Percentage Of African Ancestry Research Articles

HLA-DQB1*06 and Select Neighboring HLA Variants Predict Chlamydia Reinfection Risk.

Associations of HLA class II alleles with genital chlamydial infection outcomes have been reported, especially HLA DQB1*06. However, the potential role of DQB1*06 in influencing reinfection risk has still not been established. The purpose of this study was to determine whether the association of DQB1*06 with chlamydia reinfection was impacted by any other nearby HLA class II variants that were also associated with reinfection. We used next-generation sequencing to map HLA class II variants spanning the HLA-DQ and -DR loci. DQB1*06 as well as DQB1*04 were confirmed as significant predictors of chlamydia reinfection, when controlling for age and percent African ancestry. SKAT analysis revealed one region each in DRB1, DRB5, DQA2, and three intergenic regions that had variants associated with reinfection. Further analyses of these variants revealed that rs112651494 within DRB5 and an intergenic SNP rs617058 in DRB1:DQA1 were significantly associated with reinfection, but this did not impact the significance of the association of DQB1*06 or DQB1*04 with reinfection.

Association of self-identified race and genetic ancestry with the immunogenomic landscape of primary prostate cancer.

The genomic and immune landscapes of prostate cancer differ by self-identified race. However, few studies have examined the genome-wide copy number landscape and immune content of matched cohorts with genetic ancestry data and clinical outcomes. Here, we assessed prostate cancer somatic copy number alterations (sCNA) and tumor immune content of a grade-matched, surgically treated cohort of 145 self-identified Black (BL) and 145 self-identified White (WH) patients with genetic ancestry estimation. A generalized linear model adjusted with age, preoperative prostate-specific antigen (PSA), and Gleason Grade Group and filtered for germline copy number variations (gCNV) identified 143 loci where copy number varied significantly by percent African ancestry, clustering on chromosomes 6p, 10q, 11p, 12p, and 17p. Multivariable Cox regression models adjusted for age, preoperative PSA levels, and Gleason Grade Group revealed that chromosome 8q gains (including MYC) were significantly associated with biochemical recurrence and metastasis, independent of genetic ancestry. Finally, Treg density in BL and WH patients was significantly correlated with percent genome altered, and these findings were validated in the TCGA cohort. Taken together, our findings identify specific sCNA linked to genetic ancestry and outcome in primary prostate cancer and demonstrate that Treg infiltration varies by global sCNA burden in primary disease.

Relative impact of genetic ancestry and neighborhood socioeconomic status on all-cause mortality in self-identified African Americans

Self-identified race/ethnicity is a correlate of both genetic ancestry and socioeconomic factors, both of which may contribute to racial disparities in mortality. Investigators often hold a priori assumptions, rarely made explicit, regarding the relative importance of these factors. We studied 2,239 self-identified African Americans (SIAA) from the Prostate, Lung, Colorectal and Ovarian screening trial enrolled from 1993–1998 and followed prospectively until 2019 or until death, whichever came first. Percent African genetic ancestry was estimated using the GRAF-Pop distance-based method. A neighborhood socioeconomic status (nSES) index was estimated using census tract measures of income, housing, and employment and linked to participant residence in 2012. We used Directed Acyclic Graphs (DAGs) to represent causal models favoring (1) biomedical and (2) social causes of mortality. Hazard ratios were estimated using Cox models adjusted for sociodemographic, behavioral, and neighborhood covariates guided by each DAG. 901 deaths occurred over 40,767 person-years of follow-up. In unadjusted (biomedical) models, a 10% increase in percent African ancestry was associated with a 7% higher rate of all-cause mortality (HR: 1.07, 95% CI: 1.02, 1.12). This effect was attenuated in covariate adjusted (social) models (aHR: 1.01, 95% CI: 0.96, 1.06). Mortality was lower comparing participants in the highest to lowest nSES quintile following adjustment for covariates and ancestry (aHR: 0.74, 95% CI: 0.57, 0.98, Ptrend = 0.017). Higher African ancestry and lower nSES were associated with higher mortality, but African ancestry was not associated with mortality following covariate adjustment. Socioeconomic factors may be more important drivers of mortality in African Americans.

