Native American Ancestry Research Articles

Genetic and self‐perceived ancestries in Argentina: Beyond the three‐hybrid model

AbstractObjectivesThe increased availability of genome‐wide data allows capturing the fine genetic structure of present days populations. Here we analyze the genetic ancestry at a fine scale of an Argentinean Patagonia population to understand the origins beyond the three‐hybrid model, and to compare these results with volunteers' self‐perceived ancestry in a broad context encompassed by historical and familiar information.Materials and MethodsWe compare high‐throughput genotyping data for 92 individuals that we generated to data sets from the literature by applying fully haplotype‐based methods to examine patterns of human population substructure. The volunteers filled out a semi‐structured questionnaire, including questions about their history, ancestors, and self‐perceived ancestry. Finally, we used non‐parametric tests in order to compare genomic ancestry against self‐perception.ResultsGenetic ancestry from Iberian populations accounted for 0.176 (Spain and Basque origins), while the component associated with Italian populations accounted for 0.140. We observed a 0.169 Native American genetic ancestry. Participants significantly over‐ and under‐ self‐perceived Native American and European origins, respectively. Components of origins from North Africa to Central South Asia accounted for 0.225 of the genetic ancestry in the sample, with significantly higher proportions for people that mentioned such origins in their genealogical history.DiscussionWe captured the fine‐genetic architecture of a Puerto Madryn population sample in Chubut province, showing that self‐perceived ancestry remains a poor proxy for genetic ancestry. The presence of North Africa to Central South Asia components and its correlate with self‐perception of these origins justifies its inclusion in future miscegenation studies in Argentina.

New insights from GWAS on BMI-related growth traits in a longitudinal cohort of admixed children with Native American and European ancestry

Body-mass index (BMI) is a hallmark of adiposity. In contrast with adulthood, the genetic architecture of BMI during childhood is poorly understood. The few genome-wide association studies (GWAS) on children have been performed almost exclusively in Europeans and at single ages. We performed cross-sectional and longitudinal GWAS for BMI-related traits on 904 admixed children with mostly Mapuche Native American and European ancestries. We found regulatory variants of the immune gene HLA-DQB3 strongly associated with BMI at years old. A variant in the sex-determining gene DMRT1 was associated with the age at adiposity rebound (Age-AR) in girls (P ). BMI was significantly higher in Mapuche than in Europeans between 5.5 and 16.5 years old. Finally, Age-AR was significantly lower (P ) by 1.94 years and BMI at AR was significantly higher (P ) by 1.2kg/ , in Mapuche children compared with Europeans.

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.

Abstract A079: Genetic ancestry and vitamin D may predict degree of prostatic apoptosis in prostate tumor and benign epithelium among men undergoing radical prostatectomy

