Persons Of African Ancestry Research Articles

Sex differences in Alzheimer's disease blood biomarkers in a Caribbean population of African ancestry: The Tobago Health Study.

Alzheimer's disease (AD) is increasing in the Caribbean, especially for persons of African ancestry (PAA) and women. However, studies have mostly utilized surveys without AD biomarkers. In the Tobago Health Study (n = 309; 109 women, mean age 70.3±6.6), we assessed sex differences and risk factors for serum levels of phosphorylated tau-181 (p-tau181), amyloid-beta (Aβ)42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Blood samples were from 2010 to 2013 for men and from 2019 to 2023 for women. Women were more obese, hypertensive, and sedentary but reported less smoking and alcohol use than men (age-adjusted p<0.04). Compared to men, women had worse levels of AD biomarkers, with higher p-tau181 and lower Aβ42/40, independent of covariates (p<0.001). In sex-stratified analyses, higher p-tau181 was associated with older age in women and with hypertension in men. GFAP and NfL did not differ by sex. Women had worse AD biomarkers than men, unexplained by age, cardiometabolic diseases, or lifestyle. Studying risk factors for AD in PAA is warranted, especially for women earlier in life.

High placental expression of FLT1, LEP, PHYHIP and IL3RA – In persons of African ancestry with severe preeclampsia

IntroductionMortality from preeclampsia (PE) and PE-associated morbidities are 3-to 5-fold higher in persons of African ancestry than in those of Asian and European ancestries. MethodsTo elucidate placental contribution to worse PE outcomes in African ancestry pregnancies, we performed bulk RNA sequencing on 50 placentas from persons with severe PE (sPE) of African (n = 9), Asian (n = 18) and European (n = 23) ancestries and 73 normotensive controls of African (n = 10), Asian (n = 15) and European (n = 48) ancestries. ResultsPreviously described canonical preeclampsia genes, involved in metabolism and hypoxia/angiogenesis including: LEP, HK2, FSTL3, FLT1, ENG, TMEM45A, ARHGEF4 and HTRA1 were upregulated sPE versus normotensive placentas across ancestries. LTF, NPR3 and PHYHIP were higher in African vs. Asian ancestry sPE placentas. Allograft rejection/adaptive immune response genes were upregulated in placentas from African but not in Asian or European ancestry sPE patients; IL3RA was of particular interest because the patient with the highest placental IL3RA expression, a person of African ancestry with sPE, developed postpartum cardiomyopathy, and was the only patient out of 123, that developed this condition. Interestingly, the sPE patients with the highest IL3RA expression among persons of Asian and European ancestries developed unexplained tachycardia peripartum, necessitating echocardiography in the European ancestry patient. The association between elevated placental IL3RA levels and unexplained tachycardia or peripartum cardiomyopathy was found to be significant in the 50 sPE patients (p = .0005). DiscussionHigh placental upregulation of both canonical preeclampsia and allograft rejection/adaptive immune response genes may contribute to worse PE outcomes in African ancestry sPE patients.

LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Abstract 104: Cytochrome B5 Reductase 3 Regulates The Erythropoietin Response To Ischemic Stroke In A Mouse Model Of Chronic Anemia And Oxidative Stress

Introduction: Cytochrome b5 reductase 3 (Cyb5R3) is a heme iron reductase that reverses oxidized soluble guanylate cyclase (sGC) heme iron (Fe 3+ Fe 2+ ) to preserve nitric oxide signaling. Under oxidative stress, such as occurs with sickle cell disease (SCD) and ischemic stroke, Cyb5R3 redox signaling provides resilience against tissue damage. A loss-of-function (roughly 50%) Cyb5R3 missense variant (T117S) occurs with high frequency (0.23 minor allele) in persons of African ancestry, who also suffer a greater burden of sickle cell anemia and ischemic stroke than other races. We hypothesized that Cyb5R3 regulates the erythropoietin response to ischemic stroke in a mouse model of SCD. Methods: Age-matched male SCD mice with wild-type Cyb5R3 (SS WT ) or T117S Cyb5R3 (SS T117S ) underwent middle cerebral artery occlusion (55 min) and reperfusion (48 hr). Blood was sampled at baseline and 48h reperfusion for hematology measurements. Brains were stained with 2,3,5-triphenyltetrazolium chloride to quantify infarct volume. Erythropoietin (EPO), heme oxygenase 1 (HMOX1) and sGC were assayed by Western blot. Results: We found brain infarct volume to be greater in SS T117S vs SS WT (63 vs 27 cm 3 , respectively; P=0.003). Red cells, hematocrit and hemoglobin decreased in SS T117S post-stroke, which was opposite to SS WT (red cells: -13% vs 13%, P=0.01; hematocrit: -20% vs 0%, P=0.03; hemoglobin: -18% vs 3%, P=0.02, respectively). In the absence of stroke (age-matched controls), SS WT had elevated HMOX1 protein compared to SS T117S , which normalized in post-stroke SS WT but was unchanged in post-stroke SS T117S . Kidney and plasma EPO levels significantly increased in SS WT post-stroke, but not in SS T117S . In vitro studies using HEK293 cells showed EPO and HMOX1 decrease with Cyb5R3 knockdown by siRNA. Conclusion: Our findings suggest a modifying role for Cyb5R3 in brain-kidney crosstalk during ischemic stroke, wherein loss of T117S Cyb5R3 activity negatively impacts renal and plasma EPO levels and resilience against infarct of ischemic brain tissue. The Cyb5R3 axis on which the brain-kidney-blood response to stroke in SCD turns represents a novel target for precision medicine approaches to managing stroke risk and pathology in SCD carriers of the T117S variant.

