Proportion Of African Ancestry Research Articles

Genetic ancestry proportion influences risk of adverse events from tuberculosis treatment in Brazil.

Tuberculosis (TB) treatment is highly effective, but response to therapy can vary by geography, race, and ethnicity. We assessed for differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry proportion according to major ancestry groups (African, European, and Amerindian ancestry) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. TB treatment outcomes that were attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Ancestry proportion was the main predictor in logistic regression for each outcome, with adjustments for candidate confounders. There were 941 pulmonary TB patients included in this study. We observed a decreased risk of Grade 2+ ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20 -0.85) and an increased risk for Grade 2+ ADR with increasing European ancestry (OR 2.84, 95% CI 1.47 - 5.48). We then performed the same analysis adding HIV status as an interaction term. The decreased risk for Grade 2+ ADR seen for African ancestry proportion did not hold for persons living with HIV; we observed increased risk for Grade 2+ ADR with increasing African ancestry proportion. There were no associations with Amerindian ancestry or for other treatment outcomes. In this Brazilian TB cohort, toxicity risk was associated with African and European ancestry, divergent, and affected by HIV. #RePORT-Brazil Consortium members include: Aline Benjamin and Flavia M. Sant'Anna Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil Jamile Garcia de Oliveira and João Marine Clínica de Saúde Rinaldo Delmare, Rio de Janeiro, Brazil Adriana Rezende and Anna Cristina Carvalho Secretaria de Saúde de Duque de Caxias, Rio de Janeiro, Brazil Michael Rocha and Betânia Nogueira Instituto Brasileiro para Investigação da Tuberculose, Fundação José Silveira, Salvador, Brazil Alexandra Brito and Renata Spener Fundação Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil Megan Turner Vanderbilt University Medical Center, Nashville, USA.

Dominance of African racial ancestry in honey bee colonies of Mexico 30 years after the migration of hybrids from SouthAmerica.

The Africanized honey bee, a hybrid of Apis mellifera scutellata from Africa with European subspecies, has been considered an invasive species and a problem for beekeeping. Africanized bees arrived in Mexico in 1986, 30 years after their accidental release in Brazil. Although government programs were implemented for its eradication, Africanized populations persist in Mexico, but precise information on the patterns of genetic introgression and racial ancestry is scarce. We determined maternal and parental racial ancestry of managed and feral honey bees across the five beekeeping regions of Mexico, using mitochondrial (mtDNA, COI-COII intergenic region) and nuclear markers (94 ancestrally informative SNPs), to assess the relationship between beekeeping management, beekeeping region, altitude, and latitude with the distribution of maternal and parental racial ancestry. Results revealed a predominantly African ancestry in the Mexican honey bees, but the proportion varied according to management, beekeeping regions, and latitude. The Mexican honey bees showed 31 haplotypes of four evolutionary lineages (A, M, C, and O). Managed honey bees had mitochondrial and nuclear higher proportions of European ancestry than feral honey bees, which had a higher proportion of African ancestry. Beekeeping regions of lower latitudes had higher proportions of African nuclear ancestry. Managed and feral honey bees showed differences in the proportion of maternal and nuclear racial ancestry. Managed honey bees from the Yucatan Peninsula and feral honey bees had a higher mtDNA than nuclear proportions of African ancestry. Managed honey bees, except those on the Yucatan Peninsula, had a higher nuclear than mtDNA proportion of African ancestry. Our study demonstrates that Africanized honey bee populations are genetically diverse and well established in Mexico, which highlights the limitations of management and government programs to contain the Africanization process and demands the incorporation of this lineage in any breeding program for sustainable beekeeping.

Infantile pyknocytosis, a neonatal hemolytic anemia with Heinz bodies: A cohort study.