Abstract There is evidence that vitamin D metabolites such as 25 hydroxyvitamin D [25(OH)D], may be protective against prostate cancer (PCa). Vitamin D and its analogs are hypothesized to have pro-apoptotic effects in multiple cell lines. Blacks have higher rates of vitamin D deficiency, higher tumor progression rates 1,2, and higher apoptosis rates3 compared to Whites. West African ancestry (WAA) may confound this relationship if it is associated with both vitamin D status and apoptosis rates. Our objective is to assess for independent associations between in vivo vitamin D status, genetic ancestry, and degree of apoptosis using prostatic epithelial Terminal deoxynucleotide transferase dUTP Nick End Labeling (TUNEL) staining. Radical prostatectomy specimens of men with clinically localized PCa were stained for TUNEL. Prostatic and serum levels of 25(OH)D and serum levels of 1,25 hydroxyvitamin D were assessed at the time of surgery. Ancestry informative markers were used to estimate the percentage of genetic West African, Native American, and European ancestry. Continuous variables were compared using medians tests across three groups of vitamin D status. Categorical variables were compared using the Chi-Squared test. Correlations between the degree of TUNEL staining and vitamin D metabolites were assessed using Spearman correlations. Linear regressions were used to access the bivariant associations between tumor and benign epithelial TUNEL staining with quartiles of ancestry, and serum and prostatic vitamin D metabolite levels. Multivariate linear regressions for the percentage of benign and tumor TUNEL staining were used to test the independent associations of vitamin D metabolites and genetic ancestry. Overall, 121 men, age 40-79, who underwent radical prostatectomy were enrolled between 2013-2018. Serum 25(OH)D correlated positively with both tumor (ρ = 0.17, p = 0.03), and benign (ρ = 0.16, p = 0.04) prostatic epithelial TUNEL staining. Similarly, prostatic 25(OH)D correlated positively with both tumor (ρ = 0.31, p < 0.001) and benign (ρ = 0.20, p = 0.03) prostatic tissue TUNEL staining. Relative to West African ancestry, Native American ancestry was more strongly positively correlated with tumor (ρ = 0.22, p = 0.05) and benign (ρ = 0.27, p= 0.02) TUNEL staining. In multivariate regression models, increasing quartiles of prostatic 25(OH)D (β = 0.25, p = 0.04) and Native American ancestry (β = 0.327, p = 0.004) were significant predictors of tumor TUNEL staining. Physiologic levels of serum and prostatic 25(OH)D and percentage of Native American ancestry are positively associated with the degree of apoptosis in tumor and benign prostatic epithelium from men with clinically localized PCa. Vitamin D may have secondary chemoprevention benefits in preventing PCa progression in localized disease. Citation Format: Cordero L. McCall, James Stinson, Ryan W. Dobbs, Neil Mistry, Adrian Rosenberg, Oluwarotimi Nettey, Pooja Sharma, Michael Dixon, Jamila Sweis, Virgilia Macias, Roohollah Sharifi, Rick A. Kittles, Andre Kajdacsy Balla, Adam B. Murphy. Genetic ancestry and vitamin D may predict degree of prostatic apoptosis in prostate tumor and benign epithelium among men undergoing radical prostatectomy [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A079.

Abstract A006: Increased germline mutational burden in individuals of African ancestry: Implications for interpretation of tumor mutation burden

Abstract Introduction: Tumor mutation burden (TMB), defined as the number of somatic gene mutations per megabase in a tumor genome, is used clinically to identify cancer patients that may respond to immune checkpoint inhibitors. Recent studies suggest that patient ancestry can influence TMB, where individuals of African ancestry were found to have elevated TMB values based on tumor-only sequencing analysis. However, the impact of patient ancestry on germline mutational burden and implications for interpretation of tumor-only mutational burden data is largely unexplored. Methods: We examined the influence of patient ancestry on germline and tumor mutation burden using tumor-normal whole exome sequencing (WES) data from a pan-cancer cohort of 1228 individuals from a single institution. Genetic ancestry was estimated from constitutional WES data using single nucleotide polymorphism weights from external reference panels. Variant calling was performed using constitutional, tumor-only, and paired tumor-normal workflows. Total and loss-of-function burden scores were calculated for each participant from each workflow based on the total number of mutations detected in each sample and the total number of predicted loss-of-function mutations, based on snpEff annotations, respectively. Results: Genetic ancestry analysis found that one-third of this pan-cancer cohort was of non-European ancestry. 9.4% of individuals were of Eastern Asian ancestry, 5.3% of African ancestry, 1.0% of South Asian ancestry, 0.2% of Native American ancestry, and 17.1% of admixed ancestry, predominantly European and Native American admixed ancestry (15.6%). Total and loss-of-function germline burden scores varied across ancestral groups, with individuals of African ancestry showing significantly increased germline burden scores compared to other ancestral groups (p<0.0001). Tumor-only analysis also showed increased mutation burden for individuals of African ancestry. However, when private and rare germline variation was taken into account using paired tumor-normal analysis, tumor mutation burden did not differ based on patient ancestry, suggesting the differences seen in tumor-only analysis are due to germline variation rather than differences in true somatic mutation burden. Conclusion: Our study reveals that the paucity of knowledge of ancestry-specific reference genomes leads to unacceptable health disparities in cancer, specifically in patients with African ancestry. We show that germline mutational burden varies by ancestral background, with individuals of African ancestry displaying increased genetic variation compared to other ancestral populations. These results suggest that patient ancestry should be considered when interpreting tumor mutational burden values, particularly from tumor-only analysis. Approaches utilizing paired tumor-normal analysis or ancestry-specific reference genomes can aid in more accurate assessment of TMB, thereby avoiding futile treatments targeted at presumed high mutational burden tumors specifically in African American populations. Citation Format: Janith Don, Sara A. Byron, Guangfa Zhang, Tyler Izatt, Jiaming Zhang, Bethany Davis, Bryce Turner, Jonathan J. Keats, Jeffrey M. Trent, Lorna Rodriguez-Rodriguez, Nicholas J. Schork. Increased germline mutational burden in individuals of African ancestry: Implications for interpretation of tumor mutation burden [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A006.