Loss of Cyb5R3 Function Silences Fetal Hemoglobin and Hematocrit Responses to Hydroxyurea in Patients with Sickle Cell Anemia

BACKGROUND: Hydroxyurea (HU) is the first FDA-approved and most widely prescribed drug for sickle cell (SS) patients due to its beneficial effects (decreased Hb polymerization, pain crises and hospitalization) and relative safety profile. While the clinical benefits of HU have been found to associate with increased nitric oxide (NO) and fetal hemoglobin (HbF) in most SS patients, there has been considerable interpatient variability in HbF response to the drug. From this standpoint, HU is imperfectly understood mechanistically. Cytochrome b5 reductase 3 (Cyb5R3), also known as methemoglobin reductase, is an enzyme known to modulate redox signaling in erythrocytes and vascular cells by catalyzing one electron transfer reactions using reduced nicotinamide adenine dinucleotide (NADH) as an electron donor. Functionally, membrane-associated CYB5R3 exerts antioxidant properties by modulating heme iron reduction, plasma membrane coenzyme Q reduction, elongation and unsaturation of fatty acids, cholesterol biosynthesis and drug metabolism, while the soluble form of CYB5R3 reduces red blood cell methemoglobin. Unremitting oxidation of the soluble guanylate cyclase (sGC) heme iron in the absence of sufficient Cyb5R3 activity in vascular smooth muscle has been shown to explain some NO resistance that characterizes pulmonary arterial hypertension and other vasculopathy associated with SCD. More than 40 variants of Cyb5R3 have been identified. Of particular interest is a Cyb5R3 variant (T117S) that contains a threonine to serine substitution in the flavoprotein, which lessens the reductase's activity by roughly 50% compared to wild-type. This variant occurs with high frequency (0.23 minor allele) in persons of African ancestry but is rare (<1%) in all other races. Nothing is known about the role of Cyb5R3 in the anemia of sickle cell disease. We hypothesized that Cyb5R3 may act as a modifier of HbF induction by HU in sickle cell anemia. METHODS: Male and female SS patients (n=633, 12-70 years of age) from the Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST) trial were recruited for genetic analysis (University of Pittsburgh IRB Protocol Study 19060255). Genotyping of rs1800457 (T117S SNP) was performed using Taqman genotyping assay. One-way ANOVA and Holms Sidak were used for multiple comparisons of HbF levels by Cyb5R3 genotype and HU treatment status. Intrapatient correlation analyses of HbF and hematocrit (HCT) were conducted using Pearsons r. RESULTS: Comparisons of HbF levels by Cyb5R3 genotype (CC, wild-type; CG, heterozygous wild-type and T117S; GG, homozygous T117S) and HU treatment status (treated vs. untreated) at time of study enrollment (baseline) show that HU is a less potent HbF inducer in the GG group (4.32 mean diff, P=0.344) versus the CC and CG patient groups (CC: 6.027 mean diff, P<0.0001 and CG: 6.914 mean diff, P<0.0001). Correlation analyses showed that as HbF levels increased among HU-untreated patients, the trend was for HCT to decrease. This was true for all SS patients, irrespective of Cyb5R3 genotype (CC: r = -0.336, P<0.0001, n=320; CG: r = -0.437 P<0.0001, n=120; GG: r = -0.253, P=0.136, n=36). However, with HU therapy, the inverse relationship between HbF and HCT was less negative in SS patients carrying at least one copy of the wild-type Cyb5R3 gene (CC or CG). In these individuals, increasing levels of HbF (up to 10%) correlated with positive gains in HCT at HbF greater than 5-6% (CC: r = -0.161, P=0.097, n=107) and 6-7% (CG: r = -0.186, P=0.25, n=40). In patients homozygous for T117S, HCT continued trending downward as HbF increased (GG: r = -0.419, P=0.228, n=10). These data indicate that the positive relationship between HbF and HCT is subject to uncoupling by loss of Cyb5R3 function. In vitro studies with human erythroleukemic K562 cells reveal loss of gamma globin induction by HU treatment when wild-type Cyb5R3 is knocked down by siRNA, indicating a requirement for Cyb5R3 in HU-stimulated HbF induction. SUMMARY andCONCLUSION: Loss of Cyb5R3 activity negatively impacts HbF and HCT in HU treated SS patients. We conclude that the T117S variant may be a useful marker for predicting which SS patients will incur beneficial HbF and HCT responses to HU, thereby improving clinical decision-making about best drug choices for preventing HbS polymerization and treating anemia in SS patients.

