The Limitation of HLA Diversity as a Risk Factor for Pediatric-Onset Autoimmune Rheumatic Disease

Background: HLA homozygosity of specific alleles at a single locus is associated with increased risk for autoimmunity and/or more severe clinical phenotypes. However, the contribution of the overall limitation of HLA diversity across multiple loci to autoimmunity risk remains to be determined. Methods: We conducted a proof-of-concept case-control study of 413 individuals (279 cases with pediatric-onset autoimmune rheumatic diseases, 134 matched controls) examining the "Limitation of HLA Diversity" (LoHLAD) across multiple loci as an allele-independent risk factor for autoimmunity. We examined the association of LoHLAD with pediatric-onset autoimmune rheumatic diseases at five HLA loci (A, B, DQB1, DRB1, DRB3/4/5). LoHLAD was defined as (1) homozygosity at any of the examined loci, and/or (2) the presence of a single allele or the complete lack of an allele at the HLA-DRB3/4/5 locus. Results: The frequency of LoHLAD at any locus was significantly higher in cases compared to controls (65.95% vs. 30.60%, OR 4.39 [2.82-6.84], p < 0.0001). Higher frequencies of LoHLAD in cases compared to controls were observed at both class I (19.35% vs. 10.45%, OR 2.06 [1.10-3.86], p = 0.031) and class II (54.48% vs. 20.15%, OR 4.74 [2.92-7.69], p < 0.0001) loci. Specifically, significant differences between cases and controls were observed at the B (OR 8.63 [1.14-65.55], p = 0.016), DQB1 (OR 3.34 [1.27-8.78], p = 0.016), and DRB3/4/5 (OR 4.64 [2.77-7.75], p < 0.0001) loci. Multiple logistic regression models confirmed the ability of LoHLAD to positively predict autoimmunity. Conclusions: LoHLAD is a significant allele-independent risk factor for pediatric-onset autoimmune rheumatic disease.