The Autosomal Short Tandem Repeat Polymorphisms Are Potentially Associated with Cardiovascular Disease Predisposition in the Latin American Population: A Mini Review.

According to the World Health Organization, cardiovascular diseases (CVDs) are the leading cause of death worldwide across nearly all ethnic groups. Inherited cardiac conditions comprise a wide spectrum of diseases that affect the heart, including abnormal structural features and functional impairments. In Latin America, CVDs are the leading cause of death within the region. Factors such as population aging, unhealthy diet, obesity, smoking, and a sedentary lifestyle have increased the risk of CVD. The Latin American population is characterized by its diverse ethnic composition with varying percentages of each ancestral component (African, European, and Native American ancestry). Short tandem repeats (STRs) are DNA sequences with 2-6 base pair repetitions and constitute ~3% of the human genome. Importantly, significant allele frequency variations exist between different populations. While studies have described that STRs are in noncoding regions of the DNA, increasing evidence suggests that simple sequence repeat variations may be critical for proper gene activity and regulation. Furthermore, several STRs have been identified as potential disease predisposition markers. The present review is aimed at comparing and describing the frequencies of autosomal STR polymorphisms potentially associated with cardiovascular disease predisposition in Latin America compared with other populations.

Abstract C052: Endometrial cancer genomics varies by race

Abstract Introduction Variability in endometrial cancer (EC) risk and outcomes exist, with Black women disproportionately negatively affected related to White women. The biologic etiologies of these observations are poorly understood. Our objective was to describe the somatic mutations of the tumor genome and compare them to RNA expression in self-identified Black and White women diagnosed with EC. Methods Women with newly diagnosed EC and undergoing hysterectomy were recruited prospectively. Fresh tumors obtained at the time of surgery were flash-frozen, underwent DNA and RNA extraction and were submitted for whole exome sequencing (WES) analysis (DNA) or bulk RNA sequencing analysis. Differentially expressed genes between racial groups and tumor grade were calculated using Deseq2. Genomic ancestry was determined using ADMIXTURE. Chi-square and Mann Whitney U tests were used for analyses, with a threshold for significance of p<0.05. Results A total of 49 patients with EC were included. Thirty (61.2%) women were diagnosed with low-grade EC and 19 (38.8%) with high grade EC. Twenty (40.8%) women self-identified as Black, 27 (55.1%) as White and 2 (4.1%) as Asian/other. Admixture analysis showed that 36 (73.4%) had >14% African ancestry. The remaining 13 (26.5%) patients had admixed European and Native American ancestry, with <1% African ancestry. In the RNA-seq, we found significant DEGs by tumor grade; with 2132 DEG in High grade compared to Low grade tumors with a false discovery rate of <0.05 and a fold change (FC) of ≤-1.5 or ≥1.5. Top 10 DEG included MT4, TAF15, SLFN5 and PLEKHS1 (upregulated) and MCRIP1, MAZ, MYOM3, PRPH, BCL7C, AC016700.5 (downregulated). In the WES analysis, 8 Black women had mutations in GON4L compared to 1 in the White woman (44.4% vs 3.7%, padj=0.04); and 7 Black women had a mutation in PRAMEF14 compared to 1 White woman (38.8% vs 3.7%, padj= 0.06). Conclusion GON4L, which is a transcription factor associated with decreased apoptosis and promotion of tumor growth through CD24 regulation, was significantly more mutated in the EC genome of Black women relative to White women. Somatic mutation and transcriptional changes are seen between tumor grade and self-identified race and require further exploration for its relationship to aggressive disease. Citation Format: Alex P. Sanchez-Covarrubias, Ramlogan Sowamber, Leah Dodds, Andre Pinto, Sophia George, Matthew Schlumbrecht. Endometrial cancer genomics varies by race [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C052.