Abstract 702: Interaction between genetic ancestry and EWS-FLI induced transcription in Ewing sarcoma tumorigenesis

Abstract Ewing Sarcoma (ES) is a rare but deadly pediatric bone and soft tissue tumor, with little improvement in survival for decades despite knowing the driving fusion oncoprotein EWS-FLI1. EWS-FLI1 is notably toxic, acting as an aberrant transcription factor and leading to growth arrest and apoptosis in all but a few cell types. ES incidence in populations of European ancestry is nearly ten times that found in children with primarily African ancestry. To better understand how EWS-FLI1 transforms the transcriptome and the protective effect of the African genome, we leveraged this disparate genomic context to study ES tumorigenesis by introduction of EWS-FLI1 into cells derived from donors with a range of African ancestry followed by RNA sequencing (RNA-seq). Induced pluripotent stem cell (iPSC) lines with genome wide SNP genotyping data were obtained and local ancestry was assessed using RFMix to establish genetic ancestry. Two lines each of ~100% European and African ancestry and four lines with intermediate European/African admixture (45% to 90% African) were differentiated into neural crest cells (iNCC, a proposed cell-of-origin for ES) and transduced with a lentivirus expressing either a GFP reporter or a GFP-2A-EWS/FLI1 cassette. Interestingly, iNCC derived from European lines maintained a higher frequency of cells expressing GFP/EWS-FLI1 than the pure African lines, with admixed lines showing an intermediate frequency. RNA was extracted at 48- and 96-hour time points and sequenced for gene expression analysis. As expected, we identified pronounced changes to the transcriptional landscape in EWS-FLI1-induced cells compared to control with 13,578 differentially expressed genes (adjusted p-value < 0.05). More interestingly we identified 3,128 genes with ancestry-associated gene expression differences in response to EWS-FLI1 expression. Gene Set Enrichment Analysis (GSEA) using MSigDB 50 hallmark gene sets (v7.4) detected 24 significantly enriched gene sets with an inverse correlation with percent African ancestry, including those sets involved with oxidative phosphorylation, MYC v1 and v2, and MTORC1 signaling. To identify those expression changes that are key to ES tumorigenesis we are comparing the transcriptional profiles of our EWS-FLI1 expressing iNCC to ES tumors and ES cell lines as well as other models of ES derived from mesenchymal stem cells. Ongoing studies will include profiling of chromatin accessibility and EWS-FLI1 occupation for each ancestral iNCC line following EWS-FLI1 transduction to determine the early, ancestry-linked transitions that are permissive to oncogenic transformation. As EWS-FLI1 itself has proven elusive to direct targeting, studying its immediate downstream effects has the potential for establishing new druggable biologic pathways for treatment of ES. Citation Format: Rachel M. Moss, Kelsie L. Becklin, Lauren J. Mills, Branden S. Moriarity, Beau R. Webber, Logan G. Spector. Interaction between genetic ancestry and EWS-FLI induced transcription in Ewing sarcoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 702.

Admixture mapping of anthropometric traits in the Black Women's Health Study: evidence of a shared African ancestry component with birth weight and type 2 diabetes.

Prevalence of obesity, type 2 diabetes (T2D), and being born with low birth weight are much higher in African American women compared to U.S. white women. Genetic factors may contribute to the excess risk of these conditions. We conducted admixture mapping of body mass index (BMI) at age 18, adult BMI, and adult waist circumference and waist-to-hip ratio adjusted for BMI using 2918 ancestral informative markers in 2596 participants of the Black Women's Health Study. We also searched for evidence of shared African genetic ancestry components among the four examined anthropometric traits and among birth weight and T2D. We found that global percent African ancestry was associated with higher adult BMI. We also found that African ancestry at 9q34 was associated with lower BMI at age 18. Our shared ancestry analysis identified ten genomic regions with local African ancestry associated with multiple traits. Seven out of these ten genomic loci were related to T2D risk. Of special interest is the 12q14-21 region where local African ancestry was associated with low birth weight, low BMI, high BMI-adjusted waist-to-hip ratio, and high T2D risk. Findings in the 12q14-21 genomic locus are consistent with the fetal insulin hypothesis that postulates that low birth weight and T2D have a common genetic basis, and they support the hypothesis of a shared African genetic ancestry component linking low birth weight and T2D in African Americans. Future studies should identify the actual genetic variants responsible for the clustering of these conditions in African Americans.

Abstract PO-146: Copy number landscape of primary African-American and European-American prostate tumors

