HLA-DRB1 allele distribution in Chilean population: Insights into rheumatoid arthritis susceptibility and protection

Diego Catalán¹Lilian Soto^1,2Óscar Neira³María C Cuéllar-Gutiérrez³Roberto Díaz-Peña^4,5Octavio Alexis Aravena¹Eduard Palou⁶Montserrat Carrascal⁷Juan C Aguillón^1*Jaxaira Maggi^7*

• ¹Immune Regulation and Tolerance Research Group (IRT Group), Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Santiago Metropolitan Region (RM), Chile
• ²Hospital Clínico de la Universidad de Chile, Santiago, Santiago Metropolitan Region (RM), Chile
• ³Hospital del Salvador, Universidad de Chile, Santiago, Chile
• ⁴Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
• ⁵Immunogenetics Lab, Fundación Pública Galega de Medicina Xenómica, SERGAS, Grupo de MedicinaXenómica-USC, Instituto de investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain
• ⁶Servicio de Inmunología, Hospital Clínic de Barcelona, Barcelona, Spain
• ⁷Biological and Environmental Proteomics Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC/IDIBAPS), Barcelona, Spain

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease influenced by genetic factors, particularly HLA-DRB1 alleles. The objective of this study was to characterize the distribution of HLA-DRB1 alleles in Chilean RA patients and healthy controls (HC) and evaluate associations with susceptibility or protection, autoantibody seropositivity, and disease activity. Methods: We genotyped 367 RA patients and 623 HC for HLA-DRB1 using PCR-SSO. Then, we examined allele frequencies and distribution, including known RA risk alleles of the "Shared Epitope" (SE) of HLA-DRB1 and protective (PR) alleles, using the Chi-square or Fisher's exact tests. Odds ratios with 95% confidence intervals were calculated to measure the degree of association, and unpaired T-tests were used to compare continuous variables. Results: The most frequent SE alleles among RA patients were *04:01 (16.1%), *04:04 (13.9%), and *14:02 (11.7%). SE alleles *04:01, *04:04, *04:05, *04:08, and *10:01, along with non-SE alleles *09:01 and *15:02, were associated with RA susceptibility. In addition, allele *14:02 showed an association with the presence of anti-cyclic citrullinated peptides (anti-CCP) antibodies. Meanwhile, PR alleles *11:01 (14.8%) and *16:02 (9.8%) were observed most frequently in HC and RA patients, respectively. PR alleles *11:01, *11:04, and *13:01, as well as the non-PR alleles *15:01, *04:07, *03:01, *07:01, and *08:02, were associated with protection from RA, and showed no significant associations with autoantibody seropositivity. Discussion: This study provides a comprehensive overview of HLA-DRB1 allele distribution in the Chilean population, identifying both well-known and novel allele associations with RA susceptibility, protection, and disease activity.