Correlation Study Of HLA-DQ Gene Polymorphisms And Myasthenia Gravis

Objectives:Childhood-onset and ocular myasthenia gravis (MG) are more common in Chinese compared to Caucasian populations. HLA-DQ was typed to investigated whether the polymorphism of HLA-DQ genes correlates with onset age of disease, MG clinical subgroups and acetylcholine receptor (AChR) antibody levels.Methods:196 Chinese Han myasthenia gravis patients from East China and 100 healthy controls from the same region underwent high resolution HLA DQ analysis using polymerase chain reaction- sequence based typing (PCR-SBT) that covered exon 1-4 of DQA1 gene and exon 2 and 3 of DQB1 gene. Serum AChR antibody was determined by enzyme-linked immunosorbent assay in 133 patients before immunosupressive therapy or during clinical exacerbation. DQA1-DQB1 haplotype was estimated using maximum-likelyhood method (EM algorithm). Significancy of differences between case and control was tested by Fisher’s exact test. Relative risk was represented by odd ratio (OR).Results and Conclusions:1) Haplotype frequency of DQA1*03:02-DQB1*03:03:02 (DQ9) was significantly higher in childhood-onset MG patients (OR=4.6, p<0.001). DQ9 was observed in 88% childhood-onset MG patients.2) HLA haplotype DQA1*03:01:01-DQB1*03:02:01 (DQ8) and DQ9 frequencies were significantly increased in ocular MG (oMG) patients (OR=3.4, p<0.01; OR=3.5, p<0.001; respectively). DQ8 was assiociated with late-onset oMG (onset age> 40), while DQ9 was associated with early-onset oMG (onset age<= 40).3) Haplotype frequency of DQ9 was also increased in MG patients with concurrent autoimmune diseases (OR=3.9, p<0.01). This MG subgroup was characterized by low AChR antibody levels, which might due to the effect of DQ9.4) DQA1*03:02 allele is in high linkage disequilibrim with DQB1*03:03:02, both of which are part of the asian ancestral haplotype. DQ9’s high haplotype frequency in Chinese and extremely low frequency in Caucasians is probably the reason underlies the ethnic differences of MG phenotypes.