A positively selected FBN1 missense variant reduces height in Peruvian individuals.

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.

The genetic structure and adaptation of Andean highlanders and Amazonians are influenced by the interplay between geography and culture.

Western South America was one of the worldwide cradles of civilization. The well-known Inca Empire was the tip of the iceberg of an evolutionary process that started 11,000 to 14,000 years ago. Genetic data from 18 Peruvian populations reveal the following: 1) The between-population homogenization of the central southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes, and Amazonia accompanied cultural and socioeconomic interactions revealed by archeology. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower, and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia. 2) The genetic homogenization between the populations of the arid Andes is not only due to migrations during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the Wari Empire (600 to 1,000 years before present). 3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, a putative enhancer in HAND2-AS1 (heart and neural crest derivatives expressed 2 antisense RNA1, a noncoding gene related to cardiovascular function) and rs269868-C/Ser1067 in DUOX2 (dual oxidase 2, related to thyroid function and innate immunity) genes and, in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T and B lymphocytes in viral-host interaction.

GSTT1/GSTM1 Genotype and Anti-Tuberculosis Drug-Induced Hepatotoxicity in Peruvian Patients.

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.

Origins, Admixture Dynamics, and Homogenization of the African Gene Pool in the Americas.

The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed a genome-wide analysis using 6,267 individuals from 25 populations to infer how different African groups contributed to North-, South-American, and Caribbean populations, in the context of geographic and geopolitical factors, and compared genetic data with demographic history records of the Transatlantic Slave Trade. We observed that West-Central Africa and Western Africa-associated ancestry clusters are more prevalent in northern latitudes of the Americas, whereas the South/East Africa-associated ancestry cluster is more prevalent in southern latitudes of the Americas. This pattern results from geographic and geopolitical factors leading to population differentiation. However, there is a substantial decrease in the between-population differentiation of the African gene pool within the Americas, when compared with the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This between-population homogenization in the Americas is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the United States and Southeast-Brazil, with respect to historical-demography expectations. We also inferred that in most of the Americas, intercontinental admixture intensification occurred between 1750 and 1850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural, and political debate regarding ancestry, admixture, and the mestizaje process in the Americas.

Biased pathogenic assertions of loss of function variants challenge molecular diagnosis of admixed individuals.

Diagnosis of individuals affected by monogenic disorders was significantly improved by next-generation sequencing targeting clinically relevant genes. Whole exomes yield a large number of variants that require several filtering steps, prioritization, and pathogenicity classification. Among the criteria recommended by ACMG, those that rely on population databases critically affect analyses of individuals with underrepresented ancestries. Population-specific allelic frequencies need consideration when characterizing potential deleteriousness of variants. An orthogonal input for classification is annotation of variants previously classified as pathogenic as a criterion that provide supporting evidence widely sourced at ClinVar. We used a whole-genome dataset from a census-based cohort of 1,171 elderly individuals from São Paulo, Brazil, highly admixed, and unaffected by severe monogenic disorders, to investigate if pathogenic assertions in ClinVar are enriched with higher proportions of European ancestry, indicating bias. Potential loss of function (pLOF) variants were filtered from 4,250 genes associated with Mendelian disorders and annotated with ClinVar assertions. Over 1,800 single nucleotide pLOF variants were included, 381 had non-benign assertions. Among carriers (N = 463), average European ancestry was significantly higher than noncarriers (N = 708; p = .011). pLOFs in genomic contexts of non-European local ancestries were nearly three times less likely to have any ClinVar entry (OR = 0.353; p <.0001). Independent pathogenicity assertions are useful for variant classification in molecular diagnosis. However, European overrepresentation of assertions can promote distortions when classifying variants in non-European individuals, even in admixed samples with a relatively high proportion of European ancestry. The investigation and deposit of clinically relevant findings of diverse populations is fundamental improve this scenario.

Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes.

BACKGROUND/OBJECTIVES: Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil. SUBJECTS/METHODS: Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European, and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of body mass index (BMI) in three Brazilian population-based cohorts from Northeast (Salvador), Southeast (Bambuí), and South (Pelotas). RESULTS: We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p = 2.76e-06). This variant is rare in Europeans but with frequencies of ~3% in West Africa and has a strong female-specific effect (95% CI: 2.32-5.65 kg/m2 per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from São Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains ~9% among women with morbid obesity from Pelotas, São Paulo, and Bambuí. The effect size of rs114066381 is at least five times higher than the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects. CONCLUSIONS: We identified six candidate SNPs associated with BMI. rs114066381 stands out for its high effect that was replicated and its high frequency in women with morbid obesity. We demonstrate how admixed populations are a source of new relevant phenotype-associated genetic variants.

