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Diversity of Brazilian Ancestry in 3 Cohorts: Challenges and Insights for Precision Medicine

Ethical Legal Social Issues (ELSI) Public Health and Policy
  • Primary Categories:
    • Health Care Inequities and health disparities
  • Secondary Categories:
    • Health Care Inequities and health disparities
Introduction:
Genetic diversity plays a critical role in understanding complex diseases, and the calculation of Polygenic Risk Scores (PRS) is heavily influenced by ancestry background. Brazilian populations exhibit a unique admixed ancestry composition due to centuries of immigration and social integration. While numerous studies have investigated Brazilian genetic ancestry, only a few have undertaken comprehensive analyses using genome sequencing.

In this study, we explore the ancestry composition of 3 Brazilian cohorts currently being analyzed for PRS adjustability in admixed populations — breast cancer, prostate cancer, and coronary artery disease (CAD). Additionally, we compare these cohorts with the Arquivo Brasileiro Online de Mutações (ABraOM), a cohort representative of the elderly community in São Paulo, Brazil's largest and most cosmopolitan city.

Methods:
The breast and prostate cancer cohorts, consisting of cases and controls, were recruited at the Instituto do Câncer do Estado de São Paulo (ICESP) and the Hospital das Clínicas da FMUSP, both public health institutions in São Paulo, located in the Southeast region of Brazil. The CAD cohort was recruited from private health institutions in São Paulo and Salvador, the latter, located in the state of Bahia, Northeastern region of Brazil.

We performed genome sequencing (15x coverage) on DNA extracted from mononuclear cells of 1,051 participants. The cohorts include 247 individuals in the breast cancer group (223 cases, 24 controls), 700 in the prostate group (564 cases, 136 controls), and 104 in the CAD group (87 cases, 17 controls). Participants were adults who provided informed consent to participate in the research.

Ancestry composition was calculated using ancestry-informative markers derived from global populations, grouped by continent or sub-region (Africa, Americas, Asia, Europe, Middle-East, Oceania).

Results:
The mean ancestry composition in each cohort was: CAD: European 65.51%, African 24%, Middle-Eastern 5.56%, American 4.87%, Asian 0.06%; breast cancer: European 55%, African 27.05%, American 8.87%, Middle Eastern 5.03%, Asian 3.05%; prostate: European 61.41%, African 24.57%, American 7.68%, Middle Eastern 4.75%, Asian 1.59%.

The ancestry composition analysis revealed: 1) A small but significant proportion of genetic ancestry from Asia and the Middle-East, that may reflect historical immigration patterns, particularly from Japan (and more recently China and Korea) and the Middle-East (primarily Syria and Lebanon) over the past two centuries; 2) Cancer participants exhibited a higher percentage of African ancestry compared to the ABraOM cohort (representative of São Paulo's elderly general population) and the cardiology cohort, which primarily includes individuals treated in private hospitals; 3) Regional differences, as participants from Salvador, Bahia, displayed a higher proportion of African ancestry and lower Asian ancestry compared to participants from São Paulo, even within the same cohorts; 3) The breast cancer cohort, predominantly composed of premenopausal women, demonstrated higher African ancestry, supporting literature suggesting an increased prevalence of early-onset breast cancer in women with this ancestral background.

Conclusion:
The Brazilian genetic ancestry admixture, shaped by contributions from European, African, Indigenous, Asian, and Middle-Eastern ancestries, is distinct from the patterns reported for admixed populations in the USA, which predominantly include European, African, Andean, and Caribbean ancestries.

Moreover, Brazil's internal geographic diversity introduces significant regional variations in genetic ancestry due to the country's vast size and population heterogeneity. These complexities present unique challenges for validating and calibrating PRS in the Brazilian population. This research underscores the importance of understanding these nuances for advancing precision medicine and improving personalized healthcare in Brazil. Future work will focus on the application of these findings to PRS development and clinical implementation.

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