Native Americans from the Amazon, Andes, and coastal geographic regions of South America have a rich cultural heritage but are genetically understudied, therefore leading to gaps in our knowledge of ...their genomic architecture and demographic history. In this study, we sequence 150 genomes to high coverage combined with an additional 130 genotype array samples from Native American and mestizo populations in Peru. The majority of our samples possess greater than 90% Native American ancestry, which makes this the most extensive Native American sequencing project to date. Demographic modeling reveals that the peopling of Peru began ∼12,000 y ago, consistent with the hypothesis of the rapid peopling of the Americas and Peruvian archeological data. We find that the Native American populations possess distinct ancestral divisions, whereas the mestizo groups were admixtures of multiple Native American communities that occurred before and during the Inca Empire and Spanish rule. In addition, the mestizo communities also show Spanish introgression largely following Peruvian Independence, nearly 300 y after Spain conquered Peru. Further, we estimate migration events between Peruvian populations from all three geographic regions with the majority of between-region migration moving from the high Andes to the low-altitude Amazon and coast. As such, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern-day Peruvians and a Native American ancestry dataset that will serve as a beneficial resource to addressing the underrepresentation of Native American ancestry in sequencing studies.
In Peru, 29 292 people were diagnosed with tuberculosis in 2022. Although tuberculosis treatments are effective, 3.4%–13% are associated with significant adverse drug reactions, with drug‐induced ...liver injury (DILI) considered the most predominant. Among the first‐line antituberculosis drugs, isoniazid is the main drug responsible for the appearance of DILI. In liver, isoniazid (INH) is metabolized by N‐acetyltransferase‐2 (NAT2) and cytochrome P450 2E1 (CYP2E1). Limited information exists on genetic risk factors associated with the presence of DILI to antituberculosis drugs in Latin America, and even less is known about these factors in the native and mestizo Peruvian population. The aim of this study was to determine the prevalence of NAT2 and CYP2E1 genotypes in native and mestizo population. An analytical cross‐sectional analysis was performed using genetic data from mestizo population in Lima and native participants from south of Peru. NAT2 metabolizer was determined as fast, intermediate and slow, and CYP2E1 genotypes were classified as c1/c1, c1/c2 and c2/c2, from molecular tests and bioinformatic analyses. Of the 472 participants, 36 and 6 NAT2 haplotypes were identified in the mestizo and native population, respectively. In mestizo population, the most frequent NAT2*5B and NAT2*7B haplotypes were associated with DILI risk; while in natives, NAT2*5G and NAT2*13A haplotypes were associated with decreased risk of DILI. For CYP2E1, c1/c1 and c1/c2 genotypes are the most frequent in natives and mestizos, respectively. The linkage disequilibrium of NAT2 single nucleotide polymorphisms (SNPs) was estimated, detecting a block between all SNPs natives. In addition, a block between rs1801280 and rs1799929 for NAT2 was detected in mestizos. Despite the limitations of a secondary study, it was possible to report associations between NAT2 and CYP2E alleles with Peruvian native and mestizo by prevalence ratios. The results of this study will help the development of new therapeutic strategies for a Tuberculosis efficient control between populations.
Linkage disequilibrium for SNPs associated with metabolizer NAT2. (A) mestizo population (B) native population.
As whole-genome sequencing (WGS) becomes the gold standard tool for studying population genomics and medical applications, data on diverse non-European and admixed individuals are still scarce. Here, ...we present a high-coverage WGS dataset of 1,171 highly admixed elderly Brazilians from a census-based cohort, providing over 76 million variants, of which ~2 million are absent from large public databases. WGS enables identification of ~2,000 previously undescribed mobile element insertions without previous description, nearly 5 Mb of genomic segments absent from the human genome reference, and over 140 alleles from HLA genes absent from public resources. We reclassify and curate pathogenicity assertions for nearly four hundred variants in genes associated with dominantly-inherited Mendelian disorders and calculate the incidence for selected recessive disorders, demonstrating the clinical usefulness of the present study. Finally, we observe that whole-genome and HLA imputation could be significantly improved compared to available datasets since rare variation represents the largest proportion of input from WGS. These results demonstrate that even smaller sample sizes of underrepresented populations bring relevant data for genomic studies, especially when exploring analyses allowed only by WGS.