Infantile pyknocytosis (IP) is a rare, probably misestimated, cause of non-immune neonatal hemolytic anemia evolving in two phases: an initial phase with severe jaundice, followed by a second phase with hemolytic anemia, which may require neonatal intensive care. The diagnosis of IP is based on the transient presence on blood smear of hyperdense, contracted, and/or spiculated red blood cells (pyknocytes), associated with the spontaneous resolution of clinico-biological features and the exclusion of other causes. If the etiology remains undetermined, some contributing factors, such as oxidative stress, have been proposed. We report the description of 16 patients with IP aiming at clarifying the circumstances associated with the development of this acquired disorder. In the acute phase, the mean hemoglobin nadir and pyknocyte count were 7.8g/dL and 11%, respectively, and strikingly, Heinz bodies were evident in 50% of the newborns, but in 100% after prolonged incubation (4hours). A high proportion of Mediterranean or African ancestry was noted in newborns, as well as a significant number of peripartum events, such as respiratory distress. If the etiology of IP is certainly multifactorial, our series reinforces the role of oxidative stress, which may, at least in part, find origin in desaturation episodes in newborns.

Abstract PO2-09-08: Biological and non-biological predictors of breast cancer disease-free survival among young Black females

Abstract Introduction: Young Black females bear a disproportionate burden of breast cancer (BC) deaths compared to White females yet remain underrepresented in clinical studies. We sought to discover predictors of disease-free survival (DFS) in a cohort of young Black females with BC. Methods: Black females diagnosed with invasive BC ≤ age 50 from 2005 to 2016 were recruited through the Florida and Tennessee state cancer registries. Participants were asked to complete a questionnaire, medical records release, and tissue/tumor release. Saliva was also requested for germline DNA extraction. For the primary outcome of BC DFS, univariate analyses were conducted using the following variables: proportion of West African ancestry, RNA expression based on PAM50 analyses, body mass index (BMI), social determinants of health (i.e., employment and insurance), immunohistochemistry (IHC) subtype, treatment category (i.e., chemotherapy, radiation, and surgery), and BC family history. Multivariate analyses were conducted using backward selection among these variables to analyze in the reduced model. Results: Of 701 consented, 687 participants with early-stage disease were included in the analysis; 14 participants with stage 4 disease at diagnosis were excluded. Among the 687 participants, the median age at diagnosis was 44, 28% had triple-negative breast cancer (TNBC), 13% were deceased, and 5% had recurrent disease. Clinically, participants with TNBC and lymph node involvement had worse BC DFS (p=0.001 and p=0.0002, respectively). Socio-economically, full-time employement was associated with higher BC DFS (p=0.0003). Among those for whom global ancestry data were available (n=551), multivariate analysis showed an association between increased percent of West African ancestry and worse BC DFS with HRIQR=1.23*, which approached significance (p=0.085). Additional subgroup analyses among those with hormone receptor-positive (HR+) (estrogen and/or progesterone receptor positive) BC (n=431) showed that participants with private insurance had better BC DFS (HR=0.45; p=0.05), while those with lymph node involvement had worse BC DFS (HR=2.07; p=0.001). Among HR+ participants with available ancestry data (n=349), worse BC DFS was associated with increased West African ancestry (p=0.05) and lymph node involvement (p=0.08). When ancestry was included in the model, private insurance was no longer associated with BC DFS in this HR+ subgroup (p=0.31). Other predictors analyzed did not reach statistical significance. Conclusion: Our findings confirm prior established adverse predictors of BC DFS, such as TNBC with lymph node involvement and the protective effect of full-time employment. We also found a novel association with West African ancestry among patients with HR+ breast cancer. Although further large-scale studies are needed, results from this cohort of young Black females with BC and highlight the critical need to support research to understand biological and non-biological factors contributing to BC DFS and develop targeted strategies to improve survival outcomes. * HRIQR is the ratio of hazard rates corresponding to upper and lower quartiles of percent West African (interquartile range (IQR): 70.0%-80.8%). Citation Format: Sonya Reid, Run Fan, Lindsay Venton, Anne Weidner, Ann Tezak, Mya Roberson, Susan Vadaparampil, Xuefeng Wang, Sean Yoder, Marilin Rosa, Jibril Hirbo, Jennifer Whisenant, Jennifer Pietenpol, Sheila Rajagopal, Brian Lehmann, Fei Ye, Tuya Pal. Biological and non-biological predictors of breast cancer disease-free survival among young Black females [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-09-08.

Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers.

Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to β-blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP-lowering mechanisms of TDs and BBs. Among hypertensive participants enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, we previously identified 8 metabolites associated with baseline PRA and 4 metabolic clusters (including 39 metabolites) that are different between those with GWAA <45% versus ≥45%. In the current study, using Ingenuity Pathway Analysis (IPA), we integrated these signals. Three overlapping metabolic signals within three significantly enriched pathways were identified as associated with both PRA and %GWAA: ceramide signaling, sphingosine 1- phosphate signaling, and endothelial nitric oxide synthase signaling. Literature indicates that the identified pathways are involved in the regulation of the Rho kinase cascade, production of the vasoactive agents nitric oxide, prostacyclin, thromboxane A2, and endothelin 1; the pathways proposed to underlie TD- and BB-induced vasodilatation. These findings may improve our understanding of the BP-lowering mechanisms of TDs and BBs. This might provide a possible step forward in personalizing antihypertensive therapy by identifying patients expected to have robust BP-lowering effects from these drugs.

Abstract 6119: Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium

Abstract Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks target treatments. It has been reported that African-American women have a higher incidence of TNBC and are diagnosed at an earlier age than women of European ancestry. This disparity may be attributed to both genetic and non-genetic risk factors that are associated with the African ancestry. In this study, we investigated whether genotype-derived African ancestry might be related to an elevated risk of TNBC, with adjustments for several known genetic and non-genetic risk factors. Included in the study are self-reported Black breast cancer patients diagnosed with TNBC (n =2,292) or estrogen receptor (ER)-positive cancer (n =7,863) and 9,324 controls included in the African-ancestry Breast Cancer Genetics (AABCG) Consortium. We estimated the global ancestry by Admixture and the local ancestry by FLARE, using reference of the European- and African-ancestry samples from the 1000 Genome Project. Odds ratios (OR) and 95% confidence interval (CI) per ten percent increase of the global African ancestry proportion were estimated using logistic regressions comparing TNBC with controls (case-control analyses) or with ER-positive cases (case-case analyses), adjusted for age. Similar analyses were conducted for the local African ancestry proportion at each of the 12 genomic regions that were identified in AABCG in relation to TNBC risk. Results for each participating study were meta-analyzed using fixed or random effect models. We further adjusted for non-genetic risk factors including body mass index (BMI), number of live births, breastfeeding, and menopausal status. A polygenic risk score (PRS) was constructed using 13 independent risk variants at the 12 TNBC risk loci. The PRS was additionally adjusted to investigate whether these risk variants mediated the association of African ancestry with TNBC risk. No significant association was observed between TNBC risk and global African ancestry proportion (OR: 1.03, 95% CI: 0.98-1.08) in case-control comparisons. Compared with ER-positive cases, however, TNBC cases had a higher global African ancestry, resulted in an OR of 1.09 (95% CI: 1.04, 1.13, P =5.35×10-5). A similar association was observed with additional adjustment for non-genetic risk factors, with an OR of 1.08 (95% CI: 1.03, 1.12, P =0.003). Similar patterns were also found for local ancestry proportion at six of the 12 TNBC risk loci (P &amp;lt;0.05). Further adjustment for the PRS attenuated the association between global ancestry and a TNBC diagnosis in case-case comparisons (OR: 1.05, 95% CI: 1.01, 1.10, P =0.013). Our study suggests that women with a higher African ancestry are more likely to be diagnosed with a TNBC than ER-positive breast cancer and genetic factors identified to date partially explain this association. Citation Format: Guochong Jia, Lili Liu, Julie R. Palmer, Christopher A. Haiman, Wei Zheng. Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6119.

Pharmacogenomic implications of the differential distribution of CYP3A5 metabolic phenotypes among Latin American populations.

This study shows that the distribution of CYP3A5 alleles (*1, *3, *6 and *7) and genotype-predicted CYP3A5 phenotypes vary significantly across Latin American cohorts (Brazilians and the One Thousand Genomes Admixed American superpopulation), as well as among subcohorts comprising individuals with the highest proportions of Native, European or sub-Saharan African ancestry. Differences in biogeographical ancestry across the study groups are the likely explanation for these results. The differential distribution of CYP3A5 phenotypes has major pharmacogenomic implications, affecting the proportion of individuals carrying high risk CYP3A5 phenotypes for the immunosuppressant tacrolimus and the number of patients that would need to be genotyped to prevent acute rejection in kidney transplant recipients under tacrolimus treatment.