Epigenetic aging differences between Wichí and Criollos from Argentina: Insights from genomic history and ecology.

Epigenetic estimators based on DNA methylation levels have emerged as promising biomarkers of human aging. These estimators exhibit natural variations across human groups, but data about indigenous populations remain underrepresented in research. This study aims to investigate differences in epigenetic estimators between two distinct human populations, both residing in the Gran Chaco region of Argentina, the Native-American Wichí, and admixed Criollos who are descendants of intermarriages between Native Americans and the first European colonizers, using a population genetic approach. We analyzed 24 Wichí (mean age: 39.2 ± 12.9 yo) and 24 Criollos (mean age: 41.1 ± 14.0 yo) for DNA methylation levels using the Infinium MethylationEPIC (Illumina) to calculate 16 epigenetic estimators. Additionally, we examined genome-wide genetic variation using the HumanOmniExpress BeadChip (Illumina) to gain insights into the genetic history of these populations. Our results indicate that Native-American Wichí are epigenetically older compared to Criollos according to five epigenetic estimators. Analyses within the Criollos population reveal that global ancestry does not influence the differences observed, while local (chromosomal) ancestry shows positive associations between specific SNPs located in genomic regions over-represented by Native-American ancestry and measures of epigenetic age acceleration (AgeAccelHannum). Furthermore, we demonstrate that differences in population ecologies also contribute to observed epigenetic differences. Overall, our study suggests that while the genomic history may partially account for the observed epigenetic differences, non-genetic factors, such as lifestyle and ecological factors, play a substantial role in the variability of epigenetic estimators, thereby contributing to variations in human epigenetic aging.

Abstract C039: Influence of patient ancestry on homologous recombination repair deficiency in cancer

Abstract Homologous recombination repair deficiency (HRD) is a common driver of tumorigenesis that carries therapeutic implications, particularly in breast, ovarian, prostate, and pancreatic cancers. The influence of genetic ancestry on the incidence of HRD in these tumors remains to be defined. Previous studies have reported a higher incidence of variants of unknown significance (VUS) in individuals of non-European ancestry. Here, we evaluated the frequency of HR-deficiency within a diverse cohort of 566 patients with breast, prostate, ovarian, or pancreatic cancer. Genetic ancestry was estimated from constitutional whole exome sequencing data using a single nucleotide polymorphism weight model containing five ancestral populations: European, Native American, African, East Asian, and South Asian. Frequencies of clinical genetic testing, germline variants in HR-genes, and tumor HRD were compared between individuals of admixed Native American and European ancestry (n=82) and those of European ancestry (n=378). Admixed Native American/European individuals had a younger age at diagnosis compared to individuals of European ancestry (median 52.4 years (range, 20.8-83.6) vs 62.9 years (range, 20.9-87.9), p<0.0001; two-tailed unpaired t-test), driven by a younger age of diagnosis in admixed Native American/European individuals with breast cancer. 22.6% of patients received genetic testing as part of their clinical care, with an increased rate of genetic testing in admixed Native American/European individuals with breast cancer, consistent with the younger age of diagnosis in this population. Among individuals who received clinical germline testing, there was no significant difference based on patient ancestry in the time from cancer diagnosis until germline testing was performed. In the cohort overall, individuals of admixed Native American/European ancestry and those of European ancestry had a similar frequency of both pathogenic/likely-pathogenic (P/LP) (8.5% vs 6.3%) and VUS (17.1% vs 15.1%) germline variants in HR genes. In breast cancer patients who were younger than 50 years at diagnosis, admixed Native American/European individuals showed a trend toward a higher frequency of P/LP events compared to European individuals (17.6% vs 7.0%, p=0.1722). The frequency of somatic variants in HR genes and the rate of tumor HR-deficiency were similar between patients of admixed Native American/European ancestry and those of European ancestry. In summary, in this retrospective analysis, women of admixed Native American/European ancestry showed a younger age of breast cancer diagnosis and a trend toward increased incidence of pathogenic or likely-pathogenic germline variants in HR genes compared to women of European ancestry. These data support a role for genetic ancestry influencing cancer risk and phenotypes. Additional studies evaluating the impact of genetic ancestry on HRD are needed to reduce disparities in genetic testing and improve application of therapies targeting HRD in diverse cancer populations. Citation Format: Sara A. Byron, Guangfa Zhang, Kimber Slater, Jiaming Zhang, Tyler Izatt, Bryce Turner, Xiao-Yu Xia, Rick A. Kittles, Jonathan J. Keats, Jeffrey M. Trent, Nicholas J. Schork, Lorna Rodriguez-Rodriguez. Influence of patient ancestry on homologous recombination repair deficiency in cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C039.

Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population.

The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity.

Vitamin D and genetic ancestry are associated with apoptosis rates in benign and malignant prostatic epithelium.

Vitamin D metabolites may be protective against prostate cancer (PCa). We conducted a cross-sectional analysis to evaluate associations between in vivo vitamin D status, genetic ancestry, and degree of apoptosis using prostatic epithelialterminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL) staining. Benign and tumor epithelial punch biopsies of participants with clinically localized PCa underwent indirect TUNEL staining. Serum levels of 25 hydroxyvitamin D [25(OH)D] and 1,25 dihydroxyvitamin D were assessed immediately before radical prostatectomy; levels of prostatic 25(OH)D were obtained from the specimen once the prostate was extracted. Ancestry informative markers were used to estimate the percentage of genetic West African, Native American, and European ancestry. One hundred twenty-one newlydiagnosed men, age 40-79, were enrolled between 2013 and 2018. Serum 25(OH)D correlated positively with both tumor (ρ = 0.17, p = 0.03), and benign (ρ = 0.16, p = 0.04) prostatic epithelial TUNEL staining. Similarly, prostatic 25(OH)D correlated positively with both tumor (ρ = 0.31, p < 0.001) and benign (ρ = 0.20, p = 0.03) epithelial TUNEL staining. Only Native American ancestry was positively correlated with tumor (ρ = 0.22, p = 0.05) and benign (ρ = 0.27, p = 0.02) TUNEL staining. In multivariate regression models, increasing quartiles of prostatic 25(OH)D (β = 0.25, p = 0.04) and Native American ancestry (β = 0.327, p = 0.004) were independently associated with tumor TUNEL staining. Physiologic serum and prostatic 25(OH)D levels and Native American ancestry are positively associated with the degree of apoptosis in tumor and benign prostatic epithelium in clinically localized PCa. Vitamin D may have secondary chemoprevention benefits in preventing PCa progression in localized disease.

Native American Ancestry is associated with lower risk of Alzheimer’s Disease: results from the Genetic of Alzheimer’s disease in Peruvian Populations (GAPP) study.

AbstractBackgroundAlzheimer’s Disease Related Dementias (ADRD) is not equally distributed among racial and ethnic groups. The APOE‐ɛ4 allele alone does not explain the different frequency of the disease. In fact, Hispanics (HI) and African Americans e4 non‐carriers still show a two‐to‐four‐fold higher incidence of ADRD, compared with non‐Hispanic Whites. Ancestry is an understudied yet a critical aspect of health disparities, as it may explain observed differences in frequency of ADRD across ethnic groups. We recently launched a genetic study in Peruvians, whose genome is characterized by large Native‐American ancestry proportions (higher than other HI populations such as Caribbean Hispanics or Mexicans), and studied the association between Ancestry, APOE‐e4 and ADRD.MethodWe recruited 264 Peruvians across three main sites in Peru (Lima, Arequipa, Puno). Genotyping was conducted on GSA Illumina platform, and, after QC, global ancestries (Native American [NAT], European [EUR], African [AFR]) were estimated using the Human Genome Diversity Project as reference (Figure 1). Number of APOE‐e4 alleles were entered as predictor along with proportion of global ancestries in regression models, adjusting for age, sex and education. AD status was employed as main outcome; episodic memory scores were used as secondary outcomes in healthy controls.Result51 were diagnosed with AD, 213 were healthy controls (mean age 72 years old). Average ancestry was estimated to be 73.0% NAT, 23.8% EUR, 3.2% AFR. APOE‐e4 was found associated with AD (OR [95%CI] = 4.09 [1.98‐8.47], p&lt;0.001). NAT ancestry proportion was found protective at trend in the whole cohort (OR = 0.73[0.50‐1.06], p = 0.096). When restricted to e4 non‐carriers, NAT ancestry was found significantly associated with lower AD risk (OR = 0.57[0.36‐0.91], p = 0.019). Consistently, higher NAT ancestry was associated with better episodic memory scores in healthy controls (e.g. delayed recall: betastandardized = 0.26, p&lt;0.001).ConclusionTo our knowledge, this is the largest collection of individuals with predominant Native American ancestry showing protective effect towards ADRD. This is particularly evident in those individuals not carrying the APOE‐e4 allele. APOE is confirmed as strong risk factor for ADRD (larger than other HI populations).

