Genetics of High-Altitude Population Correlated With Better Response to Treatment for MPNs

A new study has identified genetic factors that can affect the molecular pathways involved in inflammation, hypoxia sensing, blood clots, and the response to treatment among patients with certain myeloproliferative neoplasms (MPNs).

At the 66th American Society of Hematology Annual Meeting & Exposition, Josef T. Prchal, MD, of the Huntsman Cancer Institute at the University of Utah, and colleagues presented late-breaking data showing that patients with a genetic profile common among the Aymara Indigenous community in the Andean mountains—the NFKB1 gene variants that encode several different mRNA transcripts—correlated with a lower expression of genes involved in inflammation and a better response to ropeginterferon-α, a drug used to treat polycythemia vera (PV) and essential thrombocythemia (ET).

“We identified some genetic variants which are evolutionarily selected to be beneficial to the Aymara high-altitude population in the Andean mountains, and we have now shown, for the first time, that these variants are also present in other populations and correlate with some differences in disease phenotype,” said Dr. Prchal. “Our study suggests that with genotyping, the NFKB1 variant can be used as a biomarker for determining which patients may be more or less responsive to ropeginterferon-α treatment.”

In the study, Dr. Prchal and colleagues analyzed the genetic profiles, gene expression profiles, and clinical outcomes of 30 people with PV and 15 with ET. They also looked at the linkages between a person’s NFKB1 genotype and the likelihood of achieving a complete hematologic response after ropeginterferon-α treatment.

The genetic markers used in the study reflected three genotypes of the NFKB1 variant (rs230511), delineated as C/C, C/T, and T/T. The study showed that the T variant was associated with decreased inflammatory, prothrombotic, and hypoxia-inducible factor activity and a better response to ropeginterferon-α in PV and ET, which are characterized by chronic inflammation. In addition, the C/T genotype was more common in patients who achieved complete hematologic response (58.6%) compared with the cohort that did not respond (33.3%; P<.0001).

“Most high-altitude adaptation studies correlate genes with phenotypes such as high hemoglobin or low oxygen saturation, but the important finding that our study adds is that there is also an association with modulation of inflammation, which can affect outcomes for diseases like PV and ET,” said Dr. Prchal. “The people with a better response to ropeginterferon-α showed more C/T genotype, which was correlated with less inflammatory gene expression, so we suspect that people with this genotype will also tolerate the treatment better and have fewer side effects.”

Reference

Song J, Kim SJ, Prchal JT, et al. Andean enriched NFKB1 haplotype reduces inflammation and improves response to ropeginterferon alfa-2b in polycythemia vera (PV) and essential thrombocythemia (ET). Abstract #LBA-4. Presented at the 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.