Idiopathic collapsing glomerulopathy is associated with APOL1 high-risk genotypes or Mendelian variants in most affected individuals in a highly admixed population

Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis. Causative genetic bases, assessed by targeted-gene panel or whole-exome sequencing, were identified in 58.6% of patients. Among these cases, 80.5% harbored APOL1 high-risk genotypes (HRG) and 19.5% causative Mendelian variants (MV). Self-reported non-White patients more frequently had HRG. MV was an independent risk factor for progression to CKD-KRT by 36 months and the end of follow-up, while remission was an independent protective factor. All patients with HRG manifested CG at 9-44 years of age, whereas in those with APOL1 low-risk genotype, the disease arose throughout life. HRGs were associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2 and PLCE1 and previously described causative MVs were identified in MYH9, TRPC6, COQ2, COL4A3 and TTC21B. Three patients displayed HRG combined with a variant of uncertain significance (ITGB4, LAMA5 or PTPRO). MVs were associated with worse kidney prognosis. Thus, our data reveal that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly admixed Brazilian population.

Association of apoptosis-related variants to malaria infection and parasite density in individuals from the Brazilian Amazon

BackgroundIn malaria infection, apoptosis acts as an important immunomodulatory mechanism that leads to the elimination of parasitized cells, thus reducing the parasite density and controlling immune cell populations. Here, it was investigated the association of INDEL variants in apoptotic genes—rs10562972 (FAS), rs4197 (FADD), rs3834129 and rs59308963 (CASP8), rs61079693 (CASP9), rs4647655 (CASP3), rs11269260 (BCL-2), and rs17880560 (TP53)—and the influence of genetic ancestry with susceptibility to malaria and parasite density in an admixed population from the Brazilian Amazon.MethodsTotal DNA was extracted from 126 malaria patients and 101 uninfected individuals for investigation of genetic ancestries and genotypic distribution of apoptosis-related variants by Multiplex PCR. Association analyses consisted of multivariate logistic regressions, considering the following comparisons: (i) DEL/DEL genotype vs. INS/DEL + INS/INS; and (ii) INS/INS vs. INS/DEL + DEL/DEL.ResultsIndividuals infected by Plasmodium falciparum had significantly higher African ancestry proportions in comparison to uninfected controls, Plasmodium vivax, and mixed infections. The INS/INS genotype of rs3834129 (CASP8) seemed to increase the risk for P. falciparum infection (P = 0.038; OR = 1.867; 95% CI 0.736–3.725), while the DEL/DEL genotype presented a significant protective effect against infection by P. falciparum (P = 0.049; OR = 0.446; 95% CI 0.185–0.944) and mixed infection (P = 0.026; OR = 0.545; 95% CI 0.281–0.996), and was associated with lower parasite density in P. falciparum malaria (P = 0.009; OR = 0.383; 95% CI 0.113–1.295). Additionally, the INS/INS genotype of rs10562972 (FAS) was more frequent among individuals infected with P. vivax compared to P. falciparum (P = 0.036; OR = 2.493; 95% CI 1.104–4.551), and the DEL/DEL genotype of rs17880560 (TP53) was significantly more present in patients with mono-infection by P. vivax than in individuals with mixed infection (P = 0.029; OR = 0.667; 95% CI 0.211–1.669).ConclusionsIn conclusion, variants in apoptosis genes are associated with malaria susceptibility and parasite density, indicating the role of apoptosis-related genetic profiles in immune responses against malaria infection.

