The genotypes of variations of VEGFA in Sherpa highlanders and non-Sherpa lowlanders

Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitudes for restoring oxygen supply to tissues. Vascular endothelial growth factors (VEGFs) are important signaling proteins involved in vasculogenesis and angiogenesis stimulated by hypoxia. We hypothesize that the VEGF-A isoform and the gene encoding VEGF-A (VEGFA) are involved with the mechanism of adaptation to high-altitude hypoxia in Sherpa highlanders.

Materials & Methods:  Five-one Sherpa highlanders at a high altitude of 3,440 meters (m) above sea level and 76 non-Sherpa lowlanders at 1,300 m in Nepal were recruited. The plasma VEGF-A concentrations were measured in both groups. Meanwhile, five single-nucleotide polymorphisms (SNPs, rs699947, rs833061, rs1570360, rs2010963, and rs3025039) in the VEGFA were genotyped in the two groups.

Results: The average oxygen saturation (SpO₂) differed significantly between the two groups due to the difference of altitude (93.7 ± 0.2% in Sherpas at 3,440 m vs. 96.7 ± 0.2% in non-Sherpas at 1,330 m, P < 0.05). However, the plasma VEGF-A concentration in Sherpas at high altitude (262.8 ± 17.9 pg/ml) was equivalent to that in non-Sherpas at low altitude (266.8 ± 21.8 pg/ml, P > 0.05), indicating that the plasma VEGF-A concentration did not respond to high-altitude hypoxia to increase its level in Sherpas at high altitude. Moreover, the allele frequencies of the SNPs of rs699947, rs833061, and rs2010963 were significantly diverse between the Sherpa highlanders and non-Sherpa lowlanders (corrected P = 3.30 × 10⁻⁵, 4.95 × 10⁻⁴, 1.19 × 10⁻⁷, respectively). 

Conclusions: The VEGF-A isoform in Sherpa highlanders exhibited a phenotype of tolerance to high-altitude hypoxia, which was likely based on the distinctive genetic background with significant variations of the VEGFA in Sherpa highlanders.