Abstract African-American (AA) men are more likely to be diagnosed with and to die of prostate cancer than their European-American counterparts. Much of this disparity is due to access to care and social determinants of health; however, there is emerging evidence of molecular differences in prostate tumors arising in patients of different genetic ancestry. We investigated the copy number landscape of 290 grade and race-matched primary prostate tumors through interrogation of Infinium MethylationEPIC Array (Illumina) data derived from primary prostate tumors at radical prostatectomy. Our cohort was composed of 145 self-identified AA patients and 145 self-identified EA surgically-treated patients with accompanying genetic ancestry estimation via SNP array (GSAv3). EPIC array-derived copy number data estimated through the Conumee package on R was significantly correlated with genomic losses and gains identified by exome sequencing of a panel with 100 cancer driver genes. We also observed a significant association between genomic losses of the PTEN gene and PTEN protein loss by immunohistochemistry (P<0.001). Similar observations were made for p53 protein nuclear accumulation detected by immunohistochemistry and TP53 gene copy loss (P<0.001). Next, we derived percent genome altered (PGA) from EPIC array data for our 290 patients. PGA from EPIC array was significantly correlated with PGA obtained from targeted sequencing of a subset of AA tumors (n=119, P<0.0001, R²=0.50). No difference in PGA was found between self-identified AA and EA patients (P<0.05), though PGA levels were significantly associated with Gleason Grade groups for both AA (P<0.0001) and EA (P=0.003). We then used the genetic ancestry estimation derived from SNP arrays to identify regions of genomic loss and gain differing by percent African ancestry. We used a comprehensive genome annotation with >80k coding and non-coding regions from FANTOM CAT. Adjusted LIMMA models with age, Gleason Grade Group, and pre-operative PSA levels showed significant copy number differences by percent African ancestry in chromosomes 6p, 10q, 11p, 12p, and 17p. PTEN losses (as expected) and WT1 gains were more frequent in patients with lower percent African ancestry. Gene expression data from TCGA data showed that WT1 expression was significantly increased for self-identified EA patients. Multivariable Cox regression models adjusted for age, Gleason Grade Group, and pre-operative PSA levels revealed that chromosome 8q gains (including MYC, GRHL2, and FZD6) were significantly associated with biochemical recurrence and metastasis. However, when we stratified the models by self-identified race, only AA tumors showed significant associations with 8q gains and poor outcome. Further in silico and mechanistic validation will be conducted to confirm whether chromosome 8 gains may be a potential biomarker for prostate cancer outcome in AA men. Citation Format: Thiago Vidotto, Eddie Imada, Farzana Faizal, Siqun Zheng, Jianfeng Xu, Karen S. Sfanos, Luigi Marchionni, Tamara L. Lotan. Copy number landscape of primary African-American and European-American prostate tumors [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-146.

Abstract PO-201: African ancestry predicts serous and copy number high endometrial cancer

Abstract Introduction: Endometrial cancer (EC) is the leading gynecologic malignancy in the United States. Histologic classification is binary, with type I, low-grade tumors being exclusively endometrioid and type II, high-grade tumors inclusive of aggressive histologies like serous carcinoma. Molecular classification defines EC as POLE ultra-mutated, microsatellite instability (MSI), copy number low (CNL) and copy number high (CNH). Relative to White women, Black women have a higher risk of serous/CNH EC with worse overall survival. We aimed to understand whether self-identified race and genetic ancestry are associated with the probability of developing serous/CNH tumors among women diagnosed with EC. Methods: We reviewed tumor genomic data from The Cancer Genome Atlas (TCGA) and The Cancer Genetic Ancestry Atlas (TCGAA) under the project Uterine Corpus Endometrial Carcinoma. We merged both datasets matching the Patient ID and extracted age of diagnosis, histology, molecular classification, self-identified race, genomically-assigned race by EIGENSTRAT, and percentage of African, European, Asian, and Native American ancestry. We used chi-square or one-way ANOVA to test for associations to Serous/CNH diagnosis. Controlling for age, we used multivariate logistic regression to determine the odds of diagnosis with serous or CNH EC. Results: We identified 568 women with EC, including 115 (20%) self-identified Black, 417 (73%) White, and 23 (4%) Asian. Significant differences in mean age at diagnosis (p<0.01), self-identified race (p<0.01), and genomically-assigned race (p<0.01) were present between women with endometrioid and serous histologies. Self-identified race and genomically-assigned race were both significantly associated with molecular subtype of cancer (p<0.01). A greater percentage of African Ancestry was seen in CNH vs CNL (27% vs 11%, p<0.01) and CNH vs MSI (27% vs 15%, p<0.001). In logistic regression, self-identified Black women had higher probability of diagnosis with serous EC (OR=2.129, CI [1.273–3.561], p<0.01) and CNH tumors (OR=2.846, CI [1.759–4.604], p<0.001) compared to self-identified White women. Relative to women characterized as European American (≥48% European Ancestry), African Americans (≥35% African ancestry) had greater odds of serous EC diagnosis (OR=2.289, CI [1.376–3.806], p<0.01) and CNH molecular type (OR=2.839 CI [1.760–4.579], p<0.01). For every 1% increase in African ancestry there was 1% increase in the probability of diagnosis with serous EC (CI [1.004–1.017], p<0.01) and 1.4% increase on the likelihood of diagnosis with CNH EC (CI [1.008–1.020], p<0.01), with this percentage increasing directly proportional. Conclusion: Our findings suggest that African ancestry is associated with an increased odds for both high-grade EC histology and molecular EC classification. Self-identified race and genomically-assigned race demonstrate similar associations with aggressive disease. Further characterization of the molecular drivers of EC, with consideration of environmental factors and how they may impact risk, is warranted. Citation Format: Alex P. Sanchez-Covarrubias, Angel D. Tabuyo-Martin, Caiden J. Walter, Alexandra Diaz, Sophia H.L. George, Matthew P. Schlumbrecht. African ancestry predicts serous and copy number high endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-201.

