Association of LILRA3 gene variants with central nervous system demyelinating syndromes of autoimmune origin in patients with late disease onset

Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3) gene variants have been previously associated with multiple sclerosis (MS). This study aimed to explore the prevalence of LILRA3 gene variants in a Greek cohort of patients with CNS demyelinating disorders, including those with MS, Systemic Autoimmune Disease (SAD) with CNS involvement, and Demyelinating disease with Autoimmune Features (DAF). The latter describes a group of patients who present with MS-like manifestations, as well as features of systemic autoimmunity. We included 439 patients (344 MS, 27 SAD with CNS involvement, 68 DAF) and 381 healthy controls (HC) that were genotyped for LILRA3 gene variants. The LILRA3 +/− heterozygous deletion was significantly less frequent in MS patients compared to HCs (8.14% vs. 14.43%, p-value: 0.0086; OR [95% CI] 0.53 [0.33–0.85]). Of interest, in adult-onset MS (AOMS), the LILRA3 +/− genotype frequency was significantly lower than in their HC counterparts (7.53% vs. 15.69%, p = 0.0424, OR [95% CI] 0.44 [0.21–0.94]). When focusing on MS patients aged 50 or older (Late-onset MS, LOMS), no such differences were observed. Finally, the LILRA3 +/− heterozygous deletion was found to be significantly more prevalent in DAF patients compared to MS and HC groups of age distribution ≥ 50 years old (40.0% vs. 5.56% and vs. 14.03, p-values 0.03 and 0.016, respectively; ORs [95% CI] 11.3 [1.18–109.26] and 4.085 [1.38–12.12) respectively. In summary, these findings support that the type and age of onset of different demyelinating syndromes is shaped by distinct underlying genetic background.