Do Andean Aymaras' Evolutionary Selected Genes to High Altitude Hypoxia Also Influence Hemoglobin Concentration of Europeans and Their Acute Hypoxia Responses?

The major regulation of hemoglobin levels (Hb) is hypoxia regulated by hypoxia inducible factors (HIFs). Some mutations of hypoxia sensing pathway increase HIFs and cause erythrocytosis (PMID: 23733342). Some high-altitude dwellers developed beneficial genomic evolution, facilitating their existence in high altitude hypoxia. Tibetans have been exposed to longer evolutionary selection than Andeans for approximately 44,000 and 14,000 years, respectively (PMID: 28448578, 25342802). This evolutionary pressure accounted for unique Tibetan haplotypes; it decreased HIFs activity and lowered Hb (PMID: 25129147). In contrast, Andean natives, Quechuas and Aymaras underwent different evolutionary adaptations to environmental hypoxia developinghigh Hb. We previously studied Aymaras at high-altitude and identified their evolutionary selected genes. The 5 most selected genes - BRINP3, NOS2, TBX5,SH2B1, and PYGM have some roles in cardiopulmonary development, but their functional consequences are unknown. None of these 5 highly selected Aymara genes are correlated with their Hb levels (PMID: 29100088). The single nucleotide polymorphisms (SNPs) of these genes also exist in Europeans, although in much lower frequency (Table).

In contrast, NFKB1 rs230511 (allele frequency: 88% of Aymaras) underwent lower selection, but was still significant and correlated with the elevated hemoglobin in Aymaras (Song, ASH2018). It is also present in Europeans but at lower gene frequency (38%). NFKB1 is an inhibitor of NF-kB. Our previous analysis of differential exon usage of Aymara transcriptome found two previously unreported alternative splice transcripts of NFKB1 with exons 4 or 5 skipped transcripts. These transcripts correlated with Aymara enriched NFKB1 rs230511 and resulted in non-functional truncated-NFKB1 protein. Decreased NFKB1 results in increased NF-kB levels leading to NF-kB driven increased inflammation as well as increased HIFs activity (PMID: 26513405).

Here, we interrogated associations among 6 Aymara hypoxia selected SNPs with physiological changes akinwith being rapidly exposed to hypobaric hypoxia (equivalent to 4500m) (Table). We isolated DNA from plasma 79 young and fit Austrian volunteers before and after exposure to hypoxia. Mean age was 26 ± 5.4 years (female = 34, male = 40 ). Their physiological responses to acute hypoxia were monitored at specific time intervals (0hr, 3hr, 6hr). These intervals included heart rate, systolic and diastolic blood pressures, oxygen saturation SpO₂ and SaO₂, PaCO_2, blood pH, lactate and parameters of acute mountain sickness by Lake Louis score(PMID: 29583031). Their baseline Hb levels were also measured. These parameters were correlated with their 6 Aymara-enriched SNP.

The Hb was only significantly higher in females with Aymara selected NFKB1 rs230511 by T test (p= 0.0163) and by Bartlett's test at p=0.017.

Other SNPs have reached statistical significance in correlation with physiological parameters corresponding to acute hypoxic exposure. NOS2 rs34913975 correlated negatively with SpO₂ (p= 0.0451), systolic blood pressure (p=0.0307) and diastolic blood pressure (p=0.0388), while SH2B1 rs 12448902 negatively correlated with SpO₂ in heterozygotes (p=0.0068, )_. The PYGM rs487105 correlated with systolic blood pressure (p=0.0095), and heart rate p=0.0442. However, some of these associations revealed trends for correlation.Since several Aymara-enriched SNPs had low allele frequency in Europeans, some correlations may not have reached enough statistical significance. A larger cohort may be needed for evaluation.

In contrast, NFKB1 rs230511 correlated in females with higher Hb, but also with several other physiological responses to acute hypoxia in this cohort. It correlated positively with SpO₂, systolic blood pressure (p=0.0041) and diastolic blood pressure (p=0.0114) while negatively with PaCO₂ (p=0.0487) and Lake Louis score(p=0.0184).

We conclude that the evolutionary-selected genes to chronic environmental hypoxia in Aymaras appear to also have function in Europeans. NFKB1 rs230511 has a significant association with higher Hb in the European females and is beneficial in some physiological responses to acute hypoxia.

DS and GM contributed equally in this abstract.

No relevant conflicts of interest to declare.