Abstract PO-100: Association of B7-H3 expression with racial ancestry, immune cell density and AR activation in prostate cancer

Abstract Background: B7-H3 (CD276, PD-L3) is an immunomodulatory molecule highly expressed in prostate cancer and belonging to the B7 superfamily that also includes PD-L1 (B7-H1). Immunotherapies (antibodies, antibody-drug conjugates, and CAR-T cells) targeting B7-H3 are currently in clinical trials; thus elucidating the clinical, molecular and tumor immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. Methods: We developed an automated, clinical-grade immunohistochemistry assay to digitally quantify B7-H3 protein expression across two racially diverse cohorts of primary prostate cancer (including one with previously reported transcriptomic data), a set of prostatic neuroendocrine small cell carcinoma, and pre- and post-treatment tumor tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression is significantly lower in self-identified Black patients and inversely correlates with percent African ancestry by ancestry-informative markers. This association with race is independent of the significant association of B7-H3 expression with ERG/ETS and PTEN status. CD276 mRNA level, but not B7-H3 protein expression, is significantly correlated with regulatory (FOXP3+) T-cell density. Finally, androgen receptor activity (AR-A) scores are significantly correlated with CD276 mRNA expression, and neoadjuvant intensive hormonal therapy is associated with a significant decrease in B7-H3 protein expression. Conclusion: These data underscore the importance of studying racially and molecularly diverse prostate cancer cohorts in the era of immunotherapy. Our study is among the first to use genetic ancestry markers to add to emerging evidence that prostate tumors from men of African ancestry may have a distinct immune milieu associated with B7-H3 expression. Citation Format: Adrianna A. Mendes, Jiayun Lu, Harsimar B Kaur, Siqun Zheng, Jianfeng Xu, Edward M. Schaeffer, Karen S. Sfanos, Janielle Maynard, Ashley E. Ross, Steven P. Balk, Mary-Ellen Taplin, Emmanuel S. Antonarakis, Corinne E. Joshu, Eugene Shenderov, Tamara L. Lotan. Association of B7-H3 expression with racial ancestry, immune cell density and AR activation in prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-100.

Advanced glycation end-products (AGEs) are lower in prostate tumor tissue and inversely related to proportion of West African ancestry.

The metabolism of normal prostate relies on glycolysis, with prostate cancer having reduced glycolysis and increased aerobic metabolism. Advanced glycation end products (AGEs) accumulate in tissues as a result of age and glycolytic rate. Differential AGE levels were recently observed in prostate cancer tissues. Herein we sought to quantify AGEs in benign and cancer prostate tissue in a diverse cohort of patients. Levels of the AGE Nε-(carboxylethyl)lysine (CML) were quantified by immunohistochemistry (IHC) in a tissue microarray which consisted of 3 cores from tumor and 2 cores from benign areas from 118 patients (87 African American and 31 European American). Ancestry informative markers for African Ancestry were available for 79 patients. Epithelial and stromal areas were quantified separately using an E-cadherin mask. CML levels were compared with clinical grade group and ancestry by mixed linear effect models. Age, prostate-specific antigen (PSA) levels, body mass index (BMI), and hemoglobin A1C were included as covariates. CML levels were lower in areas of the tumor, for both epithelium and surrounding stroma, compared with benign, but did not significantly change with tumor grade group. Age, PSA levels, BMI, and hemoglobin A1C did not associate with CML levels. CML levels were inversely associated with the percentage of African Ancestry in all tissues. The low CML levels in cancer may reflect the reduced glycolytic state of the tissue. The inverse relationship between African Ancestry and CML levels in both benign and cancer areas suggests a state of reduced glycolysis. It is yet to be determined whether altered glycolysis and CML levels are bystanders or drivers of carcinogenesis.