Single Nucleotide Polymorphisms of MTHFR (rs1051266) and SLC19A1 (rs1801133) Associated to Genomic Ancestry in Cuban Healthy Population

Background: Several single nucleotide polymorphisms on methotrexate pathway have been implicated with hyperhomocysteinemia, susceptibility to autoimmune diseases and the therapy effectiveness of methotrexate Objective: The present study estimates the ethnogeographic prevalence of rs1801133 (c.665C&gt;T) in methylenetetrahydrofolate reductase and rs1051266 (c.80A&gt;G) in solute carrier family Methods: Genomic data was collected from a dense genome-wide genotyping array analysis of a large sample of individuals from all provinces of Cuba, with a final sample of 946 individuals for rs1801133 and 948 individuals for rs1051266. Results: For rs1801133, T allele and TT genotype were more prevalent in Mayabeque, the province with the highest European (p&lt;0.0001) and the lowest African ancestry proportion (p&lt;0.0001). Whereas, T allele and TT genotype frequency were low in Guantánamo (23.7% and 1.8%), the province with the highest African ancestry proportion (p&lt;0.0001) and the lowest European ancestry proportion (p&lt;0.0001). For rs1051266, the higher frequency of G allele was observed in Villa Clara, Las Tunas, Holguín and Granma and this group was associated with AG and GG genotypes (p=0.0045). This seems to be related to high Native American ancestry proportion in Las Tunas (p&lt;0.0001), Holguín (p&lt;0.0001) and Granma (p&lt;0.0001); with the low African ancestry proportion in Villa Clara (p&lt;0.0001) and with a Native American ancestry-enriched pattern observed for these provinces (p=0.0005). Conclusion: These results provide evidence that ancestry contribution impacts in the ethnogeographic prevalence of rs1801133 (c.665C&gt;T) and rs1051266 (c.80A&gt;G) polymorphisms in healthy Cuban individuals.

Gene expression in African Americans, Puerto Ricans and Mexican Americans reveals ancestry-specific patterns of genetic architecture

We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene–trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities.

Abstract 634: The impact of IL-4 on migration in triple negative breast cancer cell lines

Abstract In the United States, triple-negative breast cancer (TNBC), an aggressive form of breast cancer (BCa), disproportionately affects women of African descent and contributes to racial disparities in BCa mortality. Various risk factors are thought to drive this disparity, including socioeconomic status, tumor characteristics, comorbidities, and quality of treatment. Complex diseases and environmental insults all invoke and/or disrupt host inflammation, with individual immune and variable responses to therapeutic agents being dictated in part by genetic variants. This latter has seldom been studied with regards to precision diagnosis and prognosis of individual patient responses, in the frame of geographical ancestry and TNBC. Interleukin-4 receptors (IL4R) have been shown to be upregulated in many epithelial cancers and could be a promising target for metastatic tumor therapy. Yet, IL4R overexpression and/or IL4R variants have not been evaluated in TNBC cell lines of varying genetic ancestry. In view of this, we investigated the effects of IL-4 treatment in four TNBC cell lines varying in proportions of West African Ancestry (WAA) in each cell line: MDA-MB-231 (0.019), HCC-1143 (0.012), HCC-1806 (0.807), MDA-MB-468 (0.803). The frequency of IL4R variants also differed in each cell line. We used high content live cell imaging to evaluate the effect of IL-4 treatment on cellular migration by measuring wound healing. We show that IL-4 treatment on TNBC cells enhances migration as indicated by increased wound healing when compared to non-treated cells. High glucose, at a concentration of 10 g/L, delays cell migration in IL4-treated TNBC cells. This data suggests that comorbidities, such as high glucose levels (i.e., uncontrolled diabetes) could impact tumor behavior and mortality disparities between populations. Citation Format: Portia Andrews, Kevin S. Kimbro. The impact of IL-4 on migration in triple negative breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 634.

Abstract 1945: Racial disparities in comprehensive cancer tumor profiling testing from real-world data of 100,000 cancer patient records