Abstract WMP112: Cyb5r3 Provides Resilience Against Cerebral Infarct And Hemorrhagic Transformation In Mice Following Stroke

Introduction: Cytochrome B5 reductase 3 (CYB5R3) is a heme reductase, ubiquitously expressed in red cells and somatic cells. We discovered a novel role for smooth muscle cell (SMC) CYB5R3 in reducing oxidized heme (Fe 3+ ) of soluble guanylate cyclase back to its reduced form (Fe 2+ ) to enable nitric oxide signaling for cyclic guanosine monophosphate production and vessel dilation. We have published higher systemic and pulmonary artery pressures in mice with conditional SMC-specific CYB5R3 knockdown. While there are over 40 CYB5R3 variants, the T117S loss-of-function (~50%) variant is interesting as it is enriched (0.23 minor allele) in persons of African ancestry. We hypothesized that the T117S variant increases risk for stroke with poor outcomes. Methods: We studied transient middle cerebral artery occlusion (50 min) in mice with CRISPR-Cas9 induced T117S CYB5R3 (T117S), Cre/Lox induced endothelial cell-specific CYB5R3 knockdown (EC-KD), Cre/Lox induced SMC-specific CYB5R3 knockdown (SMC-KD), global CYB5R3 overexpression (OE), and wild-type (WT) mice; all were adult males on a C57Bl6 background. Cerebral infarct volume (mm 3 ) was determined 24 hr later using 2,3,5-Triphenyltetrazolium chloride (TTC) and ImageJ. Results: Infarct volume was larger in T117S (132 vs 71; P=0.002) versus WT controls, which SMC-KD replicated (123 vs 70; P=0.01) and OE reversed (49 vs 100; P=0.02); EC-KD had little effect (88 vs 72). Hemorrhagic transformation was greatest in EC-KD (7/8 vs 5/9) and SMC-KD (3/6 vs 1/6), whereas there was no effect for T117S or OE. Conclusion: A congenital global point mutation causing CYB5R3 loss-of-function (T117S) enhances area at risk for cerebral infarct after stroke, while conditional deletion of EC and SMC CYB5R3 contribute to hemorrhagic transformation. Determining T117S carrier status of patients may help predict stroke risk and allow CYB5R3-targeted precision therapy approaches to stroke management.

Comparison of Demographic and Clinical Features of Bipolar Disorder in Persons of African and European Ancestry.

This study quantified and compared demographic and clinical features of bipolar disorder (BD) in persons of African ancestry (AA) and European ancestry (EUR). Participants enrolled in the Mayo Clinic Bipolar Biobank from 2009 to 2015. The structured clinical interview for DSM-IV was used to confirm the diagnosis of BD, and a questionnaire was developed to collect data on the clinical course of illness. Descriptive statistics and bivariate analyses were completed to compare AA versus EUR participants. Subsequently, clinical outcomes were compared between AA and EUR participants using linear regression for continuous outcomes or logistic regression for binary outcomes while controlling for differences in age, sex, and recruitment site. Of 1865 participants enrolled in the bipolar biobank, 65 (3.5%) self-identified as AA. The clinical phenotype for AA participants, in comparison to EUR participants, was more likely to include a history of PTSD (39.7% vs. 26.2%), cocaine use disorder (24.2% vs. 11.9%), and tardive dyskinesia (7.1% vs. 3%). The low rate of AA enrollment is consistent with other genetic studies. While clinical features of bipolar disorder are largely similar, this study identified differences in rates of trauma, substance use, and tardive dyskinesia that may represent health disparities in bipolar patients of African ancestry. Future bipolar biomarker studies with larger sample sizes focused on underrepresented populations will provide greater ancestry diversity in genomic medicine with greater applicability to diverse patient populations, serving to inform health care policies to address disparities in bipolar disorder.

SSDoH and Aging in Persons of African Ancestry

Persons of African Ancestry (Black) encompasses a broad spectrum of individuals across the African diaspora. The diversity of the Black community must be considered in the context of SSDoH especially as it relates to diseases of aging. Blacks report higher levels of discrimination as a barrier to Alzheimer’s Disease or related dementia (ADRD) care, are less likely to receive timely diagnoses of ADRD, and many do not trust that a future cure for ADRD will be shared equally and equitability with their community compared to their white counterparts. Once diagnosed, older Blacks, are twice as likely as their white counterparts to have ADRD. A key to addressing the Black community’s ADRD needs is speaking openly about the historical underpinnings related to social injustice and racism as a link to appropriate ADRD diagnoses. Ultimately, SSDoH impact treatment, healthcare policy, and the future of biomedical research for the Black community.

APOL1 renal risk variants are associated with obesity and body composition in African ancestry adults: An observational genotype-phenotype association study.

