Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 0 0 2026 05 17 1 15 Ensiye Torki Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Nahid Eskandari Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Kiana Sami Aix-Marseille University, Marseille, France Arezou Gharezadeh Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Mark Sullman Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus AND Department of Social Sciences, University of Nicosia, Nicosia, Cyprus Shakiba Soltani Shiraz Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Hamed Fouladseresht Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran AND Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran 2025 09 10 2026 02 01 Long COVID syndrome (LCS) is characterized by persistent multi-system manifestations with an unclear underlying pathophysiology. Identifying the genetic and immunological factors associated with LCS is essential for improved risk stratification and clinical management. This study investigated whether incorporating HLA-DRB1* and HLA-DQB1* genotyping data could enhance the predictive value of laboratory parameters for identifying individuals at higher risk of developing LCS. Demographic characteristics and relevant clinical history data were extracted from the medical records of 88 individuals diagnosed with LCS (LCS+) and 96 individuals without LCS (LCS−). Serum levels of anti-receptor binding domain IgG (anti-RBD IgG), anti-β2-glycoprotein I IgG (anti-β2GPI IgG), and C-reactive protein (CRP) were measured. Low-resolution genotyping was performed to identify HLA-DRB1* and HLA-DQB1* alleles. Logistic regression analysis was employed to examine the associations between HLA alleles and LCS status. Subsequently, mediation analysis was conducted to explore the potential mechanistic roles of anti-RBD IgG, CRP, and anti-β2GPI IgG in these observed relationships. The LCS+ group exhibited a significantly higher frequency of the HLA-DRB1*01 allele and a lower frequency of the HLA-DRB1*11 than the LCS− cohort. Serum levels of both CRP and anti-β2GPI IgG were substantially higher in the LCS+ cohort, whereas anti-RBD IgG levels were significantly lower. After adjusting for key variables, HLA-DRB1*01 and HLA-DRB1*11 remained significantly associated with LCS. Mediation analysis suggested that these HLA associations might be partially mediated by CRP, anti-RBD IgG, and anti-β2GPI IgG levels. Our findings indicate that the combination of HLA-DRB1*01 and HLA-DRB1*11 allele screening with serological profiling (anti-RBD IgG, CRP, and anti-β2GPI IgG) may contribute to refining predictive models of LCS susceptibility, though clinical utility requires validation in larger, independent cohorts. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4581 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4581/2339