Collection of genetic data in ethnic‐based studies across Aymaras, Quechuas and Mestizos: the challenges of the Genetics of Alzheimer’s in Peruvian Population (GAPP) study

AbstractBackgroundThe Genetics of Alzheimer’s Disease in Peruvian Population (GAPP) study aims to investigate genetic and environmental risk factors for Alzheimer’s Disease (AD) in Peru. The project is led by Columbia University (CU, New York, US) and the Instituto Peruano de Neurociencias (IPN, Lima, Peru). For the past year and a half, despite the ongoing COVID‐19 pandemic, the study has collected data on cognitive function, health, diet and numerous clinical and biological risk factors for AD. In addition, we collected blood samples for DNA extraction as well as serum and plasma to look at core AD biomarkers.MethodRecruitment prioritized populations from south Peru, the Quechuas and Aymaras, because of their high proportion of Native American ancestry (or, in other words, low admixture with European ancestry) as well as Mestizo (mixed Native‐European ancestry). Three recruitment sites were established in Lima, Puno and Arequipa. Interviewers were trained to clinically and cognitively assessed the participants and collect and ship blood samples to the main site (IPN). DNA samples were then sent to CU for processing. Serum and plasma samples were processed in Lima and stored at ‐80C for batch shipping to CU. DNA samples were sent to CD Genomics and Children’s Hospital of Philadelphia for APOE genotyping and GWAS, respectively.ResultA database with 350 participants has been created. Blood samples from all participants were collected; 268 successfully underwent GWAS and APOE genotyping. An additional 82 samples are pending QC and genotyping. No samples were dropped at extraction, and only 0.7% failed DNA quality standards for genotyping.ConclusionSample collections for genetic studies in South American indigenous populations such as Peru represent important logistic challenges. The use of blood as a main source of DNA provides an effective and reliable source for genetic data analysis. Plasma and serum biomarkers will provide additional insights into the disease manifestations and validation of the clinical diagnosis in these underrepresented populations. Ongoing recruitment will augment the analytical power of the cohort by collecting blood, serum and plasma samples from additional GAPP participants.

Unraveling Signatures of Local Adaptation among Indigenous Groups from Mexico.

Few studies have addressed how selective pressures have shaped the genetic structure of the current Native American populations, and they have mostly limited their inferences to admixed Latin American populations. Here, we searched for local adaptation signals, based on integrated haplotype scores and population branch statistics, in 325 Mexican Indigenous individuals with at least 99% Native American ancestry from five previously defined geographical regions. Although each region exhibited its own local adaptation profile, only PPARG and AJAP1, both negative regulators of the Wnt/β catenin signaling pathway, showed significant adaptation signals in all the tested regions. Several signals were found, mainly in the genes related to the metabolic processes and immune response. A pathway enrichment analysis revealed the overrepresentation of selected genes related to several biological phenotypes/conditions, such as the immune response and metabolic pathways, in agreement with previous studies, suggesting that immunological and metabolic pressures are major drivers of human adaptation. Genes related to the gut microbiome measurements were overrepresented in all the regions, highlighting the importance of studying how humans have coevolved with the microbial communities that colonize them. Our results provide a further explanation of the human evolutionary history in response to environmental pressures in this region.

Social injustice unveiled by genetic analysis: Argentina as a case study.

