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Objectives Current clinical serology (e.g., ANA, anti-dsDNA, anti-Sm) in systemic lupus erythematosus (SLE) does not fully capture disease heterogeneity. We recently screened for autoantibodies against >1600 protein antigens using the Discovery i-Ome microarray (Sengenics, UK) and identified novel SLE-associated autoantibody reactivities (e.g., LIN28A, TGIF2, HMGB2, HMG20B, TFCP2, HNRNPA2B1). 1 Here, we assessed whether HLA class I/II alleles and chr6 variation shape these autoantibody profiles with emphasis on SLE, but also in Sjögren’s disease (SjD), systemic sclerosis (SSc), and healthy controls (HC).Methods Normalised autoantibody levels were analysed in genotyped participants from the PRECISESADS project (n=638). Positivity thresholds were defined per antigen using the HC median+2xIQRs. For each HLA allele, we performed linear regression for autoantibody levels and logistic regression for autoantibody positivity, stratified by disease and in the combined cohort, adjusting for confounders. Statistical significance was set at p<0.05 with false discovery rate applied where possible. Pre-specified focus was on the novel identified SLE markers, 1 with a broad scan for additional signals.Results We observed distinct, allele-dependent autoantibody patterns that differed by disease. Some class II alleles, most notably DRB1*15/DQB1*06, showed broad increases across several novel SLE-associated specificities in the combined cohort. In contrast, DRB1*01-DQB1*05 tended to be protective in SLE across multiple reactivities, yet exhibited positive effects in SjD for selected antigens, indicating clear disease-specific directionality. HLA-B*15, C*12, DRB1*04, and DQA1*03 showed a strong, reproducible association with anti-CCNB1 across analyses. Additional alleles/haplotypes (e.g., A*26, DRB1*08/DQ4) affected multiple antigens, suggesting a haplotype-level link to autoreactivity. Not all novel SLE antigens exhibited a single dominant HLA driver, implying non-HLA or context-dependent mechanisms for some specificities.Abstract S10:02 Figure 1Conclusions HLA class II and I genotypes are linked to distinct patterns in the expanded autoantibody repertoire. HLA-DRB1*15/DQB1*06 appears associated with multiple reactivities. DRB1*01-DQB1*05 showed disease-specific directions, e.g., a positive association in SjD but negative in SLE, while A*26, C*12, and B*15 point to class I-driven profiles. These results highlight allele and haplotype candidates for replication, residue-level fine-mapping, and mechanistic studies, while supporting HLA-based serological sub-phenotyping to sharpen precision diagnostics in SLE and related autoimmune diseases.Reference Parodis et al. ARD 2025.