Session Information
Date: Tuesday, November 19, 2024
Title: Abstracts: Systemic Sclerosis & Related Disorders – Clinical III
Session Type: Abstract Session
Session Time: 11:00AM-12:30PM
Background/Purpose: Systemic sclerosis (SSc) is a complex autoimmune disease. Class II HLA alleles have been reported to play an important role in SSc pathogenesis. Calcinosis, deposition of insoluble calcium deposits in the dermis and subcutaneous tissues, contributes to morbidity in SSc patients, leading to a decreased quality of life. We previously reported the presence of rare variants in the ABCC6 and ENPP1 genes in SSc patients with severe calcinosis. ABCC6 and ENPP1 genes are involved in dysregulated phosphate metabolism leading to reduced inorganic pyrophosphate (PPi) levels which are implicated in the development of calcinosis. In this study, we examine the HLA associations in patients with SSc and severe calcinosis.
Methods: Genome sequencing, with an average 30X coverage, was performed in thirty-two SSc patients of European ancestry with severe calcinosis, defined as the simultaneous presence of calcinosis at three or more sites. HLA alleles were determined using the HLA∗PRG:LA software. Publicly available genotypes from 6,446 healthy controls of European ancestry were imputed using the Michigan Imputation Server, and the required 6,114 markers were submitted to the SNP2HLA software for HLA imputation. We examined 84 HLA allelic associations by implementing an unconditional logistic regression analysis using Golden helix SVS software. A Bonferroni’s multiple test corrected significance threshold of p-value (P) < 6×10-4 was used for association analyses.
Results: Analyzing this unique cohort of SSc patients with severe calcinosis we identified significant associations between HLA alleles and the calcinosis phenotype. HLA-DRB4*0101 allele showed the strongest association with a P=2.9×10-6 (OR 5.64, [95%CI 2.8-11.3]) (Table 1). The HLA-DQB1*0201 allele is not yet reported in SSc but has been identified as a risk factor for other autoimmune diseases. In our SSc cohort, we identified a significant association with HLA-DQB1*0201 allele (P=7.7×10-5, OR 4.2, [95% CI 2.1-8.4]). The HLA-DQA1*0401 allele was previously reported in anti-centromere antibody positive patients, and we observed a statistically significant association in our cohort as well with a P=2.2×10-4 (OR 6 [95% CI 2.7-13]). Finally, we identified two SSc patients with severe calcinosis who carried rare variants in the ABCC6 and ENPP1 genes and also carried two of the HLA risk alleles (Table 2).
Conclusion: This is the first study to report the association of the HLA-DRB4*0101 allele with calcinosis in SSc. The presence of HLA risk alleles along with rare variants in ABCC6 and ENPP1 genes raises intriguing hypotheses about the genetic contributions to severe calcinosis in SSc and highlights the need for further investigation.
To cite this abstract in AMA style:
Faghihi-Kashani S, davluri s, Kuchinad K, deng Z, Naz F, Dell'Orso S, McMahan Z, Hummers L, Kastner D, Wigley F, fiorentino d, Lood C, Shah A, Chung L, Gourh P. HLA-DRB4: A Novel Susceptibility Locus in Systemic Sclerosis Patients with Severe Calcinosis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/hla-drb4-a-novel-susceptibility-locus-in-systemic-sclerosis-patients-with-severe-calcinosis/. Accessed .« Back to ACR Convergence 2024
ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-drb4-a-novel-susceptibility-locus-in-systemic-sclerosis-patients-with-severe-calcinosis/