Mohammed Abdulrasak
Ali M. Someili3
Mostafa Mohrag- 1Department of Clinical Sciences, Lund University, Malmö, Sweden
- 2Department of Gastroenterology and Nutrition, Skåne University Hospital, Malmö, Sweden
- 3Department of Medicine, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
A Commentary on
Establishment of reference intervals for complete blood count in healthy adults at different altitudes on the Western Sichuan Plateau
by Wang, Q., Liu, J., Hu, S., Du, J., Zhou, S., Huang, Z., Liu, Y., Yang, K., Zhang, L., Yang, J., and Yuan, Q. (2025). Front. Med. 12:1586778. doi: 10.3389/fmed.2025.1586778
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.
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.
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References
1. Wang Q, Liu J, Hu S, Du J, Zhou S, Huang Z, et 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. doi: 10.3389/fmed.2025.1586778
2. Zhang F, Lupski JR. Non-coding genetic variants in human disease. Hum Mol Genet. (2015) 24(R1):R102–10. doi: 10.1093/hmg/ddv259
3. Martin L, Maric D, Idriss S, Delamare M, Le Roy A, Maaziz N, et al. Identification of hepatic-like EPO as a cause of polycythemia. N Engl J Med. (2025) 392:1684–97. doi: 10.1056/NEJMoa2414954
4. McMullin MF. Erythrocytosis and variants of EPO. N Engl J Med. (2025) 392:1742–5. doi: 10.1056/NEJMe2501849
5. Reich D, Nalls MA, Kao WH, Akylbekova EL, Tandon A, Patterson N, et 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. doi: 10.1371/journal.pgen.1000360
6. Merz LE, Achebe M. When non-whiteness becomes a condition. Blood. (2021) 137:13–5. doi: 10.1182/blood.2020008600
7. Luna SE, Camarena J, Hampton JP, Majeti KR, Charlesworth CT, Soupene E, et 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. doi: 10.1038/s41551-024-01222-6
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.
Edited by:
Eleni Gavriilaki, Aristotle University of Thessaloniki, GreeceReviewed by:
Fernando Marqués-García, Hospital Germans Trias i Pujol, SpainCopyright © 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, bW9oYW1tZWQuYWJkdWxyYXNha0BtZWQubHUuc2U=