{
  "abstract": "Background Immune-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.Methods We 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.Results We 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.Conclusions Novel 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.",
  "authors": [
    {
      "affiliations": [
        "Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Prithvi Raj"
    },
    {
      "affiliations": [
        "Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Jialiang Liu"
    },
    {
      "affiliations": [
        "Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Chengsong Zhu"
    },
    {
      "affiliations": [
        "Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Carlos Arana"
    },
    {
      "affiliations": [
        "Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Farjana J Fattah"
    },
    {
      "affiliations": [
        "Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Hong Mu-Mosley"
    },
    {
      "affiliations": [
        "Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA"
      ],
      "name": "Benjamin Switzer"
    },
    {
      "affiliations": [
        "Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Jason Y Park"
    },
    {
      "affiliations": [
        "Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Internal Medicine (Division of Hematology-Oncology), University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Mitchell S von Itzstein"
    },
    {
      "affiliations": [
        "Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Edward K Wakeland"
    },
    {
      "affiliations": [
        "Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA"
      ],
      "name": "Igor Puzanov"
    },
    {
      "affiliations": [
        "Mayo Clinic Comprehensive Cancer Center, Phoenix, Arizona, USA"
      ],
      "name": "Yousef Zakharia"
    },
    {
      "affiliations": [
        "Department of Medicine and Moores Cancer Center, University of California San Diego Health, San Diego, California, USA"
      ],
      "name": "Gregory A Daniels"
    },
    {
      "affiliations": [
        "Division of Hematology-Oncology and Mays Cancer Center, University of Texas Health Science Center, San Antonio, Texas, USA"
      ],
      "name": "Montaser F Shaheen"
    },
    {
      "affiliations": [
        "Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Yang Xie"
    },
    {
      "affiliations": [
        "Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Jeffrey A SoRelle"
    },
    {
      "affiliations": [
        "Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Department of Internal Medicine (Division of Hematology-Oncology), University of Texas Southwestern Medical Center, Dallas, Texas, USA",
        "Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "David E Gerber"
    }
  ],
  "title": "Genetic haplotypes in VWA8, OSBPL6, and ADAMTS9-AS2 are associated with immune-related adverse effects in ICI-treated patients with cancer",
  "uid": "6577349a-2db0-542f-908b-e96eeceaaa32"
}