We read with great interest the recent article by Wang et al. (1) in Frontiers in Medicine describing hematologic reference intervals among healthy adults living at different altitudes on the Western Sichuan Plateau. Their work represents an important step in refining diagnostic thresholds for high-altitude populations and highlights the limitations of applying sea-level or internationally derived laboratory standards to communities with distinct environmental exposures.
While the study focuses primarily on physiological adaptation to chronic hypoxia, we wish to extend the conversation by underscoring the need to integrate ancestral and genetic variation—particularly regulatory and noncoding variants—into such efforts (2). Population-specific diagnostics should eventually account not only for environmental modifiers like altitude but also for inherited traits that shape baseline hematologic profiles and affect disease susceptibility or therapeutic response (3).
For example, noncoding erythropoietin (EPO) promoter variants recently linked to hereditary erythrocytosis suggest that population-enriched regulatory mutations can elevate red cell production independent of serum EPO levels detectable by standard assays (3, 4). Similarly, benign ethnic neutropenia (BEN), mediated by the Duffy-null genotype (5), remains a classic illustration of how genetically influenced baselines can be misread as pathological when majority-derived reference ranges are applied (6). Moreover, recent work demonstrating the therapeutic potential of Cas9-mediated insertion of natural EPO variants points to a future where regulatory polymorphisms may not only inform diagnosis but also offer treatment options for hematologic conditions (7).
We acknowledge that integrating genetic and glycomic analyses into routine diagnostics poses cost and logistical challenges, particularly in lower-resource settings and rural or high-altitude communities (8). However, we believe that investments in scalable, context-sensitive genomics, coupled with environmental adaptation studies like that of Wang et al., will be crucial to building inclusive, precise, and globally relevant diagnostic frameworks.
We commend the authors for their contribution to hematologic equity and encourage further research at the intersection of ancestry, environment, and regulation to redefine what “normal” means in diverse populations.
Statements
Author contributions
MA: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. AS: Conceptualization, Data curation, Investigation, Methodology, Software, Supervision, Writing – review & editing. MM: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Acknowledgments
The authors thank the authors of the original study, for their important contribution to the field.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Gen AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1.
WangQLiuJHuSDuJZhouSHuangZet al. Establishment of reference intervals for complete blood count in healthy adults at different altitudes on the Western Sichuan Plateau. Front Med. (2025) 12:1586778. 10.3389/fmed.2025.1586778
2.
ZhangFLupskiJR. Non-coding genetic variants in human disease. Hum Mol Genet. (2015) 24(R1):R102–10. 10.1093/hmg/ddv259
3.
MartinLMaricDIdrissSDelamareMLe RoyAMaazizNet al. Identification of hepatic-like EPO as a cause of polycythemia. N Engl J Med. (2025) 392:1684–97. 10.1056/NEJMoa2414954
4.
McMullinMF. Erythrocytosis and variants of EPO. N Engl J Med. (2025) 392:1742–5. 10.1056/NEJMe2501849
5.
ReichDNallsMAKaoWHAkylbekovaELTandonAPattersonNet al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet. (2009) 5:e1000360. 10.1371/journal.pgen.1000360
6.
MerzLEAchebeM. When non-whiteness becomes a condition. Blood. (2021) 137:13–5. 10.1182/blood.2020008600
7.
LunaSECamarenaJHamptonJPMajetiKRCharlesworthCTSoupeneEet al. Enhancement of erythropoietic output by Cas9-mediated insertion of a natural variant in hematopoietic stem and progenitor cells. Nat Biomed Eng. (2024) 8:1540–52. 10.1038/s41551-024-01222-6
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MboowaGMwesigwaSKateeteDWayengeraMNasingheEKatagiryaEet al. Whole-genome sequencing of SARS-CoV-2 in Uganda: implementation of the low-cost ARTIC protocol in resource-limited settings. F1000Res. (2021) 10:598. 10.12688/f1000research.53567.1
Summary
Keywords
hematologic reference intervals, population genetics, regulatory variants, precision medicine, global health diagnostics
Citation
Abdulrasak M, Someili AM and Mohrag M (2025) Commentary: Establishment of reference intervals for complete blood count in healthy adults at different altitudes on the Western Sichuan Plateau. Front. Med. 12:1642003. doi: 10.3389/fmed.2025.1642003
Received
05 June 2025
Accepted
24 June 2025
Published
09 July 2025
Volume
12 - 2025
Edited by
Eleni Gavriilaki, Aristotle University of Thessaloniki, Greece
Reviewed by
Fernando Marqués-García, Hospital Germans Trias i Pujol, Spain
Updates
Copyright
© 2025 Abdulrasak, Someili and Mohrag.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mohammed Abdulrasak mohammed.abdulrasak@med.lu.se
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.