While increased obesity prevalence among persons of African ancestry (AAs) compared to persons of European ancestry (EAs) is linked to social, environmental and behavioral factors, there are no gene variants that are common and significantly associated with obesity in AA populations. We sought to explore the association between ancestry specific renal risk variants in the apolipoprotein L1 (APOL1) gene with obesity related traits in AAs.We conducted a genotype–phenotype association study from 3 electronic medical record linked cohorts (BioMe Biobank, BioVU, nuGENE); randomized controlled trials (genetic testing to understand and address renal disease disparities) and prospective cohort study (Jackson Heart Study). We analyzed association of APOL1 renal risk variants with cross-sectional measures of obesity (average body mass index (BMI), and proportion of overweight and obesity) and with measures of body composition (in Jackson Heart Study).We had data on 11,930 self-reported AA adults. Across cohorts, mean age was from 42 to 49 years and percentage female from 58% to 75.3%. Individuals who have 2 APOL1 risk alleles (14% of AAs) have 30% higher obesity odds compared to others (recessive model adjusted odds ratio 1.30; 95% confidence interval 1.16–1.41; P = 2.75 × 10−6). An additive model better fit the association, in which each allele (47% of AAs) increases obesity odds by 1.13-fold (adjusted odds ratio 1.13; 95% confidence interval 1.07–1.19; P = 3.07 × 10−6) and increases BMI by 0.36 kg/m2 (∼1 kg, for 1.7 m height; P = 2 × 10−4). APOL1 alleles are not associated with refined body composition traits overall but are significantly associated with fat free mass index in women [0.30 kg/m2 increment per allele; P = .03].Thus, renal risk variants in the APOL1 gene, found in nearly half of AAs, are associated with BMI and obesity in an additive manner. These variants could, either on their own or interacting with environmental factors, explain a proportion of ethnic disparities in obesity.

Insights into the Genetic Variations of Human Cytochrome P450 2C9: Structural Analysis, Characterization and Comparison.

Cytochromes P450 (CYP) are one of the major xenobiotic metabolizing enzymes with increasing importance in pharmacogenetics. The CYP2C9 enzyme is responsible for the metabolism of a wide range of clinical drugs. More than sixty genetic variations have been identified in CYP2C9 with many demonstrating reduced activity compared to the wild-type (WT) enzyme. The CYP2C9*8 allele is predominantly found in persons of African ancestry and results in altered clearance of several drug substrates of CYP2C9. The X-ray crystal structure of CYP2C9*8, which represents an amino acid variation from arginine to histidine at position 150 (R150H), was solved in complex with losartan. The overall conformation of the CYP2C9*8-losartan complex was similar to the previously solved complex with wild type (WT) protein, but it differs in the occupancy of losartan. One molecule of losartan was bound in the active site and another on the surface in an identical orientation to that observed in the WT complex. However, unlike the WT structure, the losartan in the access channel was not observed in the *8 complex. Furthermore, isothermal titration calorimetry studies illustrated weaker binding of losartan to *8 compared to WT. Interestingly, the CYP2C9*8 interaction with losartan was not as weak as the CYP2C9*3 variant, which showed up to three-fold weaker average dissociation constant compared to the WT. Taken together, the structural and solution characterization yields insights into the similarities and differences of losartan binding to CYP2C9 variants and provides a useful framework for probing the role of amino acid substitution and substrate dependent activity.

Advanced cancers amongst individuals of African ancestry exhibit an almost five-fold higher prevalence of high-risk HPV types not covered by the current 9-valent vaccine

<h3>Objectives:</h3> Among women with high-risk human papillomavirus (hrHPV) detected in cervical swabs, the distribution of hrHPV types is known to differ by racial/ethnic group, with East and West Africans and North Americans of African ancestry1 showing overrepresentation of hrHPV types that are not covered by the current 9-valent HPV vaccine. Possible downstream consequences in ethno-specific rates of aggressive hrHPV-related cancers, however, have not been systematically examined. Here, we surveyed a large, multiethnic database of aggressive cancers for non-9-valent-vaccine hrHPV types in association with individual ancestry data. <h3>Methods:</h3> Our archive of 290,311 unique advanced cancer samples underwent comprehensive genomic profiling (CGP) using a hybrid-capture-based DNA sequencing platform. We detected hrHPV genomic sequences in 1,690 cervical, 1,196 anogenital, and 1,380 head and neck cancers by <i>de novo</i> assembly of nonhuman reads, followed by alignment to the RefSeq database, which distinguishes hrHPV types. Patient ancestry was determined by classifying specific SNPs by CGP based on their known variation among populations in the 1000 Genomes Project. Quantitative data were analyzed using the Fisher exact test. A two-tailed P value of <.05 was considered statistically significant; the Bonferroni correction was applied for multiple simultaneous comparisons. <h3>Results:</h3> We identified four non-vaccine hrHPV types with >10 cancer cases each: HPV35 (n=71 cases), HPV51 (n=11), HPV59 (n=42), and HPV67 (n=12). Among patients whose cancers harbored hrHPV types that are covered by the 9-valent vaccine (here, HPV16, 18, 31, 33, 45, 52, and 58), 7.5% (308/4,131) were of African ancestry, lower than the overall representation of African ancestry in our database (9.1% [26,471/290,311]). In contrast, among cases with non-9-valent-vaccine hrHPV types, we identified several-fold enrichment for individuals of African ancestry (HPV35: 24% of African ancestry [17/71], HPV51: 27% [3/11], HPV59: 43% [18/42], HPV67: 25% [3/12]). In total, these four non-vaccine hrHPV types accounted for 11.4% (40/350) of all hrHPV-related advanced cancers in persons of African ancestry, but only 2.4% (95/3928) of hrHPV-related advanced cancers in individuals of other ancestries, a difference of nearly five-fold (p<0.00001, Table 1). Genomic alterations and tumor mutational burden showed no significant differences based on hrHPV type or patient ancestry, suggesting similar tumorigenic mechanisms. <h3>Conclusions:</h3> In our pan-hrHPV analysis of advanced cancers, hrHPV types not covered by the current 9-valent vaccine are strikingly increased in individuals of African ancestry. Our data strongly indicate a need to re-evaluate the choice of hrHPV types to include in the vaccine, as well as a need to re-evaluate the underlying process by which hrHPV types are chosen for inclusion.