Abstract Inequities in cancer patient outcomes and healthcare utilization by race and ethnicity are coming to the forefront. Overcoming these inequities requires a better understanding of the extent of such disparities across cancer types and medical interventions. Here, we studied the race and ethnicity of patients receiving tumor profiling for therapy decision support by examining real-world data (RWD) from 100,000 de-identified patient records across major cancer types. Tumors and normal tissue (when available) were sequenced with the Tempus xT assay, a 648-gene next-generation sequencing panel. Since race and ethnicity metadata are frequently incomplete in RWD, we imputed these categories from continental genetic ancestry inferred from genotypes of 654 ancestry informative markers obtained from sequencing data. Using a heuristic that combines East Asian, African, Amerindian, European, and South Asian ancestry proportions, we imputed Asian (A), Non-Hispanic Black (NHB), Hispanic/Latino/Native American (HIS), and Non-Hispanic White (NHW) categories with &amp;lt;2% error rate (based on available metadata), leaving 3% of unclassified patients due to complex admixture. NHW patients are overrepresented in the cohort at 72% as compared to NHB (11%), HIS (9%) and ASN (5%). We compared the distributions of patients by race/ethnicity categories across specific cancer types against the overall cohort race/ethnicity distributions. These distributions were compared to the expected distribution under the null hypothesis of no relationship by the χ2 test of independence. Significantly (p&amp;lt;0.05) over/under-represented categories in each cancer type were compared to ranks of incidence by race/ethnicities in SEER program data at the national level. Differences are of a smaller magnitude in NHW as compared to the other races/ethnicities. We observed several differences that are concordant with SEER; for example, overrepresentations of NHB in breast, colorectal, and endometrial cancers, which correspond to high incidences of these cancers for NHB. Notably, we observed several discordances with SEER incidence rate ranks, including underrepresentation of NHB in pancreatic and urinary tract cancers, underrepresentation of NHW in breast and colorectal cancers, overrepresentation of ASN in gallbladder and biliary cancer, and overrepresentation of HIS in colorectal cancer. These differences can be the result of a complex interplay of factors, such as stage of the disease at sequencing, access to early-stage curative therapies, comorbidities/cofactors, access to care, insurance, socioeconomic status, and others. Nonetheless, our results show that analysis of racial disparities can be performed with RWD, and this information can be useful in studying causes and devising strategies to improve healthcare equity. Citation Format: Francisco M. De La Vega, Brooke Rhead, Yannick Pouliot, Justin Guinney. Racial disparities in comprehensive cancer tumor profiling testing from real-world data of 100,000 cancer patient records [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1945.

Abstract 1923: Ancestry-associated differences in somatic mutation rates from tumor profiling data of a pan-cancer cohort of 100,000 patients

Abstract Racial and ethnic disparities span the continuum of cancer care and adversely impact screening, detection, diagnosis, treatment, and outcomes of cancer. These disparities are driven by a complex interplay among social, psychosocial, lifestyle, environmental, healthcare, and biological determinants of health. A challenge is that the social constructs of race and ethnicity may not fully capture shared genetic background. Genomics can capture ancestry in a more precise way, allowing genetic influences to be teased apart from the impact of social and environmental factors. Here, we searched for associations between continental genetic ancestry and somatic mutations in cancer genes in a pan-cancer cohort of 100,000 patients. A sample of de-identified records from patients who underwent tumor profiling with the Tempus xT 648-gene assay was selected from the Tempus Database. We inferred global African (AFR), Amerindian (AMR), East Asian (EAS), European (EUR), and South Asian (SAS) continental ancestry proportions with a custom set of 658 ancestry informative markers. To properly account for the collinearity of ancestry proportions, we performed logistic compositional data analysis between mutation counts and ancestry proportions from data of cancer types with at least 300 patients and for genes for which a minimum of 10 and at least 1% of patients harbored variants. Odds ratios (ORs) represent the effect of a doubling in ancestry proportion, adjusted for age, gender, assay version, and all other ancestries. We examined associations for the presence of nonsynonymous somatic mutations and predicted driver mutations with the boostDM algorithm. We adjusted for multiple comparisons at a 5% false discovery rate (FDR) with the Benjamini-Hochberg method. We identified previously reported significant (p&amp;lt;0.001) associations between EAS and predicted driver mutations in EGFR (OR=1.08) in lung cancer, and between AFR and APC (OR=1.03) and KRAS (OR=1.04) in colorectal cancer. Moreover, we found several novel associations, including AFR with TP53 (OR=1.06) and PTEN (OR=0.90) in endometrial cancer and BRAF (OR=0.93) in colorectal cancer, and EAS with CTNNB1 (OR=1.17) in lung cancer. The latter is noteworthy as CTNNB1, which has been proposed as a TTK inhibitor response biomarker, is overall infrequently mutated in lung cancer but activating mutations have been reported in East Asian patients. Indeed, we found that 7% of East Asian lung cancer patients in our cohort harbor a driver mutation in this gene vs. 1.6% in the other groups. Additionally, an association with nonsynonymous mutations was found between AMR with PTPN22 (OR=1.26) in colorectal cancer. While these associations can be the result of a combination of environmental, social, and biological factors, our results suggest that genetic ancestry can be useful to understand disparities in cancer incidence, progression, and outcomes. Citation Format: Brooke Rhead, Yannick Pouliot, Justin Guinney, Francisco M. De La Vega. Ancestry-associated differences in somatic mutation rates from tumor profiling data of a pan-cancer cohort of 100,000 patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1923.