Evolutionary genomic dynamics of Peruvians before, during, and after the Inca Empire.

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.

Human-SARS-CoV-2 interactome and human genetic diversity: TMPRSS2-rs2070788, associated with severe influenza, and its population genetics caveats in Native Americans.

For human/SARS-CoV-2 interactome genes ACE2, TMPRSS2 and BSG, there is a convincing evidence of association in Asians with influenza-induced SARS for TMPRSS2-rs2070788, tag-SNP of the eQTL rs383510. This case illustrates the importance of population genetics and of sequencing data in the design of genetic association studies in different human populations: the high linkage disequilibrium (LD) between rs2070788 and rs383510 is Asian-specific. Leveraging on a combination of genotyping and sequencing data for Native Americans (neglected in genetic studies), we show that while their frequencies of the Asian tag-SNP rs2070788 is, surprisingly, the highest worldwide, it is not in LD with the eQTL rs383510, that therefore, should be directly genotyped in genetic association studies of SARS in populations with Native American ancestry.

An Isolated TCR αß Restricted by HLA-A*02:01/CT37 Peptide Redirecting CD8+ T Cells To Kill and Secrete IFN-γ in Response to Lung Adenocarcinoma Cell Lines.

Lung cancer is a leading cause of cancer-related death among both men and women in the United States, where non-small cell lung cancer accounts for ∼85% of lung cancer. Lung adenocarcinoma (ADC) is the major histologic subtype. The presence of actionable mutations prompts the use of therapies designed to specifically address the deleterious effects of those cancer-driving mutations; these therapies have already shown promise in cases carrying those actionable mutations (∼30%). Innovative therapeutic approaches are needed for the treatment of 70% of patients suffering from lung ADC. Adoptive transfer of CD8+ T cells specific against cancer/testis (CT) Ags, whose protein expression is restricted to the gonads (testis and ovary) and cancerous cells, is an excellent alternative. In this study, we report the isolation of HLA-A*02:01/CT37 peptide-specific α and ß TCR chains from a CD8+ T cell clone obtained from a patient suffering from lung ADC. We also report the development of an innovative CD3ζ construct. With those TCR chains and the engineered (modified) CD3ζ chain, we produced a construct that when transduced into CD8+ T cells is capable of redirecting transduced CD8+ T cell cytotoxic activity and IFN-γ secretion against peptide-pulsed autologous cells and HLA-A*02:01-positive and CT37-expressing lung ADC cell lines. Our findings will launch the development of innovative adoptive transfer immunotherapies for the treatment of lung ADC, targeting the most prevalent HLA molecules and CT37 peptides restricted by these molecules.

High-resolution melting analysis for molecular detection of multidrug resistance tuberculosis in Peruvian isolates.

BACKGROUND: The emergence of multidrug-resistant strains is a major health problem especially for countries with high TB incidence such as Peru. In this study, we evaluated High Resolution Melting (HRM) assay in Peruvian isolates for the detection of mutations within rpoB, katG genes and promoter region inhA to determine isoniazid and rifampicin resistance in Mycobacterium tuberculosis (Mtb). METHODS: DNA samples extracted from a total of 167 clinical isolates of Mtb, 89 drug-sensitive and 78 multidrug-resistant, were blindly analyzed by HRM analysis and verified by DNA sequencing. RESULTS: The HRM analysis generated patterns that were specific to distinguish between sensitive and resistance isolates. The sensitivity and specificity of the HRM assays in comparison with drug susceptibility testing (DST) for detection of rifampicin resistance were 98.7 % and 97.5 %, and for isoniazid resistance were 98.7 % and 100 %. CONCLUSION: This study suggests that HRM Analysis could help with rapid diagnosis of MDR-TB cases in Peru.

Effect of isoniazid on antigen-specific interferon-γ secretion in latent tuberculosis.

Treatment of persons with latent tuberculosis (TB) infection at greatest risk of reactivation is an important component of TB control and elimination strategies. Biomarkers evaluating the effectiveness of treatment of latent TB infection have not yet been identified. This information would enhance control efforts and assist the evaluation of new treatment regimes. We designed a two-group, two-arm, randomised clinical study of tuberculin skin test-positive participants: 26 with documented contact with TB patients and 34 with non-documented contact. Participants in each group were randomly assigned to the immediate- or deferred-isoniazid treatment arms. Assays of in vitro interferon (IFN)-γ secretion in response to recombinant Rv1737 and overlapping synthetic peptide pools from various groups of immunodominant proteins were performed. During isoniazid therapy, a significant increase from baseline in the proportion of IFN-γ responders to the 10-kDa culture filtrate protein, Rv2031, Rv0849, Rv1986, Rv2659c, Rv2693c and the recombinant Rv1737 protein was observed (p⩽0.05). The peptide pool of Rv0849 and Rv1737 recombinant proteins induced the highest percentage of IFN-γ responders after isoniazid therapy. The in vitro IFN-γ responses to these proteins might represent useful markers to evaluate changes associated with treatment of latent TB infection.