A Meta-Analysis of Genome-Wide Association Studies of Multiple Myeloma in Persons of African Ancestry [African-American Multiple Myeloma Study (AAMMS)] Identifies Suggestive Risk Variants

Background: Multiple myeloma (MM) is 2-3 times more common among persons of African ancestry (AA) compared to those of European ancestry (EA). The 2-3-fold increased risk among family members of cases suggests a genetic contribution to risk. Genome-wide association studies (GWAS) in EA populations have identified 16 novel risk loci. We previously showed that 5 of these replicated in populations of AA (Rand et al., CEBP, 2016). In order to increase the power to identify additional novel common genetic risk variants, we conducted a GWAS meta-analysis using two sets of AA MM patients recruited into the African American Multiple Myeloma Study (AAMMS) and the University of Arkansas for Medical Sciences (UAMS)) Myeloma Institute.Methods: The first GWAS included 1,305 incident AA MM cases enrolled in AAMMS, recruited from 10 clinical centers and population-based cancer registries in the NCI SEER Program from 2011 to 2013 and genotyped using the Illumina HumanCore GWAS array. Control data were obtained from 4425 male controls from the African Ancestry Prostate Cancer Consortium (consisting of 14 independent studies) and 2632 female controls from a breast cancer GWAS of African-American women (consisting of 9 independent studies) and genotyped using the Illumina 1M-Duo. The second GWAS included 95 additional AAMMS patients and 435 AA MM patients enrolled from UAMS, genotyped using the Illumina MegaBead Chip and compared to 2,390 AA controls from the Multiethnic Cohort. Both GWAS were imputed with the CAAPA Haplotype Reference panel on the University of Michigan Imputation Server http://www.caapa-project.org/. Single nucleotide polymorphisms (SNPs) with a minor allele frequency of less than 0.01 and an imputation score of less than 0.8 were excluded. Associations between SNPs and MM risk in each GWAS were calculated using unconditional logistic regression adjusted for sex, age at diagnosis (cases) or cohort sample collection (controls), and the first 10 genetic ancestry principal components. A meta-analysis of the two GWAS was conducted using a fixed effects model.Results: There were 8,715,278 overlapping SNPs in the meta-analysis with a lambda (inflation) = 1.066. Seven loci were associated with MM risk at p<10-6, but none reached genome-wide significance. We found several novel SNPs at the previously reported locus 6p21.33, with odds ratios (ORs) ranging from 1.20-1.28 and p-values ranging from 3.72-8.46 x 10-7 (Figure 1). We also identified six additional suggestive novel loci at chr4q32.1, chr9p24.3, chr12q12, chr12p13.3, chr16p12.2, chr18q12.1 with ORs ranging from 1.27-2.13 and p-values from 1.2x10-7-9.39x10-7.Of the 16 known risk loci in EA MM patients, eight replicated at p<0.05 in the AA MM GWAS meta-analysis. We previously reported better localized signals in AA patients for 7 of these known risk SNPs; five of these replicated at p< 0.05 in this meta-analysis. The highest p-value for the previously identified EA or AA SNPs was 1.90 x10-5.Conclusions: We have found suggestive loci associated with MM risk in AA's that appear distinct from risk loci identified in EA's, that may explain some of the disparity for MM risk in these two populations. Further follow-up with replication is warranted.Figure 1. A Manhattan plot showing results of a fixed effects meta-analysis of two genome wide association scans based on a total of 1,835 multiple myeloma patients and 9,468 controls of African ancestry, with genome-wide significance of p= 5x10-8 (red line). Y-axis= -Log10 of the p-value; X-axis= chromosomes; green dots= previously reported risk loci, excluding those with imputation scores<0.8 and a minor allele frequency of <1%. [Display omitted] DisclosuresAilawadhi:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Research Funding. Nooka:Amgen, Novartis, Spectrum, Adaptive: Consultancy. Anderson:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; MedImmune: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Other: scientific founder; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep: Other: scientific founder. Vij:Amgen: Honoraria, Research Funding; Jazz: Honoraria; Konypharma: Honoraria; Bristol-Meyers-Squibb: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Research Funding. Zonder:Prothena: Consultancy; Pharmacyclics: Other: Data Safety Monitoring Committee; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Orlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract P726: Cytochrome B5 Reductase 3 Modifies The Brain-Blood Axis Response To Ischemic Stroke In Mice With Sickle Cell Disease