Abstract NG03: Multiomics in disparities research: Identifying African ancestry-specific mechanisms in the triple negative breast cancer tumor microenvironment

Abstract NG03: Multiomics in disparities research: Identifying African ancestry-specific mechanisms in the triple negative breast cancer tumor microenvironment

Ethnic disparities in ambient air and traffic-related pollution exposure and ethnic-specific impacts on clinical biomarker levels

BackgroundAlthough characterizing the inequality in pollution exposure burden across ethnic groups and the ethnic-specific exposure associations is of great social and public health importance, it has not been systematically investigated in large population studies. MethodsThe UK Biobank data (N = 485, 806) of individual-level air ambient and traffic-related pollution exposure, biomarkers routinely used in clinical practice, genotype, life-style factors, and socioeconomic status were analyzed. Air pollution exposure estimates were compared among six genetically inferred ethnic groups. We also quantified the association between exposure and biomarkers within and across ethnicities. ResultsNon-European participants (defined by genetics) disproportionately bear a higher burden of exposure than their European counterparts even after adjusting for covariables including socioeconomic status. For example, exposure to NO2 in people with African ancestry was 30.7 % higher (p = 1.5E-786) than European subjects. Within the genetically defined African group, larger African genetic ancestry proportion (AGAP) was linked to higher ambient air pollutant exposure. Trans-Ethnic analysis identified 32 clinical biomarkers associated with environmental exposure. For 13 biomarkers, the association with exposure was significantly different or even in opposing directions across ethnic groups. ConclusionsSubstantial disparities in air pollution exposure was observed among genetically-defined ethnic groups. Most importantly, we show that the impact of exposure on biomarkers varies by ethnicity. Reducing the disproportionally high exposure burden on non-European populations and alleviating the adverse consequences in an ethnic-specific manner are of great urgency and significance.

Genetic Factors Associated with Absolute and Relative Plasma Concentrations of Calcitriol.

Little is known regarding factors associated with calcitriol and a relative measure of calcitriol, the calcitriol-24,25-dihydroxyvitamin D3-calcifediol proportion ratio (C24CPR). Using a cross-sectional study design, healthy young adults of African and European descent, matched (1:1) on age (±5 years) provided a blood sample in non-summer months (N = 376). Vitamin D metabolites were measured in plasma with HPLC/MS-MS. West African genetic ancestry proportion (WGA) was estimated using STRUCTURE modeling of genetic ancestry-informative markers. Multivariable regression models were used to estimate the association of WGA and vitamin D-pathway gene variants with calcitriol and C24CPR, controlling for days from summer solstice, age, sex, blood pressure, body mass index, dietary vitamin D intake, oral contraceptive/medroxyprogesterone acetate use, smoking, tanning bed use, and time of day. Calcitriol and C24CPR were not highly correlated (rho = 0.14), although both were significantly, positively, and monotonically associated with WGA (Ptrend 0.025 and <0.001, respectively). In fully adjusted models, genetic factors explained a greater proportion of variability in C24CPR (R2 = 0.121 and 0.310, respectively). Variants in genes with associated with calcitriol (CALB1, CYP27B1, GC, and PPARGC1A) differed from those associated with C24CPR (CYP3A43, FGF23, KL, and VDR). Both absolute and relative measures of calcitriol were significantly higher among African Americans. Otherwise, these biomarkers appear to be genetically distinct. C24CPR may be better suited to personalized medicine, due to a higher proportion of population variability explained by genetic variation and a less skewed distribution.

