Genetic haplotypes in VWA8, OSBPL6, and ADAMTS9-AS2 are associated with immune-related adverse effects in ICI-treated patients with cancer

Prithvi Raj; Jialiang Liu; Chengsong Zhu; Carlos Arana; Farjana J Fattah; Hong Mu-Mosley; Benjamin Switzer; Jason Y Park; Mitchell S von Itzstein; Edward K Wakeland; Igor Puzanov; Yousef Zakharia; Gregory A Daniels; Montaser F Shaheen; Yang Xie; Jeffrey A SoRelle; David E Gerber

doi:10.1136/jitc-2025-012012

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Genetic haplotypes in VWA8, OSBPL6, and ADAMTS9-AS2 are associated with immune-related adverse effects in ICI-treated patients with cancer

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Genetic haplotypes in VWA8, OSBPL6, and ADAMTS9-AS2 are associated with immune-related adverse effects in ICI-treated patients with cancer

Prithvi Raj, Jialiang Liu, Chengsong Zhu, Carlos Arana, Farjana J Fattah, Hong Mu-Mosley, Benjamin Switzer, Jason Y Park, Mitchell S von Itzstein, Edward K Wakeland, …

Journal for immunotherapy of cancer, Vol.13(10), e012012

10/28/2025

DOI: 10.1136/jitc-2025-012012

PMCID: PMC12570911

PMID: 41151836

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https://doi.org/10.1136/jitc-2025-012012View

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Abstract

BackgroundImmune-related adverse events (irAEs) remain largely unpredictable, potentially affecting multiple organ systems and occurring at almost any point during and even occasionally after immune checkpoint inhibitor (ICI) treatment. To identify populations at risk for these immune-mediated toxicities, we analyzed genetic characteristics and immune markers associated with clinically significant irAEs.MethodsWe carried out a genome-wide association study on 373 white patients receiving ICI treatment. We identified single nucleotide polymorphisms associated with irAEs. Blood cytokine profiling and peripheral blood mononuclear cell RNA sequencing were performed at pretreatment baseline and 6–8 weeks after ICI initiation. Findings were validated in two external cohorts.ResultsWe identified genetic haplotypes in VWA8 (Von Willebrand Factor A Domain Containing 8), OSBPL6 (Oxysterol Binding Protein Like 6), and ADAMTS9-AS2 (ADAM Metallopeptidase With Thrombospondin Type 1 Motif 9 Antisense RNA 2) associated with grade ≥2 irAEs. Patients carrying risk haplotypes for one or more genes exhibited significantly greater rates of grade ≥2 (OR 3.02; 95% CI 1.83 to 5.02; p<0.001), grade ≥3 (OR 3.59; 95% CI 1.93 to 6.64; p<0.001), and multiple type irAE (OR 2.60; 95% CI 1.53 to 4.39; p<0.001). Serum CCL3 levels were significantly elevated in individuals carrying risk haplotypes (p=0.03). Gene expression analysis demonstrated activated autoimmune and inflammatory pathways in the genetic risk group.ConclusionsNovel polymorphisms in VWA8, OSBPL6, and ADAMTS9-AS2 may impact immune pathways, promote inflammation, potentiate autoimmune phenotypes, and convey risk of irAE in ICI-treated patients.

Genetic

Immune related adverse event - irAE

Immunotherapy biomarkers

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Title: Subtitle: Genetic haplotypes in VWA8, OSBPL6, and ADAMTS9-AS2 are associated with immune-related adverse effects in ICI-treated patients with cancer
Creators: Prithvi Raj - The University of Texas Southwestern Medical Center
Jialiang Liu - The University of Texas Southwestern Medical Center
Chengsong Zhu - The University of Texas Southwestern Medical Center
Carlos Arana - The University of Texas Southwestern Medical Center
Farjana J Fattah - The University of Texas Southwestern Medical Center
Hong Mu-Mosley - The University of Texas Southwestern Medical Center
Benjamin Switzer - Roswell Park Comprehensive Cancer Center
Jason Y Park - The University of Texas Southwestern Medical Center
Mitchell S von Itzstein - The University of Texas Southwestern Medical Center
Edward K Wakeland - The University of Texas Southwestern Medical Center
Igor Puzanov - Roswell Park Comprehensive Cancer Center
Yousef Zakharia - Mayo Clinic in Florida
Gregory A Daniels - University of California San Diego
Montaser F Shaheen - Mays Cancer Center at UT Health San Antonio
Yang Xie - The University of Texas Southwestern Medical Center
Jeffrey A SoRelle - The University of Texas Southwestern Medical Center
David E Gerber - The University of Texas Southwestern Medical Center
Resource Type: Journal article
Publication Details: Journal for immunotherapy of cancer, Vol.13(10), e012012
DOI: 10.1136/jitc-2025-012012
PMID: 41151836
PMCID: PMC12570911
NLM abbreviation: J Immunother Cancer
ISSN: 2051-1426
eISSN: 2051-1426
Publisher: BMJ Publishing Group Ltd
Grant note: 1P30 CA 142543-03 / Simmons Comprehensive Cancer Center N/A / American Cancer Society (http://dx.doi.org/10.13039/100000048) P50CA070907-21 / Lung Cancer Specialized Program of Research Excellence (SPORE) 1U01AI156189-01 / National Institute of Allergy and Infectious Disease N/A / University of Texas DT2019-007; MRAT-18-114-01-LIB / Melanoma Research Alliance (http://dx.doi.org/10.13039/100005190)
Language: English
Date published: 10/28/2025
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9985016524702771

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