While South Americans are underrepresented in human genomic diversity studies, Brazil has been a classical model for population genetics studies on admixture. We present the results of the EPIGEN ...Brazil Initiative, the most comprehensive up-to-date genomic analysis of any Latin-American population. A population-based genome-wide analysis of 6,487 individuals was performed in the context of worldwide genomic diversity to elucidate how ancestry, kinship, and inbreeding interact in three populations with different histories from the Northeast (African ancestry: 50%), Southeast, and South (both with European ancestry >70%) of Brazil. We showed that ancestry-positive assortative mating permeated Brazilian history. We traced European ancestry in the Southeast/South to a wider European/Middle Eastern region with respect to the Northeast, where ancestry seems restricted to Iberia. By developing an approximate Bayesian computation framework, we infer more recent European immigration to the Southeast/South than to the Northeast. Also, the observed low Native-American ancestry (6–8%) was mostly introduced in different regions of Brazil soon after the European Conquest. We broadened our understanding of the African diaspora, the major destination of which was Brazil, by revealing that Brazilians display two within-Africa ancestry components: one associated with non-Bantu/western Africans (more evident in the Northeast and African Americans) and one associated with Bantu/eastern Africans (more present in the Southeast/South). Furthermore, the whole-genome analysis of 30 individuals (42-fold deep coverage) shows that continental admixture rather than local post-Columbian history is the main and complex determinant of the individual amount of deleterious genotypes.
To determine whether polymorphisms of the IL10 and IL17 genes are associated with severe asthma control and bronchodilator reversibility in children and adolescents with severe asthma.
This was a ...cross-sectional study, nested within a prospective cohort study of patients with severe asthma. Two outcomes were evaluated: asthma control and bronchodilator reversibility. We extracted DNA from peripheral blood and genotyped three single nucleotide polymorphisms: rs3819024 and rs2275913 in the IL17A gene; and rs3024498 in the IL10 gene. For the association analyses, we performed logistic regression in three genetic models (allelic, additive, and dominant).
The rs3024498 C allele in the IL10 gene was associated with failure to achieve asthma control despite regular treatment (p = 0.02). However, the G allele of the IL17A rs3819024 polymorphism was associated with failure to respond to stimulation with a b2 agonist. The rs2275913 polymorphism of the IL17A gene showed no relationship with asthma control or bronchodilator reversibility.
In pediatric patients with severe asthma, the IL10 polymorphism appears to be associated with failure to achieve clinical control, whereas the IL17A polymorphism appears to be associated with a worse bronchodilator response. Knowledge of the involvement of these polymorphisms opens future directions for pharmacogenetic studies and for the implementation of individualized therapeutic management of severe asthma in pediatric patients.
Background
In Peru, 32,970 people were diagnosed with tuberculosis (TB) in 2019. Although TB treatment is effective, 3.4%–13% is associated with significant adverse drug reactions (ADR), considering ...drug‐induced liver injury (DILI) as the most prevalent. Among the first‐line anti‐TB drugs, isoniazid (INH) is primarily responsible for the occurrence of DILI. INH is metabolized in the liver by the enzymes N‐acetyltransferase‐2 (NAT2) and Cytochrome P450 2E1 (CYP2E1). Based on the previous studies, we hypothesized that the interactions between slow CYP2E1 genotype and NAT2 slow acetylators will induce DILI in TB patients.
Methods
In this cross‐sectional study, all 377 participants completed their anti‐TB treatment, and we genotyped SNPs: rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2 and rs3813867 and rs2031920 for CYP2E1.
Results
We found that rapid, intermediate, and slow NAT2 acetylator were 15%, 38%, and 47%, respectively, in the general population. Intermediate NAT2 acetylator is the least prevalent among patients with adverse reactions (p = 0.024). We did not confirm our hypothesis, however, we found that the combination of intermediate NAT2 acetylators and CYP2E1 c1/c1 genotype significantly protected (OR = 0.16; p = 0.049) against the development of DILI in our population.
Conclusion
We propose that the presence of NAT2 intermediate and CYP2E1 c1/c1 genotype could help in therapeutic drug monitoring, and optimize its therapeutic benefits while minimizing its risk for side effects or toxicity.
According to our results, the combination of the NAT2 polymorphism associated with the intermediate phenotype and the CYP2E1 C1/C1 genotype associated with the slow phenotype does not affect the therapeutic response and is suspected to be a protective factor against INH‐induced hepatotoxicity in Peruvian tuberculosis patients.
