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. 2024 Nov 12;8(21):5529-5538.
doi: 10.1182/bloodadvances.2024012776.

Genetic variants in canonical Wnt signaling pathway associated with pediatric immune thrombocytopenia

Taylor Olmsted Kim  1   2 , Jennifer M Geris  3   4 , Jonathan M Flanagan  3   4 , Rachael F Grace  5   6 , Michele P Lambert  7   8 , Candelaria O'Farrell  3   4 , Melissa J Rose  9   10 , Kristin A Shimano  11 , Omar Niss  12   13 , Cindy Neunert  14   15 , Taizo A Nakano  16 , Derek MacMath  17 , Bogdan Dinu  3   4 , Susan E Kirk  3   4 , Ellis J Neufeld  18 , Jenny M Despotovic  19 , Michael E Scheurer  3   4 , Amanda B Grimes  3   4
Affiliations

Genetic variants in canonical Wnt signaling pathway associated with pediatric immune thrombocytopenia

Taylor Olmsted Kim et al. Blood Adv. .

Abstract

Through the use of genetic sequencing, molecular variants driving autoimmunity are increasingly identified in patients with chronic and refractory immune cytopenias. With the goal of discovering genetic variants that predispose to pediatric immune thrombocytopenia (ITP) or increase risk for chronic disease, we conducted a genome-wide association study in a large multi-institutional cohort of pediatric patients with ITP. A total of 591 patients were genotyped using an Illumina Global Screening Array BeadChip. Six variants met genome-wide significance in comparison between children with ITP and a cohort of healthy children. One variant in NAV2 was inversely associated with ITP (adjusted odds ratio [aOR], 0.52; P = 3.2 × 10-11). Two other variants in close proximity to NKD1 were also inversely associated with ITP (aOR, 0.43; P = 8.86 × 10-15; aOR, 0.48; P = 1.84 × 10-16). These genes have been linked to the canonical Wnt signaling pathway. No variants met genome-wide significance in comparison of those with ITP that self-resolved in <1 year versus those who developed chronic ITP. This study identifies genetic variants that may contribute to ITP risk and raises a novel pathway with a potential role in ITP pathogenesis.

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Conflict of interest statement

Conflict-of-interest disclosure: R.F.G. reports research funding from Agios, Novartis, and Sobi; and reports consultancy role with Agios and Sanofi. M.P.L. reports advisory board membership with Octapharma, Dova, Principia, Rigel, Argenx, Platelet Disorder Support Association (PDSA), 22qSociety, and CdLS Foundation; serves as a consultant for Novartis, Dova, Principia, Argenx, Rigel, Sobi, Sanofi, and Janssen; and reports research funding from Foundation for Women & Girls with Blood Disorders, PDSA, the US National Institutes of Health, Sysmex, Novartis, Principia, Argenx, Dova, Octapharma, and Sanofi. K.A.S. reports research funding from Novartis, Pfizer, Sobi, and Sanofi. C.N. reports research funding from Novartis; and received an honorarium from Sobi, Novartis, and Sanofi. S.E.K. serves on the advisory board of Sanofi; and reports honoraria from X4 Pharmaceuticals and BioMarin. D.M. reports salary support in part of Division of Clinical Research at National Institute of Allergy and Infectious Disease/the US National Institutes of Health. E.J.N. serves on data and safety monitoring board for Merck, LFB, Sobi, and Agios; serves on the advisory boards of Genentech, Takeda, Saliogen, and Pfizer; and reports stock options in Saliogen. A.B.G. reports research funding from Novartis. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
ITP case-control analysis Manhattan plot. Six variants met the threshold for genome-wide significance. Genome-wide significance threshold is P < 5 × 10−8 (red line) and suggestive genome-wide significance, P < 1 × 10−5 (blue line).
Figure 2.
Figure 2.
ITP case-control analysis forest plot. Forest plot showing the OR, confidence intervals, and P values for SNVs in ITP vs healthy controls. Two variants were present at increased frequency in ITP, whereas the remaining 4 SNVs had a negative association with ITP. 95% CI, confidence interval.
See this image and copyright information in PMC

References

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