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Poster Session

Scleroderma

Poster Session C

Session: (1855–1876) Systemic Sclerosis & Related Disorders – Basic Science Poster II

1862: Comprehensive analysis of the major histocompatibility complex in systemic sclerosis-associated interstitial lung disease identifies novel associated loci and potential progression biomarkers

Tuesday, October 28, 2025
10:30 AM - 12:30 PM Central Time
Location: Hall F1

    Abstract Poster Presenter(s)

  • Cd

    Carlos de la Rosa Báez, MSc

    Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC
    Granada, Spain

    Disclosure(s): No financial relationships with ineligible companies to disclose


Background/Purpose: The main causes of death in systemic sclerosis (SSc) are pulmonary complications such as SSc-associated interstitial lung disease (SSc-ILD). SSc-ILD is highly heterogeneous and difficult to manage. Although several studies have proven the crucial role of genetics in SSc susceptibility, especially in the major histocompatibility complex (MHC) region, genetic research focusing on SSc-ILD patients is scarce, with limited sample size and statistical power. Considering this, we aimed to conduct a comprehensive MHC genetic scan in the largest cohort of SSc-ILD to date, encompassing a total of 2,363 SSc-ILD patients, 3,526 SSc patients without ILD, and 15,026 controls from 10 international cohorts of European ancestry.

Methods: After genotypic quality controls, the MHC region was imputed using the human leukocyte antigen (HLA) imputation tool from the Michigan Imputation Server. Variants with imputation quality > 0.3 and minor allele frequency > 0.01 were considered for association analyses. Logistic regressions were performed adjusting for the first five principal components and sex, considering two comparisons: SSc-ILD vs SSc patients without ILD, and SSc-ILD vs controls. Finally, inverse variance weighted meta-analyses were performed. To identify jointly significant variants, conditional stepwise analyses were carried out separately for HLA classical alleles, polymorphic amino acid positions (AAs), and single nucleotide polymorphisms (SNPs).

Results: Results from the meta-analyses identified 2,966 significant variants associated with SSc-ILD when compared to SSc patients without ILD, and 5,610 variants when compared to controls. After conditional analysis, the most significant associations mapped in class II HLA genes, such as HLA-DQA1*01:01:01:01 (odds ratio [OR] = 0.54 and 95% confidence interval [95%CI] [0.48 – 0.61] p-value = 3.41 x 10-21) and, interestingly, we also found novel associated variants implicating class I HLA genes as HLA-B*35:02:01:01 (OR = 2.44 [1.81 – 3.29], p-value = 5.64 x 10-9), HLA-C*07:01:01:01 (OR = 1.30 [1.19 – 1.42], p-value = 1.54 x 10-9), and the serine substitution in position 24 of HLA-B (OR = 1.28 [1.18 – 1.39], p-value = 4.44 x 10-9).

Conclusion: In this study, we identify for the first time class I HLA associated with SSc-ILD. These results emphasize the potential role for CD8⁺ T cell mediated cytotoxicity in the pathogenesis of this clinical manifestation. Risk variants in class I HLA region may contribute to the unpaired immune response and tissue injury in the lungs, leading to inflammation and fibrosis. These findings could have significant clinical implications, with potential role as progression biomarkers in SSc patients with lung involvement.