Alternatively spliced NFKB1 transcripts enriched in Andean Aymara modulate inflammation, HIF and hemoglobin

Jihyun Song, Seonggyun Han, Ricardo Amaru, Lucie Lanikova, Teddy Quispe, Dongwook Kim, Jacob E. Crawford, Soo Jin Kim, Younghee Lee () and Josef T. Prchal ()
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Jihyun Song: University of Utah and VA Hospital
Seonggyun Han: University of Utah
Ricardo Amaru: National Academy of Sciences
Lucie Lanikova: Institute of Molecular Genetics of the Czech Academy of Sciences
Teddy Quispe: National Academy of Sciences
Dongwook Kim: University of Utah
Jacob E. Crawford: Verily Life Sciences
Soo Jin Kim: University of Utah and VA Hospital
Younghee Lee: Seoul National University
Josef T. Prchal: University of Utah and VA Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The molecular basis of increased hemoglobin in Andean Aymara highlanders is unknown. We conducted an integrative analysis of whole-genome-sequencing and granulocytes transcriptomics from Aymara and Europeans in Bolivia to explore genetic basis of the Aymara high hemoglobin. Differentially expressed and spliced genes in Aymaras were associated with inflammatory and hypoxia-related pathways. We identified transcripts with 4th or 5th exon skipping of NFKB1 (AS-NFKB1), key part of NF-kB complex, and their splicing quantitative trait loci; these were increased in Aymaras. AS-NFKB1 transcripts correlated with both transcripts and protein levels of inflammatory and HIF-regulated genes, including hemoglobin. While overexpression of the AS-NFKB1 variant led to increased expression of inflammatory and HIF-targeted genes; under inflammatory stress, NF-kB protein translocation to the nucleus was attenuated, resulting in reduced expression of these genes. Our study reveals AS-NFKB1 splicing events correlating with increased hemoglobin in Aymara and their possible protective mechanisms against excessive inflammation.

Date: 2025
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DOI: 10.1038/s41467-025-56848-0

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