Association between the HLA-A, HLA-B, HLA-C and HLA-DRB1 gene alleles and Sjögren's syndrome with anti-Ro/SSA and anti-La/SSB autoantibodies production
Authors: Guseva I. A. , Chanyshev M. D. , Torgashina A. V. , Vlasenko N. V. , Khvan Yu. I. , Samarkina E. Yu. , Shabatina M. V. , Khafizov K. F. 
Published: December 2024

Literature data suggest that HLA alleles may be associated with the development of Sjögren's syndrome (SS) and the production of autoantibodies against the Ro/SSA and La/SSB antigens. However, such studies have not been conducted in Russia.

Objective: to study the association between alleles of the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes and the risk of developing SS and the production of autoantibodies.

Material and methods. The study included 80 patients with SS or Sjögren's disease (SD). All patients met the ACR/EULAR criteria, 2016. AntiRo/SSA and anti-La/SSB autoantibodies were detected in 67 patients (83.8%), 37 patients had the combination anti-Ro/SSA/anti-La/SSB, 30 patients had only anti-Ro/SSA, and 13 patients did not have these antibodies. The control group consisted of 160 healthy blood donors without autoimmune diseases and without a family history of autoimmune diseases, who were comparable in gender and age to the patient group. High-throughput sequencing of the alleles of the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes was performed on the Illumina MiSeq platform using the MiSeq Reagent Kit v3. To amplify the exons of the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes, 56 specially designed primers containing Illumina adapters at the 5’ ends for subsequent indexing were used. Statistical data processing, including comparison of the frequencies of HLA alleles in the group of patients with SS/SD and in the control group, was performed in the Python software environment using the Numpy, Pandas and scikit-learn libraries.

Results and discussion. In the group of patients compared to the control group we observed an increase in frequency for the alleles HLA-A*01:01:01 (OR=3.28, 95% CI [1.90–5.67], p <0.001), B*08:01:01 (OR=5.41, 95% CI [3.00–9.82], p<0.001), C*07:01:01 (OR=5.12, 95% CI [2.57– 10.19], p<0.001). In addition, all 2-, 3- and 4-allele combinations were significantly more frequent in the patient group compared to the controls. The most significant combinations of alleles as risk markers for the development of SS were the 2-allele haplotype B*08:01:01-DRB1*03:01:01 (OR=6.65, 95% CI [3.37–13.14], p<0.001) and the 4-allele haplotype A*01:01- B*08:01-C*07:01-DRB1*03:01 (OR=6.05, 95% CI [2.71–13.51], p <0.001). The most significant correlation between the production of two autoantibodies anti-Ro/SSA/anti-La/SSB was found for the haplotypes B*08:01:01-DRB1*03:01:01 (OR=9.50, 95% CI [4.16–21.70], p<0.001) and A*01:01:01-B*08:01:01-C*07:01:01-DRB1*03:01:01 (OR=7.20, 95% CI [2.81–18.43], p <0.001). In the group of 30 patients who only produced anti-Ro/SSA, the association with the above-mentioned haplotypes was less pronounced, although it remained high. Small sample of patients without anti-Ro/SSA and anti-La/SSB (13 patients), did not allow to determine statistically significant associations with HLA alleles/haplotypes.

Conclusion. A statistically significant association was found between several HLA alleles/haplotypes belonging to ancestral haplotype 8.1 (AH 8.1) as markers of susceptibility to SS and the production of Ro/SSA and La/SSB autoantibodies.