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.

No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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