Abstract 785: Is genetic ancestry associated with mortality risk after accounting for neighborhood socioeconomic status? A study of African American men

Abstract Background Genetic ancestry, a correlate of self-identified race/ethnicity, could be associated with mortality risk, allowing for more targeted treatments for cancer and other chronic diseases. However, associations may be confounded by neighborhood socioeconomic status (nSES). We investigated whether African ancestry and nSES were independently associated with all-cause mortality in a cohort of African American trial participants. Methods We constructed a cohort of American-born participants of African descent from the Prostate, Lung, Colorectal and Ovarian screening trial. Participants were enrolled from 1993-1998 and followed through 2019 or until death, whichever came first. Genetic ancestry (% African) was estimated using a principal components analysis of genome-wide SNP data and validated against European, African, and Asian panels. A nSES index was estimated using principal component analysis of census tract measures of income, housing, and employment. Census tract was assessed in 2012 for residences of living participants. Last known address was assigned to participants who died prior to 2012. We assigned 2000 census data to those who died prior to 2010, and assigned 2006-2010 American Community Survey data to those who were alive after 2010. Hazard ratios for associations between these variables and all-cause mortality were estimated using sequentially adjusted Cox proportional hazards models with sociodemographic, behavioral, and neighborhood contextual covariates. We tested whether mortality associations with ancestry varied by nSES using multiplicative interaction terms. All tests were two-sided with alpha=0.05. Results Among 2239 African American participants, there were 901 deaths over 40,767 person-years of follow-up. Mean baseline age was 61.7, 45% were men, and the mean percentage of African ancestry was 74.3. In unadjusted models, a 10% increase in African ancestry was associated with a 7% higher rate of all-cause mortality (HR: 1.07, 95% CI: 1.02, 1.12), but this attenuated to the null after adjusting for covariates (aHR: 1.01, 95% CI: 0.96, 1.06). Participants in nSES Q5 had 45% lower rate of mortality compared to those in Q1 in unadjusted models (HR: 0.55, 95% CI: 0.44, 0.68, Ptrend<.0001); similarly, this was attenuated after adjusting for covariates (aHR: 0.74, 95% CI: 0.57, 0.98, Ptrend=0.017). There was no evidence of statistical interaction between ancestry and nSES. Discussion Our findings suggest that nSES is a stronger independent correlate of mortality than genetic ancestry, which was only weakly associated with mortality after accounting for other factors. Larger studies with wider variability in African ancestry and geographic context are needed to confirm these findings. Citation Format: Hari S. Iyer, Scarlett L. Gomez, Iona Cheng, Timothy R. Rebbeck. Is genetic ancestry associated with mortality risk after accounting for neighborhood socioeconomic status? A study of African American men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 785.

More Work to Do: Differential Responses to Asthma Therapies in Black Patients, Although Not Associated with Percentage of African Ancestry

Wechsler ME, Szefler SJ, Ortega VE, Pongracic JA, Chinchilli V, Lima JJ, et al. Step-up therapy in black children and adults with poorly controlled asthma. N Engl J Med 2019;381:1227-39.

Abstract B067: Whole-exome sequencing of matched longitudinal primary and metastatic prostate cancers from African American men

Abstract The incidence and associated mortality and morbidity from prostate cancer (PCa) are disproportionately higher among African Americans (AA). Most deaths from PCa are attributable to the metastatic phase of the disease; the molecular underpinnings of which remain poorly understood. To identify somatic genomic variations associated with PCa metastases, we performed whole-exome sequencing (WES) on matched normal, primary, and metastatic prostate cancer tissue trios from AA patients. Microdissected formalin fixed paraffin embedded archival tissue was the source of the samples. The analysis to identify significant driver mutations and somatic copy number events was deduced using publicly available tools and custom bioinformatics processes. The cohort was comprised of matched tissue trios from 18 AA prostate cancer cases. Mean WES coverage for normal, primary and metastatic tumor were 79X, 76X and 72.5X, respectively. Percent African ancestry ranged from 0.755 to 0.997 based upon admixture informative markers from WES data. Somatic mutation counts varied among individual primary (26 to1,457) and metastatic (22 to 323) tumors. The extent of mutation overlaps between primary and metastatic PCa genomes varied substantially from 0 (0%) to 53 (14%). Recurrent mutations in the TECPR2 and PARP4 genes were found unique to metastatic cancers. Three missense mutations in the TECPR2 gene were found in the metastatic lesions of three individual patients: G344R (novel), S514N (novel) and R1066C (rs776056002). In silico functional annotation of these mutations showed to have a potentially deleterious (SIFT) and possibly/probably damaging (PolyPhen) effect. Two potentially deleterious missense mutations in the PARP4 gene namely E216V (novel) and L1080F (rs201405094) were found in the metastatic lesions in two patients. We observed differentially altered copy number events between primary and metastatic tumors. Significantly higher recurrent amplifications of chromosomal regions harboring JAK3 and ANK2 genes were observed in 26% of metastatic cases (p<0.05). Copy number losses (p<0.05) specific to metastatic tumors included regions harboring TPO, AFF3, and CYP7B1 genes. Here we report identification of recurrent potentially deleterious missense mutations in the TECPR2 and PARP4 genes in a subset of metastatic PCa that were not present in matched primary tumors. Several copy number alterations including amplifications of the JAK3 and ANK2 genes were also found unique to metastases. Further examination of the biological role of the identified novel mutations in the etiopathogenesis of PCa metastases is warranted, and is currently underway. Citation Format: Zarko Manojlovic, Babak Shokrani, John D Carpten, Mezbah U Faruque. Whole-exome sequencing of matched longitudinal primary and metastatic prostate cancers from African American men [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 B067.

