Aim: Multiple sclerosis (MS) is a multifactorial autoimmune disorder characterized by the destruction of the myelin sheath of neurons and progressive neurodegeneration. While the human leukocyte antigen (HLA) allele HLA-DRB1*15:01 has been consistently demonstrated to have the largest genetic contribution to MS susceptibility, evidence suggesting dysregulation of natural killer (NK) cells in disease indicates a possible role for killer immunoglobulin-like receptors (KIR) variation in disease. While previous studies have examined the association of the presence or absence of specific KIR genes and/or their ligands in MS, none have considered allele-level KIR variation.
Methods: Here, we investigated the impact of KIR allele variants and their HLA class I ligands on disease risk in a cohort of European ancestry MS patients (N=1,359) and healthy controls (N=2,130).
Results: Considering HLA-DRB1*15:01 and sex as covariates, we found that KIR2DL1*001, in combination with its ligand HLA-C2, was significantly associated with risk for disease (p=6x10-09, OR=2.00, 95% CI 1.58-2.52). This association was notably stronger than that observed for gene-content level analysis of KIR2DL1 and HLA-C2 (p=10-03, OR=1.29, 95% CI 1.11-1.51), confirming an allele-specific effect. In a subset of patients from our cohort (N=532), this allele was also associated with a strong trend toward later age of onset (p=0.06) and was present in 20% of patients with onset later than 50 years (vs. 10% with onset 50 or younger), which is often accompanied by faster disease progression and greater risk of comorbidities.
Conclusion: These findings are the first to clarify the role of KIR allelic variation in MS risk and may pave the way for NK-based therapies in this debilitating neurological disorder.