P902 Native American Mapuche ancestry is related to higher IBD risk in Chileans

Abstract Background Most genetic association studies rely on Caucasian, African and Asian individuals with inconsistent results depending on the population investigated, suggesting that genetic susceptibility to inflammatory bowel disease (IBD) may depend on interactions between ethnicity and genetic-environmental factors. Aim: To explore the contribution of genetic ancestry to IBD risk in Chileans. Aim: To explore the contribution of genetic ancestry to IBD risk in Chileans. Methods 192 Chilean IBD patients were genotyped using Illumina’s Global Screening Array. Genotype data was combined with similar information from 3147 population-based Chilean controls from a published study on gallstones, body mass index, c-reactive protein and gallbladder cancer in Chileans (Barahona et al., Hepatology 2021). The individual proportions of Aymara, African, European and Mapuche ancestry were estimated using the software ADMIXTURE (supervised estimation). Using the statistical software R version 4.2.1, we calculated the odds ratios (OR) and 95% confidence intervals (CI) for gender, as well as age and ancestry proportions grouped into quartiles using the library “epitools”. Results Table 1 shows the investigated characteristics of the study population and their association with IBD risk. For example, the 1st and 3rd quartiles of the proportion of Mapuche ancestry in IBD patients were 24.7% and 34.2%, respectively, and the corresponding OR was 2.30 (95%CI 1.52-3.48) for the lowest versus the highest group. Conclusion The type and proportion of Native American ancestry in Chileans seems to be associated with IBD risk.

Admixture mapping identifies novel Alzheimer's disease risk regions in African Americans.

This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions. We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes. Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p=2.2×10-5 ) and 18q21.33 (p=1.2×10-5 ). Our fine mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes such as the MINK1, KIF1C, and BCL2. Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus. We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.

Cross‐ancestry effect of APOE on cognitive performance

AbstractBackgroundAlzheimer's disease (AD) is more prevalent in populations of non‐European ancestry, with Black and Hispanic adults 1.5 and 2.5 times more likely to develop AD respectively. Health disparities in AD could be explained by race and ancestry, where race captures risk factors due to socio‐economic aspects of health and ancestry captures the biological mechanisms influenced by genetic variation. The APOE ε4 allele is the most significant genetic risk factor for AD; however, the risk conferred by APOE ε4 differs across populations. Here, we investigate the interactive effect of race, ancestry and APOE on episodic memory performance.MethodsEpisodic memory at last assessment was measured using the Consortium to Establish a Registry for Alzheimer’s Disease Word List Memory Task in ∼500 participants from the Alzheimer's Disease Research Center (ADRC) at the Icahn School of Medicine at Mount Sinai (ISMMS), including 82 African American, 118 Hispanics, 117 Asian Americans, and 275 White participants. Genetic ancestry was determined using principal component analysis; global ancestry proportions using ADMIXTURE; and local ancestry in the APOE locus using RFMix. The interactive effect of APOE and genetic ancestry, global ancestry proportions, and local ancestry locus on episodic memory performance was evaluated using linear regression models adjusting for age, sex, education, telehealth/in‐person visit, and year of visit.ResultsAdmixed American and African genetic ancestry assignments showed an interaction with APOE (African: p‐value=0.023 and Amerindian: p‐value=0.002). In addition, higher proportion of African and Admixed American global ancestry showed significant interactions with APOE (African: p‐value=0.032 and Admixed American: p‐value=0.029). Lastly, ancestry local to APOE region showed an interaction with the APOE e4 allele in Admixed Americans such that an Admixed American background was associated with better cognitive performance in comparison to a European ancestral background (p‐value=0.008).ConclusionsOur study showed that ancestry modifies the effect of APOE on cognitive performance. Future work needs to evaluate potential confounders associated with social determinants of health and ascertainment bias during enrollment, including age at assessment and visit type. In sum, this study corroborates a role of ancestry in modifying APOE associated AD risk.