Genomic Abnormalities Among African Individuals with Monoclonal Gammopathies Using Calculated Ancestry

Monoclonal gammopathies, including multiple myeloma (MM), represent a group of plasma cell (PC) disorders that comprise of mostly incurable hematopoietic malignancies with an increasing incidence in the US. Previous epidemiological studies demonstrated a 2-3 fold higher incidence of monoclonal gammopathy of undetermined significance (MGUS) and a similarly higher incidence of MM along with a ~4-year younger age of onset among African Americans (AA) compared to European Americans (EAs) (Fonseca, Leukemia, 2017). This suggests a possible ancestral-associated genetic predisposition of AAs to the development of monoclonal gammopathies (Landgren, Blood, 2006). When access to care is equal, AAs have a better overall survival compared to EAs suggesting that AAs may have a genetic predisposition that renders them better responders to treatment or have more favorable cytogenetic subtypes of MM (Waxman, Blood, 2010). Previous efforts to understand this disparity have relied on self-reported race rather than genetic ancestry. We hypothesize that quantifying genetic ancestry is necessary to fully understand the genetic mechanisms of racial disparities of monoclonal gammopathies. We describe our study of 881 patients with monoclonal gammopathies who had undergone uniform testing to identify MM-specific cytogenetic abnormalities. DNA from the bone marrow samples was genotyped on the Precision Medicine Research Array. Biogeographical ancestry was assessed using the Geographic Population Structure Origins tool, which provides the ancestral breakdown of 36 admixture components for each individual representing different geographic regions and outputs admixture proportions corresponding to those ancestries (Elhaik, Nat Commun, 2014). We evaluated whether an increase in the percentage of African Ancestry altered the odds of any primary cytogenetic abnormality. We demonstrated that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting either an t(11;14), t(14;16) or t(14;20) (odds ratio = 1.06, 95% CI: 1.02 - 1.11; p-value = 0.05). Although we observed an increase in the odds of each of the individual translocations with 10% increase in African ancestry, l t(11;14) (OR=1.03) t(14;16) (OR=1.11) and t(14;20) (OR=1.10), these three abnormalities were combined to achieve greater statistical power. The differences in cytogenetic abnormalities were most striking among individuals with ≥80.0% African (n=120) compared to individuals with We complement our past studies that relied on self-reported race and characterized patients9 demographic and uniformly collected cytogenetic data in relation to genetically defined African ancestry. We demonstrate the prevalence of having one of three specific subtypes (i.e., t(11;14), t(14;16), or t(14;20)) was significantly higher in those with highest (≥80%) compared to lowest ( Disclosures Elhaik:DNA Diagnostics Center: Consultancy. Baird:DNA Diagnostics Center: Employment. Cerhan:Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding; Celgene: Research Funding. Stewart:Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy; Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Kumar:Novartis: Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees; AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Roche: Research Funding.

Race, Serum Potassium, and Associations With ESRD and Mortality

Recent studies suggest that potassium levels may differ by race. The basis for these differences and whether associations between potassium levels and adverse outcomes differ by race are unknown. Observational study. Associations between race and potassium level and the interaction of race and potassium level with outcomes were investigated in the Racial and Cardiovascular Risk Anomalies in Chronic Kidney Disease (RCAV) Study, a cohort of US veterans (N=2,662,462). Associations between African ancestry and potassium level were investigated in African Americans in the Atherosclerosis Risk in Communities (ARIC) Study (N=3,450). Race (African American vs non-African American and percent African ancestry) for cross-sectional analysis; serum potassium level for longitudinal analysis. Potassium level for cross-sectional analysis; mortality and end-stage renal disease for longitudinal analysis. The RCAV cohort was 18% African American (N=470,985). Potassium levels on average were 0.162mmol/L lower in African Americans compared with non-African Americans, with differences persisting after adjustment for demographics, comorbid conditions, and potassium-altering medication use. In the ARIC Study, higher African ancestry was related to lower potassium levels (-0.027mmol/L per each 10% African ancestry). In both race groups, higher and lower potassium levels were associated with mortality. Compared to potassium level of 4.2mmol/L, mortality risk associated with lower potassium levels was lower in African Americans versus non-African Americans, whereas mortality risk associated with higher levels was slightly greater. Risk relationships between potassium and end-stage renal disease were weaker, with no difference by race. No data for potassium intake. African Americans had slightly lower serum potassium levels than non-African Americans. Consistent associations between potassium levels and percent African ancestry may suggest a genetic component to these differences. Higher and lower serum potassium levels were associated with mortality in both racial groups.

