Insights Into Immune-Related Diseases Born from Population Genomics

University Of Colorado Denver, Aurora CO

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Abstract

Summary The fundamental role of the immune system is to distinguish self from non-self, and healthy from unhealthy tissue. The ligands and receptors encoded by the major histocompatibility complex (MHC), the killer cell immunoglobulin-like receptor (KIR), and the natural killer complex (NKC), interact to help accomplish this role. Successful pathogen defense drives the genetic diversity of these regions but may also lower the threshold for autoimmunity. At the extremes of this spectrum is HLA-B*27, which protects against certain chronic infections but is also the major risk factor for spondyloarthritis (SpA) and acute anterior uveitis (AAU). Spondyloarthritis (SpA) refers to inflammatory musculoskeletal diseases, axial SpA (includes ankylosing spondylitis), psoriatic arthritis (PsA), colitis-associated arthritis, and reactive arthritis (ReA). Painful, inflamed joints are a common feature of SpA. Progression of axial disease leads to spinal fusion and reduced mobility. AAU, inflammation of the anterior chamber of the eye, commonly occurs in SpA patients, and can cause blindness. Although recent therapeutic advances have improved symptom management, whether they also improve long-term outcomes is controversial. The frequency of HLA-B*27 is high among these groups, especially in axial SpA, with up to 90% carrying HLA-B*27. About 2 million adults in the United States have SpA, with an estimated minimum of 44 million globally. Thus, SpA carries a significant health and economic burden, and there is a pressing need to understand more about the underlying disease mechanisms. The MHC region and KIR are associated with SpA. The receptor KIR3DL1 recognizes HLA-B*27 as a ligand, but how this relates to SpA is unknown. Given the shared associations but distinct manifestations of SpA, PsA, ReA and AAU, we hypothesize that the genetic polymorphism of KIR3DL1, in combination with the MHC, determines risk for specific SpA subtypes. Although genome-wide association studies have contributed to understanding the genetic landscape of SpA, the diversity of KIR and MHC limit the utility of these methods for uncovering more precise allelic associations. The Norman Lab is uniquely equipped to answer how the genetic diversity of the MHC, KIR, and NKC impacts SpA disease susceptibility and severity. In Aim 1, we will use our sequencing and bioinformatics approach to analyze these loci at high throughput and resolution from a total of 3,335 patients and 4,165 controls, with additional replication cohorts. Our cohort includes patients with axial SpA, PsA, colitis-associated arthritis, ReA, and AAU. We will generate per-individual haplotypes and fine-map the associations and interactions underlying SpA. In Aim 2, we will focus on the relationship between KIR3DL1 and HLA-B*27, by investigating how KIR3DL1 allotypes impact NK cell responses in axial SpA. In Aim 3 we will apply our targeted long-read sequencing methods to the extended MHC region and develop a method to reliably infer allele-specific expression of MHC, KIR, and NKC from single-cell RNA sequencing. Through these Aims, we will supply in-depth genetic analysis of MHC, KIR, and NKC in SpA, determine how KIR3DL1 allotypes impact NK cell function in disease, significantly advance the field with reference haplotypes and innovative bioinformatic methods, and provide a model for how to elucidate HLA/KIR associations in general.