Objectives
To investigate the association between African and Native American genomic ancestry and long‐term cognitive trajectories in admixed Brazilians.
Design
Population‐based longitudinal study.
...Setting
Bambui‐Epigen (Brazil) cohort study.
Participants
Adults aged 60 and older (N=1,215)
Measurements
Participants were followed from January 1997 to December 2011. Cognitive function was assessed annually using the Mini‐Mental State Examination (MMSE), totaling 12,208 measurements. We used linear mixed‐effects pattern models to assess MMSE score trajectories. Ancestry was assessed using a genome‐wide approach.
Results
After adjustments for covariates, the highest quintile of African ancestry was associated with poorer baseline cognitive performance (β=–0.73, 95% confidence interval (CI)=–1.36 to –0.11) but not with cognitive trajectory. Educational level modified the baseline association between highest African ancestry and cognitive performance in that the association was observed only in those with very low (<4 years) education (β=–1.13, 95% CI=–2.02 to –0.23). No association was found between Native American ancestry and baseline cognitive function or its trajectory.
Conclusion
Genomic African and Native American ancestry levels had no prognostic value for age‐related cognitive decline in this admixed population.
In Peru, 24,581 people were diagnosed with tuberculosis (TB) in 2020. Although TB treatments are effective, 3.4–13% are associated with significant adverse drug reactions (ADRs), with drug-induced ...liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid (INH) is the main drug responsible for the appearance of DILI. In the liver, INH is metabolized by the enzymes N-acetyltransferase-2 (NAT2), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase (GST) with two isoforms, GSTT1 and GSTM1. Based on previous studies, we hypothesized that interactions between the GSTT1 and GSTM1 null genotypes induce DILI in TB patients. In this cross-sectional study of 377 participants who completed their anti-TB treatment, we genotyped by revealing the presence or absence of 215- and 480-bp bands of GSTM1 and GSTT1, respectively. We found that the prevalence of the GSTM1 genotype was 52.79% and 47.21% for presence and null, respectively, and for GSTT1 it was 69.76% and 30.24% for presence and null, respectively. Neither genotype was prevalent in the patients who developed DILI (n = 16). We did not confirm our hypothesis; however, we found that the combination of GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype had a significant risk for the development of ADR (OR 11; p = 0.017; 95% CI: (0.54–186.35)). We propose that the presence of the GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype in the Peruvian population could be considered a risk factor for the development of ADR due to therapeutic drug intake.
Human Leukocyte Antigen (HLA)-G participates in several biological processes, including reproduction, vascular remodeling, immune tolerance, and hypoxia response. HLA-G is a potential candidate gene ...for high altitude adaptation since its expression is modulated in both micro and macro environment under hypoxia and constant cellular stress. Besides the promoter region, the HLA-G 3′untranslated region (UTR) influences HLA-G expression patterns through several post-transcriptional mechanisms. Currently, the 3′UTR genetic diversity in terms of altitude adaptation of Native American populations is still unexplored, particularly at high altitude ecoregions. Here, we evaluated 288 Native Americans from 9 communities located in the Andes highland (HL); ≥2,500 m (range = 2,838–4,433 m) and 8 populations located in lowland (LL) regions <2,500 m (range = 80–431 m); Amazonian tropical forest, Brazilian central plateau, and Chaco of South America. In total, nine polymorphic sites and ten haplotypes were observed. The most frequent haplotypes (UTR-1, UTR-2, and UTR-3) accounted for ∼ 77% of haplotypes found in LL, while in the HL, the same haplotypes reach ∼ 93%. Also, a remarkable high frequency of putative ancestral UTR-5 haplotype was observed in LL (21.5%), while in HL UTR-2 reaches up to 47%. Further, UTR-2 frequency positively correlates with altitude-related variables, while a negative correlation for UTR-5 was observed. From an evolutionary perspective, we observed a tendency towards balancing selection in HL and LL populations thus suggesting that haplotypes of ancient and more derived alleles may have been co-opted for relatively recent adaptations such as those experienced by modern humans in the highland and lowland of South America. We also discuss how long-term balancing selection can be a reservoir of genetic variants that can be positively selected. Finally, our study provides some pieces of evidence that HLA-G 3′UTR haplotypes may have contributed to high altitude adaptation in the Andes.
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