKR1 suggest that this common gene mutation may contribute to ethnic susceptibility to obesity-related disease, CVD, and cancer. In this narrative review, we present the evidence regarding obesity-related disparities in the bidirectional risk of CVD and cancer and also discuss the potential association of gene polymorphisms in AAs with emphasis on ACKR1.

S896 Clinical Manifestations of Crohn’s Disease in African Americans in a Rural versus Urban Setting

Introduction: The incidence of inflammatory bowel disease (IBD), both Crohn’s Disease (CD) and Ulcerative Colitis (UC), has dramatically increased in the black population in recent years. While studies have focused on genetics and environmental factors contributing to the rise in incidence, no documented studies currently exist investigating the disease presentation utilizing a large cohort of black IBD patients, particularly those located in rural and urban settings, where this rise in incidence is realized the most. This study aims to better characterize the clinical characteristics of Crohn’s Disease in black populations, including its presentation and intra- and extraintestinal and manifestations in order to better understand this rise in incidence and guide treatment parameters in the future to address this. Methods: We performed a multicenter retrospective review of black patients from both a large urban center and a rural IBD center. Patients were identified utilizing ICD-10 diagnostic codes in the electronic medical records. The clinical manifestation of disease, disease extent and severity, laboratory values were abstracted via gastroenterology clinic and colonoscopy documentation. We include only patients who self-identified as African Americans or Black in ethnicity/race. A sample of CD patients seen in clinic or who underwent colonoscopy from 2018 to 2020 were manually extracted and reviewed in the urban center. Data on rural patients from 2011-2019 was electronically exported from electronic medical records, after which random sample of 100 patients was manually reviewed for accuracy. Statistical calculations were conducted via T-test, Chi Squared, and Fisher’s Exact test. Results: A total of 428 AA CD patients were included, 300 in the rural setting, 128 in the urban setting. The rural CD patients were significantly younger, with a female predominance, while the prevalence of severe disease phenotypes was comparable between the two groups, as shown in Table 1. For extra-intestinal manifestations of IBD, there was a higher prevalence of fatty liver disease in the rural population, while the remaining EIMs were similar (Table 1). Conclusion: The younger age of presentation and female predominance of CD in AAs have not been previously reported. Our study highlighted the importance of more research efforts to include minority CD patients from rural populations.Table 1.: Baseline Patient Characteristics.