Browsing by Autor "Emerson Cayo"

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Andean Aymara Enriched Genetic Variants Are Beneficial to High Altitude Adaptation of Andean Quechuas Living at 5000 m
(Elsevier BV, 2022) Ricardo Amaru; Emerson Cayo; Julieta Luna; Teddy Quispe; Josef T. Prchal; Jihyun Song
Populations living at high altitude developed distinct evolutionary genetic adaptations allowing them to exist in extreme hypobaric hypoxia condition. Tibetans and Andean highlanders (Aymaras and Quechuas) have inhabited regions over ~4000 m for 44,000 and 14,000 years, respectively (PMID: 28448578, 25342802). Unlike other high-altitude populations, such as Tibetans, Andeans' Aymaras and Quechuas have higher hemoglobin levels. Tibetan genomic analyses revealed evolutionary selected genetic signatures EPAS1, EGLN1 and PKLR genes (PMID:25129147; Song, ASH 2018). However non-DenisovanEPAS1 variants (rs13005507 and rs142764723) are present in Aymaras and Quechuas, and ~56% of Aymaras have Tibetan PKLR variants (Song, ASH 2018). Our whole genome study found that most Aymara evolutionary-enriched genes (BRNIP3, NOS2, SH2B1, and TBX5) are associated with cardiopulmonary development but not with hemoglobin levels (PMID: 29100088); different genomic selection was reported in Andean Quechuas (PMID:23954164). We then found previously unreported Aymara enriched NFKB1 single nucleotide polymorphisms (SNP) by integrative analysis of the Aymaras' genome and transcriptome, this SNP is also enriched in Quechuas but to the lesser degree. Decreased NFKB1 results in increased NF-kB levels leading to NF-kB driven increased inflammation as well as increased HIFs activity (PMID: 26513405) and is associated with high hemoglobin and inflammatory protein and transcript levels in Aymaras (Song, ASH 2018). We studied the presence of Aymara enriched SNPs in Quechua, one of Andean population living in Chorolque (5000 m) and their association with phenotypes at high altitude. We genotyped 5 Aymara enriched SNPs and PKLR (Table) in Quechuas (45 men, 14 women) living in Chorolque (5000 m) mining district, Potosi-Bolivia. All men were smokers while none of women were smokers. We also measured laboratory phenotypes leukocytes, platelets, lymphocytes, monocytes, neutrophils, as well as hemoglobin dissociation p50, SpO2, lactose, hemoglobin and hematocrit to study if genetic variants play a role in changes in these phenotypes. All Aymara enriched allele frequencies in Quechuas were lower than in Aymaras (Table). The allele frequencies of BRINP3, SH2B1, TBX5 in Quechuas were significantly different from those in Aymara, suggesting that Quechuas share some but not all genetic background with Aymaras. Since all men were smokers, we tested smoking effect on these phenotypes. Except hemoglobin and hematocrit levels, other phenotypes were comparable to women without smoking history. BRINP3 SNP positively correlated with SpO2 levels (r=0.2252, p=0.0893), suggesting that this SNP may have a role in delivery oxygen to tissue. PKLR SNP is associated with decreased levels of pyruvate kinase transcript levels, leading to increase 2,3 DPG and shifting hemoglobin dissociation curve to the right (increase of p50) (Song, ASH 2018). However, in these subjects, we did not find association in p50 but positive correlation with SpO2 (r=0.3423, p=0.0082). It suggests that presence of BRINP3 and PKLR SNPs is beneficial to live at low oxygen tension by delivering more oxygen to tissues. Total leukocytes, lymphocytes, and neutrophils were negatively correlated with NFKB1 SNP (r=-0.2349, r=-0.281, and r=-0.1725, respectively) which differed from our previous study of Aymaras at La Paz, suggesting that Quechuas may have different mechanisms in responding to inflammation from Aymaras. None of SNPs were associated with hematocrit and hemoglobin levels in men; however, we could not exclude effect of smoking. In females, NOS2 SNP were positively correlated with both hemoglobin and hematocrit (r=0.5513, p=0.0246). NO (nitric oxide) synthesized by NOS2 inhibits erythropoiesis (PMID: 18282521), suggesting that NOS2 SNP may decrease NO production resulting in inducing erythropoiesis in Quechuas. We conclude that while Quechuas and Aymaras share some genetic variants, but they differ in degree of selection for these SNPs. BRINP3 and PKLR SNPs are helpful to transfer more oxygen to tissues at high altitude. NFKB1 SNPs` inverse correlation with immune cells may provide protective functions in response to increased inflammation at high altitude (PMID: 26855492). Decreased NO production by NOS2 SNP may augment erythropoiesis in Quechuas, resulting in their higher hemoglobin and hematocrit at high altitude compared to Europeans. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal
Andean high-altitude dwellers with the NFKB1 haplotype (rs230511) are protected from acute mountain sickness
(Elsevier BV, 2025) Ricardo Amaru; Javier Valencia; Edgar Teddy Quispe Soto; Emerson Cayo; Julieta Luna; Daniela Patón; Victor R. Gordeuk; Josef T. Prchal; Jihyun Song
Abstract Acute Mountain Sickness (AMS) occurs with rapid ascent to high altitudes (&gt;2,500m), where air and oxygen pressures are lower than at sea level. AMS symptoms are headache, loss of appetite, nausea, dizziness, insomnia, fatigue and chest tightness, but severe AMS can progress to cerebral edema or pulmonary edema (PMID:26294748). Hypoxia at high altitude activates inflammatory pathways in which NF-κB signaling plays a central role. Severe hypoxia (1–3% O2) induces NF-κB-driven production of inflammatory mediators, connecting hypoxia-induced stress mediated by hypoxia-inducible factors (HIFs) with NF-κB. HIFs are also involved in responses that increase pulmonary vascular permeability, pulmonary hypertension, and edema (PMIDs:11441701;3410239;18641050). HIFs increase blood-brain barrier permeability, a central feature of high-altitude cerebral edema (PMID:33856254). NFKB1 is part of NF-κB complex and modulates NF-κB activity. NFKB1 also augments activity of HIFs. In our study of evolutionary adaptation to extreme high altitude of Andean native Aymara who have higher hemoglobin than Europeans living at the same high-altitude (PMIDs: 24039843; 29100088), we reported that the evolutionary selected T allele of NFKB1 rs230511 haplotype is linked to previously unreported alternate splicing of NFKB1, including skipping exon 4, exon 5, or both exons 4 and 5. It is present in ~90% of Aymara, but it also exists at lower frequency in Europeans, Asians and Hispanics (~30%). These alternatively spliced NFKB1 transcripts result in partial or complete loss of NFKB1 protein expression. This Aymara NFKB1haplotype is associated with increased baseline expression of inflammatory and HIF-regulated genes and correlates with those Aymara having high hemoglobin. However, under inflammatory stress, it has the opposite effect: nuclear translocation of NF-kB protein is attenuated, resulting in reduced expression of inflammatory, HIF-regulated, and prothrombotic genes (PMID:39971917). Since the incidence of AMS in the Aymara population is 0.6 % (Viruez, Horiz Med [Lima] 2020; 20(3): e943), which is markedly lower than the 1.7 % observed in non-Aymara at the same altitude (Castellanos, Correo Científico Médico 2022; 26), we hypothesized that rs230511-T is also associated with a protective role for AMS in Aymara. We studied 35 Bolivian Aymara in LaPaz (altitude of 4000 meters) who relocated to lower altitudes (&lt;400 m) for 1 month to 5 years and then returned to 4000 m and developed AMS. Among 35 subjects, 10 participants- 5 women (age 29±14 years) and 5 men (age 39±8 years)- without a history of medical comorbidities (except for one having history of gout) developed AMS. The 25 subjects who did not develop AMS served as controls (7 women, age 40±14 years and 18 men, age 38±11 years). All participants were genotyped for the NFKB1(rs230511) and NOS2 (rs34913965) variants; NOS2 was included due to a potential relationship with AMS (PMID:29100088). Among the subjects who developed AMS, the allele frequencies for the Aymara-enrichedNFKB1 variant were C:0.75 and T:0.25, compared to C:0.0 and T:1.0 in the control group (p&lt;0.0001). The genotype frequencies were CC:50%, CT:50% and TT:0% in the AMS group and CC:0%, CT:0% and TT:100% in the control group (p&lt;0.0001). For the NOS2 C/T haplotype variant, analysis of 7 AMS patients revealed that allele frequencies (T-Aymara enriched allele PMID:29100088) were C:0.14 and T:0.86, compared to C:0.1 and T:0.9 in the control group (p=0.5146). The genotype frequencies were CC:0%, CT:29%, and TT:71% in the AMS group, but CC:4%, CT:12%, and TT:84% in the control group (p=0.011). We classified AMS severity as severe (4 patients admitted to the intensive care unit), moderate (2 patients hospitalized), and mild (4 patients managed at home). Two patients with severe AMS who developed both pulmonary and cerebral edema had an Aymara NFKB1 allele frequency of C: 1.0 and T: 0.0, a 100% CC genotype. Our findings suggest that the presence of the Aymara evolutionary selected NFKB1 haplotype protects from developing AMS, whereas its absence (CC genotype) increases the likelihood of development of severe AMS. The CT genotype of NOS2 variant may also provide some protective effect. Larger cohorts and functional assays are needed to validate these associations and to further explore the molecular mechanisms by which the NFKB1 and NOS2 variants contribute to protection against AMS.