Introduction: Stroke and silent infarcts are serious complications of sickle cell disease (SCD), occurring frequently in children. Decreased nitric oxide bioavailability and responsiveness contribute to neurovascular disease. Cytochrome b5 reductase 3 (Cyb5R3) is a heme iron reductase that reduces oxidized soluble guanylate cyclase heme iron (Fe 3+ --&gt; Fe 2+ ) to preserve nitric oxide signaling. A loss-of-function Cyb5R3 missense variant (T117S) occurs with high frequency (0.23 minor allele) in persons of African ancestry. Hypothesis: We hypothesized that impaired reductase function of T117S Cyb5R3 exacerbates brain damage after ischemic stroke in SCD. Methods: Bone marrow transplant was used to create male SCD mice with wild type (SS/WT) or T117S (SS/T117S) Cyb5R3. Blood was sampled before and after middle cerebral artery occlusion (55 minutes occlusion, 48 hours reperfusion). Infarct volume (IV) was determined by 2,3,5-triphenyltetrazolium chloride. Intravascular hemolysis and correlation (Pearson’s R) of hematology changes with IV were determined. Baseline Walk-PHaSST (NCT00492531) data were analyzed for stroke occurrence. Results: Brain IV (63 vs 27 cm 3 , P=0.003) and mortality (3/6 vs 0/8) were greater in SS/T117S vs SS/WT. Red blood cells, hemoglobin and hematocrit declined as IV increased. Plasma oxyhemoglobin increased in parallel with IV (r = 0.74, P=0.09). There were different signatures to hematologic changes that occurred with IV in SCD. Relative to wild type, T117S contracted the erythroid compartment (red blood cell: -13% vs 13%, P=0.003; hematocrit: -20% vs 1%, P=0.008; hemoglobin: -18% vs 2%, P=0.007). Mean platelet volume correlated with IV in SS/T117S (r = 0.87, P=0.06), while the inverse occurred in SS/WT (r = -0.63, P=0.09) Monocytes increased in parallel with IV in SS/T117S (r = 0.73, P=0.16), but followed the opposite trajectory in SS/WT (r = -0.77, P=0.04). WalkPHaSST participants with T117S Cyb5R3 self-reported more ischemic stroke (7.4% vs 5.1%) relative to wild type. Conclusion: Cyb5R3 is an important modifier of the evolution and outcome of ischemic brain injury in SCD and its hematologic consequences. Our findings indicate a bidirectional relationship between stroke and anemia in SCD that may axially turn on Cyb5R3 activity.

The Blueprint for Dred Scott: United States v. Dow and the Multi-Racial Jurisprudence of White Supremacy

Chief Justice Taney’s 1857 opinion in Dred Scott v. Sandford is justly infamous for its holdings that African Americans could never be citizens, that Congress was powerless to prohibit slavery in the territories, and for its proclamation that persons of African ancestry “had no rights which the white man was bound to respect.” For all of the interest in and attention to Dred Scott, however, no scholar has previously analyzed United States v. Dow, an 1840 decision of Chief Justice Taney in a Circuit Court trial which is apparently the first federal decision to articulate a broad theoretical basis for White supremacy. Dow identified Whites as the “master” race, and it explained that only those of European origin were either welcomed or allowed to be members of the political community in the colonies. Non-Whites such as members of Dow’s race, Taney explained, could be reduced to slavery, and therefore their rights continued to be subject to absolute legislative discretion. Dow, however, was not a person of African descent, he was Malay, from the Philippines. Chief Justice Taney’s employment in Dow of legal reasoning which he would later apply in Dred Scott suggests that Dred Scott should be regarded as pertinent to all people of color, not only African Americans. This understanding of Dred Scott helps explain the revival of Taney’s reputation during the Jim Crow era after Reconstruction. Courts declined to invalidate restrictions with respect to a broad range of civil rights on citizens and immigrants of African, Indian, Asian, and Mexican ancestry to which Whites were not subject. Indeed, Whites could not be subject to them, unless it is conceivable that under the U.S. Constitution, the law could provide, for example, that all races would be ineligible to testify or vote because of their race. Accordingly, even after Reconstruction, just as Dred Scott and Dow contemplated, the White race remained the master race, in the sense that they were the exclusive holder of truly inalienable rights.

Implications of Polymorphisms in the BCKDK and GATA-4 Gene Regions on Stable Warfarin Dose in African Americans.

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.

The T117S Variant of Cytochrome b5 Reductase 3 Increases the Risk for Ischemic Stroke with Enhanced Anemia in Mice with Sickle Cell Disease