The population of the American countries is genetically heterogeneous, whose genesis result from of recent admixture events. In this process, the transoceanic European component displaced the original inhabitants of the continent. To investigate whether socially differentiated cohorts exhibit underlying ancestry components within an urban admixed population, two cohorts of individuals inhabiting Argentina were studied. One cohort included genetically unrelated individuals involved in voluntary paternity testing while the other included sexual or blood-crime suspects. We analyzed over 2500 unrelated individuals: four Native American maternal lineage mtDNA markers in 1024 samples, five Y chromosome haplogroups in 658 male samples, 24 autosomal ancestry informative markers (AIMs) in 205 samples, and 15 autosomal short tandem repeats (STRs) in 1557 samples; countrywide and divided by regions. While our results confirm a tricontinental ethnic contribution to both cohorts, their proportions showed statistically significant differences, with a higher proportion of Native American ancestry in the cohort linked to violent crimes compared to those in paternity testing. This hallmark was observed with all the marker sets used and at various levels of analysis. Since paternity tests are costly, socio-economic differences might help to interpret our observations. The effect of discrimination against descendants of Native American minorities, and exposure to violent social environments, might link marginal groups to criminality. Our findings underscore the relevance of proper social management since only by improving living conditions, reducing discrimination, promoting education, and providing job opportunities will it be possible to attain equality in a heterogeneous society. Genetic markers proved to be highly informative in unveiling unexpected social differences.

Altered B cell phenotype and CD27+ memory B cells are associated with clinical features and environmental exposure in Colombian systemic lupus erythematosus patients

BackgroundB lymphocytes are dysregulated in Systemic Lupus Erythematosus (SLE) including the expansion of extrafollicular B cells in patients with SLE of African American ancestry, which is associated with disease activity and nephritis. The population of Colombia has a mixture of European, Native American, and African ancestry. It is not known if Colombian patients have the same B cell distributions described previously and if they are associated with disease activity, clinical manifestations, and environmental exposures.ObjectiveTo characterize B cell phenotype in a group of Colombian Systemic Lupus Erythematosus patients with mixed ancestry and determine possible associations with disease activity, clinical manifestations, the DNA methylation status of the IFI44L gene and environmental exposures.Materials and methodsForty SLE patients and 17 healthy controls were recruited. Cryopreserved peripheral B lymphocytes were analyzed by multiparameter flow cytometry, and the DNA methylation status of the gene IFI44L was evaluated in resting Naive B cells (rNAV).ResultsExtrafollicular active Naive (aNAV) and Double Negative type 2, DN2 (CD27− IgD− CD21− CD11c+) B cells were expanded in severe active patients and were associated with nephritis. Patients had hypomethylation of the IFI44L gene in rNAV cells. Regarding environmental exposure, patients occupationally exposed to organic solvents had increased memory CD27+ cells (SWM).ConclusionaNAV and DN2 extrafollicular cells showed significant clinical associations in Colombian SLE patients, suggesting a relevant role in the disease’s pathophysiology. Hypomethylation of the IFI44L gene in resting Naive B cells suggests that epigenetic changes are established at exceedingly early stages of B cell ontogeny. Also, an alteration in SWM memory cells was observed for the first time in patients exposed to organic solvents. This opens different clinical and basic research possibilities to corroborate these findings and deepen the knowledge of the relationship between environmental exposure and SLE.

HLA molecular study of patients in a public kidney transplant program in Guatemala

Guatemala is a country located in Central America, and while it is one of the most populated countries in the region, the genetic diversity of the population has been poorly analyzed. Currently, there are no analyses of the distribution of human leukocyte antigen (HLA) system alleles in mixed ancestry (i.e., ladino) populations in Guatemala. The HLA system exhibits the most extensive polymorphism in the human genome and has been extensively analyzed in a large number of studies related to disease association, transplantation, and population genetics (with particular importance in the understanding of diversity in the human population). Here, we present HLA typing data from 127 samples of unrelated individuals from the kidney transplant program of the San Juan de Dios General Hospital (Guatemala City) using a PCR-SSOP-based (PCR-sequence specific oligonucleotide probes) typing method. We found 16 haplotypes that accounted for 39.76 % of the total haplotype diversity, of which thirteen have been reported previously in Native American populations and three have been reported in European populations. The analyses showed no deviations from Hardy-Weinberg equilibrium, and admixture estimates calculated with k = 3 ancestral components showed that Native American was the most represented component, followed by the European component. The African component was less prominent in the Guatemala mixed ancestry sample in comparison to samples from other countries in Central America. The HLA-based admixture results for Central America showed a continuum in the distribution of Native American, European and African ancestries throughout the region, which is consistent with the complex demographic history of the region.

