Letter on ‘Downregulation of EPAS1 and EGLN1 mRNA Expression Associated With High‐Altitude Adaptive Genetic Variants in Sherpa Highlanders’

Abstract

, The study by Droma et al. ( 2026 ) reports that Sherpa high-landers carry significantly lower frequencies of the wild-type alleles of two EPAS1 (rs13419896:G > A and rs4953354:A > G) and two EGLN1 (rs1435166:G > A and rs2153364:A > G) intronic variants, and that whole-blood mRNA expression of both genes is markedly reduced in Sherpas relative to non-Sherpa lowlanders (26.7% and 39.2% of control, respectively). The authors interpret this as transcriptional modulation of the HIF pathway that blunts the erythropoietin (EPO) response and protects against chronic mountain sickness. The hypothesis is biologically coherent and aligns with prior Tibetan data. The strength of the proposed causal chain (genotype → reduced mRNA → blunted EPO → protection), however, depends on several methodological points that the present design does not fully resolve. First, mRNA was quantified from EDTA-anti-coagulated whole-blood RNA without correction for differential leukocyte composition between groups. Sherpa highlanders chronically exposed to hypoxia at 3440 m may differ from Kathmandu lowlanders in granulocyte-to-lymphocyte proportions, and bulk whole-blood expression is well documented to be confounded by underlying cell-type admixture (Shannon et al. 2018 ). A 2.5-fold expression gap between groups could reflect, at least