Genetic association meta-analysis: a new classification to assess ethnicity using the association of MCP-1 -2518 polymorphism and tuberculosis susceptibility as a model.

BACKGROUND: In meta-analyses of genetic association studies, ancestry and ethnicity are not accurately investigated. Ethnicity is usually classified using conventional race/ethnic categories or continental groupings even though they could introduce bias increasing heterogeneity between and within studies; thus decreasing the external validity of the results. In this study, we performed a meta-analysis using a novel ethnic classification system to test the association between MCP-1 -2518 polymorphism and pulmonary tuberculosis. Our new classification considers genetic distance, migration and linguistic origins, which will increase homogeneity within ethnic groups. METHODS: We included thirteen studies from three continents (Asia, Africa and Latin America) and considered seven ethnic groups (West Africa, South Africa, Saharan Africa, East Asia, South Asia, Persia and Latin America). RESULTS: The results were compared to the continental group classification. We found a significant association between MCP-1 -2518 polymorphism and TB susceptibility only in the East Asian and Latin American groups (OR 3.47, P = 0.08; OR 2.73, P = 0.02). This association is not observed in other ethnic groups that are usually considered in the Asian group, such as India and Persia, or in the African group. CONCLUSIONS: There is an association between MCP-1 -2518 polymorphism and TB susceptibility only in the East Asian and Latin American groups. We suggest the use of our new ethnic classification in future meta-analysis of genetic association studies when ancestry markers are not available. This new classification increases homogeneity for certain ethnic groups compared to the continental classification. We recommend considering previous data about migration, linguistics and genetic distance when classifying ethnicity in further studies.

Bioinformatic and empirical analysis of novel hypoxia-inducible targets of the human antituberculosis T cell response.

We analyzed whole genome-based transcriptional profiles of Mycobacterium tuberculosis subjected to prolonged hypoxia to guide the discovery of novel potential Ags, by a combined bioinformatic and empirical approach. We analyzed the fold induction of the 100 most highly induced genes at 7 d of hypoxia, as well as transcript abundance, peptide-binding prediction (ProPred) adjusted for population-specific MHC class II allele frequency, and by literature search. Twenty-six candidate genes were selected by this bioinformatic approach and evaluated empirically using IFN-γ and IL-2 ELISPOT using immunodominant Ags (Acr-1, CFP-10, ESAT-6) as references. Twenty-three of twenty-six proteins induced an IFN-γ response in PBMCs of persons with active or latent tuberculosis. Five novel immunodominant proteins-Rv1957, Rv1954c, Rv1955, Rv2022c, and Rv1471-were identified that induced responses similar to CFP-10 and ESAT-6 in both magnitude and frequency. IL-2 responses were of lower magnitude than were those of IFN-γ. Only moderate evidence of infection stage-specific recognition of Ags was observed. Reconciliation of bioinformatic and empirical hierarchies of immunodominance revealed that Ags could be predicted, providing transcriptomic data were combined with peptide-binding prediction adjusted by population-specific MHC class II allele frequency.

Pharmacogenetic variability of tuberculosis biomarkers in native and mestizo Peruvian populations.

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.

Antigen-Induced IL-1RA Production Discriminates Active and Latent Tuberculosis Infection.

The IGRA (Interferon Gamma Release Assays) test is currently the standard specific test for Mycobacterium tuberculosis infection status. However, a positive test cannot distinguish between active tuberculosis disease (ATBD) and latent tuberculosis infection (LTBI). Developing a test with this characteristic is needed. We conducted longitudinal studies to identify a combination of antigen peptides and cytokines to discriminate between ATBD and LTBI. We studied 54 patients with ATBD disease and 51 with LTBI infection. Cell culture supernatant from cells stimulated with overlapping Mycobacterium tuberculosis novel peptides and 40 cytokines/chemokines were analyzed using the Luminex technology. To summarize longitudinal measurements of analyte levels, we calculated the area under the curve (AUC). Our results indicate that in vitro cell stimulation with a novel combination of peptides (Rv0849-12, Rv2031c-14, Rv2031c-5, and Rv2693-06) and IL-1RA detection in culture supernatants can discriminate between LTBI and ATBD.

