A systematic review and meta-analysis of HLA class II associations in patients with IgG4 autoimmunity

Abstract

Autoimmune diseases caused by pathogenic IgG4 subclass autoantibodies (IgG4-AID) include diseases like MuSK myasthenia gravis, pemphigus vulgaris or thrombotic thrombocytopenic purpura. Their etiology is still unknown. Polymorphisms in the human leukocyte antigen (HLA) gene locus, particularly in HLA-DRB1, are known genetic susceptibility factors for autoimmune diseases. We hypothesized a similar role for HLA polymorphisms in IgG4-AID and conducted a systematic review and meta-analysis with case-control studies on IgG4-AID based on MOOSE/ HuGENet guidelines. Genotype (G) and allele (A) frequencies of HLA-DQB1*05 (G: OR 3.8; 95% CI 2.44-5.9; p < 0.00001; A: OR 2.54; 95% CI 1.82-3.55; p < 0.00001) and HLA-DRB1*14 (G: OR 4.31; 95% CI 2.82-6.59; p < 0.00001; A: OR 4.78; 95% CI 3.52-6.49; p < 0.00001) and the HLA-DRB1*14-DQB1*05 haplotype (OR 6.3; 95% CI 3.28-12.09; p < 0.00001/OR 4.98; 95% CI 3.8-6.53; p < 0.00001) were increased while HLA-DRB1*13 (G: OR 0.48; 95% CI 0.34-0.68; p < 0.0001; A: OR 0.46; 95% CI 0.34-0.62; p < 0.00001) was decreased in IgG4-AID patients. In conclusion, the HLA-DQB1*05, HLA-DRB1*14 alleles and the HLA-DQB1*05-DRB1*14 haplotype could be genetic risk factors that predispose for the production of pathogenic IgG4 autoantibodies and the HLA-DRB1*13 allele may protect from IgG4 autoimmunity.

Figure 1

PRISMA flow chart of study identification and eligibility screening. For specific inclusion and exclusion criteria see methods. Figure modified from Moher et al..

Figure 2

Forest plot depicting allele and genotype frequency of HLA-DRB1*14 in patients with class I IgG4-AID. Cumulative meta-analysis with a random-effects model demonstrated a significant increased frequency in patients compared to controls. ‡ Study did not differentiate between disease subgroups of pemphigus or CIDP. * Study was included after discussion with W.B. **Study in which the same control group was used for pemphigus foliaceus and pemphigus vulgaris, here data was pooled for analysis.

Figure 3

Forest plots of the allele and genotype frequency for HLA-DQB1*05 in patients with class I IgG4-AID. Meta-analysis using a random-effects model demonstrated a significant increased frequency in patients compared to controls. ‡ Study did not differentiate between disease subgroups of pemphigus or CIDP. * Study was included after discussion with W.B. ** Study in which the same control group was used for pemphigus foliaceus and pemphigus vulgaris, here data was pooled for analysis.

Figure 4

Forest plots of haplotype frequencies for HLA-DRB1*14-DQB1*05 in patients with class I IgG4-AID. Meta-analysis using a random-effects model showed a significant positive association in patients throughout all six diseases. (n): haplotype frequency was defined as the number of individuals with a specific haplotype out of the number of total individuals; (2n): haplotype frequency was defined as the total number of a specific haplotype out of the total number of alleles of all study participants. ** Study in which the same control group was used for pemphigus foliaceus and pemphigus vulgaris, here data was pooled for analysis.

Figure 5

Forest plots of allele and genotype frequency of HLA-DRB1*13 in patients with class I IgG4-AID. Meta-analysis using a random-effects model demonstrated a significant decreased frequency in patients compared to controls. ‡ Study did not differentiate between disease subgroups of pemphigus or CIDP. *Study was included after discussion with W.B. **Study in which the same control group was used for pemphigus foliaceus and pemphigus vulgaris, here data was pooled for analysis.

Figure 6

Funnel plot analysis of genotype and allele frequency data for HLA-DQB1*05, DRB1*13 and HLA-DRB1*14 in all IgG4 patients. A funnel plot analysis was undertaken to assess publication bias. Odds ratios were plotted against the standard error and the studies demonstrated symmetrical scattering along the funnel axis (pooled effect estimate from meta-analysis).