A genome-wide association study suggests the HLA Class II region as the major susceptibility locus for IgA vasculitis

Abstract

The genetic component of Immunoglobulin-A (IgA) vasculitis is still far to be elucidated. To increase the current knowledge on the genetic component of this vasculitis we performed the first genome-wide association study (GWAS) on this condition. 308 IgA vasculitis patients and 1,018 healthy controls from Spain were genotyped by Illumina HumanCore BeadChips. Imputation of GWAS data was performed using the 1000 Genomes Project Phase III dataset as reference panel. After quality control filters and GWAS imputation, 285 patients and 1,006 controls remained in the datasets and were included in further analysis. Additionally, the human leukocyte antigen (HLA) region was comprehensively studied by imputing classical alleles and polymorphic amino acid positions. A linkage disequilibrium block of polymorphisms located in the HLA class II region surpassed the genome-wide level of significance (OR = 0.56, 95% CI = 0.46-0.68). Although no polymorphic amino acid positions were associated at the genome-wide level of significance, P-values of potential relevance were observed for the positions 13 and 11 of HLA-DRB1 (P = 6.67E-05, P = 1.88E-05, respectively). Outside the HLA, potential associations were detected, but none of them were close to the statistical significance. In conclusion, our study suggests that IgA vasculitis is an archetypal HLA class II disease.

Figure 1

Manhattan plot representation of the results of this study. The −log10 of the p values are plotted against their physical chromosomal position. The red line represents the genome-wide level of significance (P < 5E-08). A less stringent threshold (p < 1E-05) is highlighted in blue.

Figure 2

Manhattan plot representation of the step-wise conditional logistic regression of the HLA region. (A) Unconditioned test of the HLA region. (B) Results of the HLA region after controlling for rs9275224. The −log10 of the p values are plotted against their physical chromosomal position. A red/green color gradient was used to represent the effect size of each analyzed variant (red for risk and green for protection). The red line represents the genome-wide level of significance (P < 5E-08).