Estrogen alone and health outcomes in black women by African ancestry: a secondary analyses of a randomized controlled trial.

In postmenopausal black women in the Women's Health Initiative randomized trial, estrogen alone reduced breast cancers but its comprehensive influence on health outcomes in black women is unknown. Therefore, we examined this issue in the Women's Health Initiative overall and by African ancestry. A total of 1,616 black women with prior hysterectomy, including 1,061 with percent African ancestry determination, at 40 US centers were randomly assigned to conjugated equine estrogen (0.625 mg/d) or placebo for 7.2 years' (median) intervention with 13 years' cumulative follow-up. Coronary heart disease (CHD) and breast cancer were primary efficacy and safety outcomes, respectively. A global index also included stroke, colorectal cancer, hip fracture, pulmonary embolism, and death. Black women in the estrogen-alone group compared with black women in the placebo group had fewer breast cancers (17 vs 40, hazard ratio [HR] 0.47, 95% CI 0.26-0.82). In women with more than 80% African ancestry, breast cancer HR was lower (0.32, 95% CI 0.12-0.86, trend P = 0.04 for ancestry effect). Most other outcomes including CHD, stroke, hip fracture, and the global index were null with estrogen use in black women; a global index effect was more favorable in younger black women (HR 0.65, 95% CI 0.43-0.98). In black postmenopausal women with prior hysterectomy, estrogen alone significantly reduced breast cancer incidence with no adverse influence on CHD, venous thromboembolism, or all-cause mortality. Favorable estrogen-alone global index effects in younger black women warrant further study.

STRATEGIES FOR EQUITABLE PHARMACOGENOMIC-GUIDED WARFARIN DOSING AMONG EUROPEAN AND AFRICAN AMERICAN INDIVIDUALS IN A CLINICAL POPULATION.

The blood thinner warfarin has a narrow therapeutic range and high inter- and intra-patient variability in therapeutic doses. Several studies have shown that pharmacogenomic variants help predict stable warfarin dosing. However, retrospective and randomized controlled trials that employ dosing algorithms incorporating pharmacogenomic variants under perform in African Americans. This study sought to determine if: 1) including additional variants associated with warfarin dose in African Americans, 2) predicting within single ancestry groups rather than a combined population, or 3) using percentage African ancestry rather than observed race, would improve warfarin dosing algorithms in African Americans. Using BioVU, the Vanderbilt University Medical Center biobank linked to electronic medical records, we compared 25 modeling strategies to existing algorithms using a cohort of 2,181 warfarin users (1,928 whites, 253 blacks). We found that approaches incorporating additional variants increased model accuracy, but not in clinically significant ways. Race stratification increased model fidelity for African Americans, but the improvement was small and not likely to be clinically significant. Use of percent African ancestry improved model fit in the context of race misclassification.

Genomic ancestry and the social pathways leading to major depression in adulthood: the mediating effect of socioeconomic position and discrimination.

BackgroundEvidence suggests that there is an association between ethnicity/skin color and depression; however, many contextual and individual variables, like sense of discrimination and socioeconomic position (SEP), might influence the direction of this association. We assessed the association between African ancestry and major depression among young adults that have been followed-up since birth in a Southern Brazilian city, and the mediating effect of SEP and discrimination.MethodsIn 1982, all hospital deliveries in Pelotas (Southern Brazil) were identified; liveborns were examined and their mothers interviewed (n = 5914). In 2012–13, at 30 years of age, we used the Mini International Neuropsychiatric Interview (MINI) for major depression diagnosis. In addition, DNA samples were genotyped for approximately 2.5 million single nucleotide polymorphisms (SNPs) using Illumina (CA, USA) HumanOmni2.5-8v1 array. Genomic ancestry estimation was based on approximately 370 000 single nucleotide polymorphisms (SNPs) mutually available for the Pelotas cohort and selected samples (used as reference panels) of the HapMap and Human Genome Diversity (HGDP). We estimated prevalence ratios (PR) using Poisson regression models and evaluated the association between percentage of African ancestry and major depression. We used G-computation for mediation analysis.ResultsAt 30 years, 3576 individuals were evaluated for major depression (prevalence = 7.9 %). Only individuals in the highest SEP, who had a percentage of African ancestry between >5–30 % and >30 % had a prevalence of major depression 2.16 (PR = 2.16 95 % CI [1.05–4.45]) and 2.74 (PR = 2.74 95 % CI [1.06–7.06]) times higher, than those with 5 % or less, respectively. Among these subjects, sense of discrimination by skin color, captured 84 % of the association between African ancestry and major depression.ConclusionSEP is an important effect modifier of the positive association between African ancestry and major depression. In addition, this association is predominantly mediated by the sense of feeling discriminated by skin color.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-016-1015-2) contains supplementary material, which is available to authorized users.