Phenotypic Variations Related to Hypoxic Responses Among Andean Highlanders Living at Different Altitudes (400m, 4000m, 5000m)
(Elsevier BV, 2022) Ricardo Amaru; Emerson Cayo; Teddy Quispe; Juan Carlos Valencia; Daniela Patón; Luis Felipe Mamani; Julieta Luna
Introduction Adaptation to high altitude poses selective evolutionary changes involving multiple and challenging adaptive responses, and one of them deals with the low pressure of oxygen. Native Bolivian Andeans have lived at an average of 3000-5000 m for about 14,000 years, and have developed different erythroid phenotypes compared to other populations living at high altitude (PMID 30781443; PMID 25342802). Although Andeans have developed genetic adaptations related to erythropoiesis regulation (Blood, ASH 2316, 2018) they still undergone with polycythemic states, and those of clinical relevance are often Chronic Mountain Sickness erythrocytosis (CMS-E), secondary erythrocytosis (SE) and polycythemia vera (PV) (Rev Hematol Mex. 2016 Jan;17(1):8-20). Either adaptation or erythrocytosis condition entails important changes in hemoglobin, SpO2, P50 and lactate, so evaluating significant changes among Andeans living at different altitudes as well as the modifications between erythrocytosis patients and healthy highlanders became of interest. Material and method We collected venous blood samples from Bolivian native Andeans born at 4000 m (n=124) but living at 3 different altitudes (400 m, 4000 m, 5000 m), aside from Europeans (n=11) residing at 4000 m. Complete blood count, venous blood gas, and oxygen saturation studies were performed. P50 was measured by using a formula described by Lichtman. Likewise, a differential diagnosis regarding healthy inhabitants and polycythemia patients was performed. Results In healthy Andean inhabitants in different altitudes, the Hb levels increased at increasing altitude (p:0.001), meanwhile SpO2 (p:0.001) and P50 (p:0.001) decreased. No lactate variations among them were observed (Table 1). European subjects at 4000 m in relation to Andean inhabitants at the same altitude displayed higher Hb levels (p: 0.01), without variations in SpO2 and P50, but a significant increased lactate (p: 0.001) (Table 1). When comparing healthy subjects and patients with erythrocytosis (CMS-E, SE, PV) at 4000 m, the latter displayed higher Hb levels (p:0.001), decreased SpO2 (p:0.001), no variations in P50, and increased lactate in CMS-E and SE patients (p:0.01) (Table 2). Similarly, patients with erythrocytosis (CMS-E, SE) at 5000 m, related to healthy subjects at the same altitude, reflected increased Hb (p:0.001), decreased SpO2 (p:0.01), P50 without variations, and increased lactate (p:0.01) (Table 2). Conclusions Native Andeans from Bolivia born at 4000 m but living at different altitudes have variations regarding hematological phenotypes, decreased P50 shifts the hemoglobin dissociation curve to left. Patients with erythrocytosis have distinct phenotypes in relation to healthy subjects characterized by decreased saturation and increased lactate. Higher Hb levels and increased lactate in Europeans living at 4000 m probably due to the different residing time at high altitude, since native Andean inhabited high-altitude regions for many years. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal
VALORES DE HEMOGLOBINA EN LA POBLACIÓN DE CHOROLQUE A 5000 MSNM
(2020) Emerson Cayo; Ricardo Amaru; Daniela Patón; Teddy Quispe; Silvia Mansilla; Julieta Luna