Introduction. Stroke and silent infarcts are serious complications of sickle cell disease (SCD), occurring frequently in children between 3 and 14 years old. A vast amount of clinical and experimental evidence has concluded that decreased nitric oxide (NO) bioavailability and/or NO responsiveness, as is seen in SCD, is a major contributing factor in the pathogenesis of neurovascular disease. NO responsiveness, which occurs via NO-induced activation of soluble guanylate cyclase (sGC), requires reduced heme iron (Fe2+) in the sGC active site. We recently identified cytochrome b5 reductase 3 (Cyb5R3) as an sGC heme iron reductase in vascular smooth muscle (VSM), where it reverses the oxidized heme iron of sGC (Fe3+ --&amp;gt; Fe2+) to preserve NO sensing/signaling under conditions of oxidative stress. In a mouse model of SCD we have shown that knockdown of Cyb5R3 in VSM accelerates the development of pulmonary hypertension and cardiac remodeling. A missense variant of Cyb5R3 (T117S) that results in loss-of-function methemoglobin reductase activity occurs at a high frequency in persons of African ancestry (0.23 minor allele frequency). Unpublished baseline data from the Walk-PHaSSt trial (NCT00492531) reveals that persons with SCD who carry the T117S variant are at increased risk of ischemic stroke; these individuals self-reported almost 50% more (74 vs 51 cases per 1000 individuals) ischemic stroke than those with wild-type (WT) Cyb5R3. Hypothesis. We hypothesized that impaired reductase function of Cyb5R3 T117S leads to sustained sGC heme oxidation, which drives cerebral vascular dysfunction and exacerbates brain damage after ischemic stroke in SCD. Methods. Bone marrow transplant was used to create SCD mice with global expression of WT or T117S Cyb5R3, hereafter referred to as SS/WT or SS/T117S, respectively. All mice were male, C57Bl/6 background, and &amp;gt;85% engrafted with SS Hb for 12 weeks. Ischemic stroke was induced using transient middle cerebral artery occlusion (MCAO: 55 min occlusion, 48 hr reperfusion), after which brains were stained with 2,3,5-triphenyltetrazolium chloride (TTC,1%) to determine infarct volume. Blood was sampled before and after MCAO to assess effects of brain infarct on hematological parameters. Student's t-test was used for analysis of 2 groups and Pearson's R used for correlation analyses of brain infarct volume with hematology changes [(post-pre/pre) * 100]. Results. Global expression of T117S Cyb5R3 in SCD caused increased cerebral infarct volume (62.9 vs 26.7 cm3, P=0.003) and mortality (3/6 vs 0/6) relative to WT Cyb5R3. WT and T117S Cyb5R3 mice with SCD were similar in that both showed declining red blood cells (RBC), hemoglobin (Hgb) and hematocrit (Hct) as infarct volumes increased. In the SS/T117S group, the anemia was more severe in keeping with larger infarct volumes. There were different signatures to the hematologic changes that occurred with cerebral infarct in SCD. When compared to WT Cyb5R3, T117S caused the erythroid compartment to contract (RBC: -12.97% vs 13.41%, P=0.01; Hct: -19.75% vs 0.31%, P=0.025; Hgb: -17.93% vs 2.78%, P=0.017). In SS/WT mice platelet numbers increased more relative to SS/T117S (17.5 vs 9.7 * 103 cells/uL); and MPV, a measure of platelet activation, inversely correlated with brain infarct volume (r = -0.94, P=0.006), the opposite of what was seen in SS/T117S (r = 0.87, P=0.056). Monocytes seem to play an important role in the volume of brain infarct in SS/T117S as their numbers increased in parallel with infarct volume (r = 0.73, P=0.16), but followed the opposite trajectory in SS/WT mice (r = -0.75, P=0.14). Conclusion. These results indicate that Cyb5R3 is an important modifying factor in the evolution and outcome of ischemic brain injury in SCD. Our findings also raise questions on just how cerebral infarct modifies the anemia of SCD, as well as the role played by Cyb5R3 in the dynamics of that relationship. To what extent is the sGC-cGMP-PKG pathway involved at the cerebrovascular and erythropoietic levels? Does Cyb5R3 contribute resilience to ischemic stroke in SCD? The development and application of targeted therapies for effectively preventing and treating cerebrovascular disease in SCD rely on finding the answers to these questions. Disclosures No relevant conflicts of interest to declare.

438 - Nigerian women are more susceptible to the impact of diabetes-and-dementia: State-of-art, Future perspectives and Directions

Among the preventable complications of diseases that require urgent effective health literacy programs in sub-Saharan Africa, crosstalk between diabetes and dementia stands out for women's health. Type 2 diabetes mellitus (DM2) in midlife is a recognised risk factor for dementia. This crosstalk is more significant in persons of African ancestry. Globally, the prevalence of DM will increase dramatically in the next few years with 75% of cases living in low-to-middle-income countries. Some major risk factors for DM2 accelerates the development of dementia in Africa-Americans, thus leading to higher prevalence of dementia compared to Caucasians. It is known that 58% of the global 46.8 million dementia subjects lives in economically developing countries. This proportion may reach 63% and 68% in 12 and 32 years' time, respectively. Females are 1.5 times likely to develop dementia, but sub-Saharan Africa women have a disproportionately two-to-eight fold increased dementia risk. In the eye of this storm is Nigeria which is home to the highest number of diabetics in Africa. Diabetes prevalence in the country is rising parallel to increased incidence of obesity, hypertension and rising population age. The socioeconomic impact of increasing prevalence of DM2 and dementia will be unsustainable for Nigeria healthcare system, given the experiences in developed economies. This study analyses the current situation of women's health in Nigeria, and explore future policy directions. The complex interplay of factors involved in the DM2-dementia crosstalk in Nigerian women include those due to biological processes (metabolic syndrome, vascular damage, inflammation, oxidative stress, insulin resistance and anaemia), nutritional habits and sedentary lifestyles. Other factors that predisposes Nigerian diabetic women to dementia are, restricted resources, lack of visibility and poor health management. They add up to increase the burden of disease in the Nigerian woman, irrespective of age. We advise urgent implementation of heath policies and actions that will increase ratio of mental health professionals / number of patients, especially in rural areas and the establishment of proactive primary healthcare centres. Importantly, interventions targeting adolescents and adult women, and others specific to mother- child interactions, are strongly needed in Nigeria and the sub-region for mitigating dementia in women.