Case Series of Patients With Hereditary Benign Intraepithelial Dyskeratosis.

The purpose of this retrospective case series was to compare the outcomes of different treatment options for patients diagnosed with hereditary benign intraepithelial dyskeratosis (HBID). The study is designed as a single-institution retrospective chart review of patients who were clinically diagnosed with HBID during their care at the Duke Eye Center. Patient demographics were obtained, and disease course after different therapies was analyzed. Seventeen patients were diagnosed with HBID. 52.9% (9/17) of patients identified with HBID reported Native American ancestry. Medical therapy alone failed to reduce the size or number of corneal lesions in any patient identified in this study. Ten of the 17 patients required surgical intervention. Two eyes received corneal biopsies, 3 eyes received a full conjunctival lesion excision with amniotic membrane grafting, 12 eyes received superficial keratectomy with amniotic membrane grafting, and 1 eye received keratoprosthesis. Lesion recurrence was seen in 9 of the 10 patients treated with surgical excision with an average time to recurrence of 1.5 and 2 months for conjunctival excisions and superficial keratectomy, respectively, when excluding patients who missed scheduled postoperative follow-up appointments. Hereditary benign intraepithelial dyskeratosis is a rare and poorly understood disorder that predominantly affects people with Native American ancestry. Medical therapy only provides symptomatic relief, and patients who receive surgical excision almost always develop recurrence. As a result, we recommend future investigations focus on identifying the optimal surgical technique and timing to limit the morbidity of HBID and improve outcomes.

The Obfuscation of Native American Presence in the French Atlantic: Natchez Indians in Saint Domingue, 1731–1791

AbstractIn 1731 a French army in colonial Louisiana enslaved hundreds of Natchez families and shipped them to Saint-Domingue where they mostly disappear from the written records. This article analyzes tantalizing clues about Natchez families and other Native American slaves on the island during the eighteenth century. By examining slave runaway advertisements, rather than the official records of colonial administrators, it becomes clear that there were hundreds, if not thousands of slaves with Native American ancestry in Saint-Domingue by 1791. Neither the violence of slavery nor the violence of the archive itself can erase the tenacious survival of Natchez people and other Native Americans on the island. In addition to theorizing about the experiences of Natchez slaves, this article suggests that historians can no longer discount the contributions and experiences of Native American people to the history of Saint-Domingue and to the creation of Haiti.

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations.

Dihydropyrimidine dehydrogenase is one of the main pharmacological metabolizers of fluoropyrimidines, a group of drugs widely used in clinical oncology. Around 20 to 30% of patients treated with fluoropyrimidines experience severe toxicity caused by a partial or total decrease in enzymatic activity. This decrease is due to molecular variants in the DPYD gene. Their prevalence and allelic frequencies vary considerably worldwide, so their description in heterogeneous groups such as the Ecuadorian population will allow for the description of pharmacogenetic variants and proper characterization of this population. Thus, we genotyped all the molecular variants with a predictive value for DPYD in a total of 410 Ecuadorian individuals belonging to Mestizo, Afro-Ecuadorian, and Indigenous ethnic groups. Moreover, we developed a genetic ancestry analysis using 46 autosomal ancestry informative markers. We determined 20 genetic variations in 5 amplified regions, including 3 novel single nucleotide variants. The allele frequencies for DPYD variants c.1627G>A (*5, rs1801159), c.1129-15T>C (rs56293913), c.1218G>A (rs61622928), rs1337752, rs141050810, rs2786783, rs2811178, and g.97450142G>A (chr1, GRCh38.p13) are significantly related to Native American and African ancestry proportions. In addition, the FST calculated from these variants demonstrates the closeness between Indigenous and Mestizo populations, and evidences genetic divergence between Afro-Ecuadorian groups when compared with Mestizo and Indigenous ethnic groups. In conclusion, the genetic variability in the DPYD gene is related to the genetic component of ancestral populations in different Ecuadorian ethnic groups. The absence and low frequency of variants with predictive value for fluoropyrimidine toxicity such as DPYD *2A, HapB3, and c.2846A>T (prevalent in populations with European ancestry) is consistent with the genetic background found.