Hypoxia induces an immunodominant target of tuberculosis specific T cells absent from common BCG vaccines.

M. tuberculosis (MTB) species-specific antigenic determinants of the human T cell response are important for immunodiagnosis and vaccination. As hypoxia is a stimulus in chronic tuberculosis infection, we analyzed transcriptional profiles of MTB subject to 168 hours of hypoxia to test the hypothesis that upregulation by hypoxia might result in gene products being recognized as antigens. We identified upregulation of two region of difference (RD) 11 (Rv2658C and Rv2659c), and one RD2 (Rv1986) absent from commonly used BCG strains. In MTB infected persons, the IL-2 ELISpot response to Rv1986 peptides was several times greater than the corresponding IFN-γ response to the reference immunodominant ESAT-6 or CFP-10 antigens. The IL-2 response was confined to two epitopic regions containing residues 61-80 and 161-180. The biggest population of IL-2 secreting T cells was single cytokine positive central memory T cells. The IL-2 response to live MTB bacilli lacking Rv1986 was significantly lower than the response to wild type or mutant complemented with Rv1986. In addition, the IL-2 response to Rv1986 was significantly lower in HIV-TB co-infected persons than in HIV uninfected persons, and significantly increased during antiretroviral therapy. These findings demonstrate that Rv1986 is an immunodominant target of memory T cells and is therefore of relevance when considering the partial efficacy of currently used BCG vaccines and provide evidence for a clinical trial comparing BCG strains.

Comparative Profiling of Circulating Exosomal Small RNAs Derived From Peruvian Patients With Tuberculosis and Pulmonary Adenocarcinoma.

Tuberculosis (TB) is one of the most fatal infectious diseases, caused by the aerobic bacteria Mycobacterium tuberculosis. It is estimated that one-third of the world's population is infected with the latent (LTB) version of this disease, with only 5-10% of infected individuals developing its active (ATB) form. Pulmonary adenocarcinoma (PA) is the most common and diverse form of primary lung carcinoma. The simultaneous or sequential occurrence of TB and lung cancer in patients has been widely reported and is known to be an issue for diagnosis and surgical treatment. Raising evidence shows that patients cured of TB represent a group at risk for developing PA. In this work, using sRNA-sequencing, we evaluated the expression patterns of circulating small RNAs available in exosomes extracted from blood samples of Peruvian patients affected by latent tuberculosis, active tuberculosis, or pulmonary adenocarcinoma. Differential expression analysis revealed a set of 24 microRNAs perturbed in these diseases, revealing potential biomarker candidates for the Peruvian population. Most of these miRNAs are normally expressed in healthy lung tissue and are potential regulators of different shared and unique KEGG pathways related to cancers, infectious diseases, and immunology.

NAT2 and CYP2E1 polymorphisms and antituberculosis drug-induced hepatotoxicity in Peruvian 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.

A mobile lab for ancient DNA extraction in Perug.

We report the use of a mobile laboratory set up to extract ancient DNA (aDNA) from 34 human coprolites (fossilized faeces) samples. Our approach enabled the rapid genetic characterization of 5,000 years old archeological samples. It is useful for the on-site screening of museums and freshly excavated samples for DNA. This approach is accessible to other investigators as the mobile laboratory was set up using commercially available instruments.

Population genetics of PDE4B (phosphodiesterase-4B) in neglected Native Americans: Implications for cancer pharmacogenetics.

PDE4B (phosphodiesterase-4B) has an important role in cancer and in pharmacology of some disorders, such as inflammatory diseases. Remarkably in Native Americans, PDE4B variants are associated with acute lymphoblastic leukemia (ALL) relapse, as this gene modulates sensitivity of glucocorticoids used in ALL chemotherapy. PDE4B allele rs6683977.G, associated with genomic regions of Native American origin in US-Hispanics (admixed among Native Americans, Europeans, and Africans), increases ALL relapse risk, contributing to an association between Native American ancestry and ALL relapse that disappeared with an extra-phase of chemotherapy. This result insinuates that indigenous populations along the Americas may have high frequencies of rs6683977.G, but this has never been corroborated. We studied ancestry and PDE4B diversity in 951 healthy individuals from nine Latin American populations. In non-admixed Native American populations rs6683977.G has frequencies greater than 90%, is in linkage disequilibrium with other ALL relapse associated and regulatory variants in PDE4B-intron-7, conforming haplotypes showing their highest worldwide frequencies in Native Americans (>0.82). Our findings inform the discussion on the pertinence of an extra-phase of chemotherapy in Native American populations, and exemplifies how knowledge generated in US-Hispanics is relevant for their even more neglected and vulnerable Native American ancestors along the American continent.