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

HLA homozygosity of specific alleles at a single locus is associated with increased risk for autoimmunity. However, the contribution of the overall limitation of HLA allele diversity to autoimmunity risk remains to be determined. We conducted a proof-of-concept case-control study of 413 subjects (279 cases, 134 matched controls) examining the “Limitation of HLA Diversity” (LoHLAD) across multiple loci as an allele-independent risk factor for pediatric-onset autoimmune rheumatic disease. The association of LoHLAD with pediatric-onset autoimmune rheumatic diseases was examined at 5 HLA loci (HLA-A, HLA-B, HLA-DQB1, HLA- DRB1, HLA- DRB3/4/5). For the purpose of this study, we introduced a novel metric of LoHLAD 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. 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