The Sickle Effect: The Silent Titan Affecting Glycated Hemoglobin Reliability.

Hemoglobin A1c (HbA1c) is a popular invaluable tool in the diagnosis of Type 2 diabetes for red blood cells (RBCs) with a lifespan of 120 days; however, many factors, including hemoglobinopathies, affect its accuracy. Sickle cell trait, primarily a benign medical condition, is a point mutation in only one of two beta-globin genes on chromosome 11. We performed a traditional review to identify how the sickle cell trait (SCT) affects the interpretation of HbA1c and the further implications it may have on the diagnosis and management of Type 2 diabetes.A literature search was performed using PubMed®/MEDLINE® and Google Scholar with formulated keywords (sickle cell trait, HbAS, HbA1c, glycosylated hemoglobin, diabetes, RBC lifespan, race, and genetics), with the majority of results being mainly observational studies. The National Glycohemoglobin Standardization Program (NGSP) is responsible for standardizing HbA1c results and also highlights factors that can interfere with HbA1c, including hemoglobin variants. Studies that utilize only an NGSP-certified method with no clinically significant interference by HbS in patients with and without SCT showed contrasting results. Additional studies showed that persons of African ancestry, the group to which the majority of SCT patients belong, have a higher HbA1c than non-Hispanic whites (NHWs), just based on race, and a greater probability of having glucose-6-phosphate dehydrogenase (G6PD) deficiency, which lowers HbA1c. The most extensive study investigating the RBC lifespan in SCT patients showed a reduction in the cell lifespan compared to normal patients; however, other smaller studies were contradictory.Our study highlights the need for hemoglobinopathy detection before or during HbA1c measurement in populations with a high degree of African ancestry and the importance of patient notification. It also shows that SCT affects the accuracy of HbA1c, through its likely reduction of RBC lifespan and its increased association with African ancestry and G6PD deficiency. This review recommends that for SCT patients with potential Type 2 diabetes, HbA1c should be used in combination with another diagnostic tool such as fasting blood glucose, fructosamine, or glycated albumin to decrease the chances of a missed diagnosis.

Abstract PR05: A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans

Abstract Background: Persons of African ancestry (AA) experience a 1.5-2-fold risk of multiple myeloma (MM) compared to persons of European ancestry (EA). We assembled a set of MM patients with self-reported AA in order to evaluate the contribution of genetics to etiology in this high-risk group. Methods: Here we present the results of a meta-analysis of two GWAS in 1,813 cases and 8,871 controls of AA. We also conducted an admixture mapping scan to identify risk alleles associated with local ancestry, fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA, and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. Finally, we conducted an eQTL analysis measuring gene expression in those genes harboring a risk variant in malignant plasma cells from 292 of the patients from a single site. Results: In GWAS analysis, we identified two suggestive novel loci located at 9p24.3 and 9p13.1 at P&amp;lt;1 × 10-6, but no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. 20 of the 23 known EA risk variants showed directional consistency and 9 replicated at P&amp;lt;0.05 in AA individuals. In eight regions, we identified markers that better capture MM risk in persons of AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95%CI: 1.56, 2.11) increased MM risk compared to those with average risk (25-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P= 5.1 × 10–12). Conclusion: Our study shows that common genetic variation contributes to MM risk individuals of AA. This abstract is also being presented as Poster C040. Citation Format: Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristen A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. Stevens, Rick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael Press, John David Carpten, Stephen Chanock, Jayesh Mehta, Graham A Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.-H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR05.

Heme oxygenase-1 promoter (GT) n polymorphism associates with HIV neurocognitive impairment.

ObjectiveTo determine whether regulatory variations in the heme oxygenase-1 (HO-1) promoter (GT)n dinucleotide repeat length could identify unique population genetic risks for neurocognitive impairment (NCI) in persons living with HIV (PLWH), we genotyped 528 neurocognitively assessed PLWH of European American and African American descent and linked genotypes to cognitive status.MethodsIn this cross-sectional study of PLWH (the CNS HIV Antiretroviral Therapy Effect Research cohort), we determined HO-1 (GT)n repeat lengths in 276 African Americans and 252 European Americans. Using validated criteria for HIV-associated NCI (HIV NCI), we found associations between allele length genotypes and HIV NCI and between genotypes and plasma markers of monocyte activation and inflammation. For comparison of HO-1 (GT)n allele frequencies with another population of African ancestry, we determined HO-1 (GT)n allele lengths in African PLWH from Botswana (n = 428).ResultsPLWH with short HO-1 (GT)n alleles had a lower risk for HIV NCI (OR = 0.63, 95% CI: 0.42–0.94). People of African ancestry had a lower prevalence of short alleles and higher prevalence of long alleles compared with European Americans, and in subgroup analyses, the protective effect of the short allele was observed in African Americans and not in European Americans.ConclusionsOur study identified the short HO-1 (GT)n allele as partially protective against developing HIV NCI. It further suggests that this clinical protective effect is particularly relevant in persons of African ancestry, where the lower prevalence of short HO-1 (GT)n alleles may limit induction of HO-1 expression in response to inflammation and oxidative stress. Therapeutic strategies that enhance HO-1 expression may decrease HIV-associated neuroinflammation and limit HIV NCI.