Air Pollution and Lung Function in Minority Youth with Asthma in the GALA II (Genes-Environments and Admixture in Latino Americans) and SAGE II (Study of African Americans, Asthma, Genes, and Environments) Studies.

Adverse effects of exposures to ambient air pollution on lung function are well documented, but evidence in racial/ethnic minority children is lacking. To assess the relationship between air pollution and lung function in minority children with asthma and possible modification by global genetic ancestry. The study population consisted of 1,449 Latino and 519 African American children with asthma from five different geographical regions in the mainland United States and Puerto Rico. We examined five pollutants (particulate matter ≤10 μm and ≤2.5 μm in diameter, ozone, nitrogen dioxide, and sulfur dioxide), derived from participant residential history and ambient air monitoring data, and assessed over several time windows. We fit generalized additive models for associations between pollutant exposures and lung function parameters and tested for interaction terms between exposures and genetic ancestry. A 5 μg/m(3) increase in average lifetime particulate matter less than or equal to 2.5 μm in diameter exposure was associated with a 7.7% decrease in FEV1 (95% confidence interval = -11.8 to -3.5%) in the overall study population. Global genetic ancestry did not appear to significantly modify these associations, but percent African ancestry was a significant predictor of lung function. Early-life particulate exposures were associated with reduced lung function in Latino and African American children with asthma. This is the first study to report an association between exposure to particulates and reduced lung function in minority children in which racial/ethnic status was measured by ancestry-informative markers.

Gun Violence, African Ancestry, and Asthma: A Case-Control Study in Puerto Rican Children

Exposure to gun violence and African ancestry have been separately associated with increased risk of asthma in Puerto Rican children. The objective of this study was to examine whether African ancestry and gun violence interact on asthma and total IgE in school-aged Puerto Rican children. This is a case-control study of 747 Puerto Rican children aged 9 to 14 years living in San Juan, Puerto Rico (n= 472), and Hartford, Connecticut (n= 275). Exposure to gun violence was defined as the child's report of hearing gunshots more than once, and the percentage of African ancestry was estimated using genome-wide genotypic data. Asthma was defined as parental report of physician-diagnosed asthma and wheeze in the previous year. Serum total IgE (IU/mL) was measured in study participants. Multivariate logistic and linear regressions were used for the analysis of asthma and total IgE, respectively. In multivariate analyses, there was a significant interaction between exposure to gun violence and African ancestry on asthma (P= .001) and serum total IgE (P= .04). Among children exposed to gun violence, each quartile increase in the percentage of African ancestry was associated with approximately 45%higher odds of asthma (95%CI, 1.15-1.84; P= .002) and an approximately 19%increment in total IgE (95%, 0.60-40.65, P= .04). In contrast, there was no significant association between African ancestry and asthma or total IgE in children not exposed to gun violence. Our results suggest that exposure to gun violence modifies the estimated effect of African ancestry on asthma and atopy in Puerto Rican children.

African Ancestry, Social Factors, and Hypertension Among Non-Hispanic Blacks in the Health and Retirement Study

The biomedical literature contains much speculation about possible genetic explanations for the large and persistent black–white disparities in hypertension, but profound social inequalities are also hypothesized to contribute to this outcome. Our goal is to evaluate whether socioeconomic status (SES) differences provide a plausible mechanism for associations between African ancestry and hypertension in a U.S. cohort of older non-Hispanic blacks. We included only non-Hispanic black participants (N = 998) from the Health and Retirement Study who provided genetic data. We estimated percent African ancestry based on 84,075 independent single nucleotide polymorphisms using ADMIXTURE V1.23, imposing K = 4 ancestral populations, and categorized into quartiles. Hypertension status was self-reported in the year 2000. We used linear probability models (adjusted for age, sex, and southern birth) to predict prevalent hypertension with African ancestry quartile, before and after accounting for a small set of SES measures. Respondents with the highest quartile of African ancestry had 8 percentage points’ (RD = 0.081; 95% CI: −0.001, 0.164) higher prevalence of hypertension compared to the lowest quartile. Adjustment for childhood disadvantage, education, income, and wealth explained over one-third (RD = 0.050; 95% CI: −0.034, 0.135) of the disparity. Explanations for the residual disparity remain unspecified and may include other indicators of SES or diet, lifestyle, and psychosocial mechanisms.