O01 Genetic risk factors associated with increased risk of uveitis in patients with juvenile idiopathic arthritis
Authors: Tordoff Melissa , Smith Samantha L , Lopez-Isac Elena , Morris Andrew , Eyre Stephen , Thomson Wendy , Bowes John 
Published: April 2021

Background/Aims 

Juvenile idiopathic arthritis (JIA) is a childhood-onset rheumatic disease, which is associated with increased risk of uveitis. Approximately 80% of childhood chronic anterior uveitis cases are JIA-associated (JIAU), where it is considered a serious complication with the potential to lead to permanent blindness. Studies have reported associations of increased risk of JIAU to genetic variation within human leukocyte antigen (HLA) genes, in particular amino acid positions of HLA-DRB1. Here we report the results of the largest fine-mapping study of HLA genes in JIAU to date.

Methods 

Genotyping was performed using Illumina Infinium CoreExome and Infinium OnmiExpress arrays. Samples were excluded with a call rate &lt;0.98, discrepancy between genetically inferred sex and database records, inferred relatedness (Identity-by-decent), or ancestral outlier based on principal component analysis (PCA). SNPs were excluded with a call rate &lt;0.98 or a minor allele frequency (MAF) &lt;0.01. HLA alleles, amino acids, and SNPs were imputed using SNP2HLA. Analysis was performed on markers with an information score &gt;0.9 and MAF &gt; 0.01 using logistic regression, or omnibus test for multi-allelic markers, including 3 PCs as covariates. Independent effects were identified using forward stepwise logistic regression by inclusion of previously identified variants as covariates.

Results 

We analysed 7,425 markers across the HLA region in 450 JIAU cases and 2,024 JIA cases. We defined study-wide significance at a Bonferroni corrected threshold of 6.7x10-6. The most significant association was at amino acid position 13 of DRB1 (p-value = 3.0x10-30) where the presence of serine (OR 1.7, 95% CI 1.4-1.9) or glycine (OR 2.0, 95% CI 1.6-2.5) were associated with increased risk of uveitis. Conditioning on DRB1 position 13, found a further association to amino acid position 67 of DRB1 (p-value = 2.4x10-6, unconditioned p-value = 3.2x10-23). The presence of isoleucine (OR 1.5, 95% CI 1.2-1.9) and phenylalanine (OR 1.8 95%, CI 1.4-2.2) at position 67 were associated with increased risk. No further study-wide associations were found at DRB1. Conditioning on all HLA-DRB1 alleles identified an independent effect at amino acid position 69 in DPB1 (p-value = 5.3x10-7, unconditioned p-value = 1.1x10-10). The presence of glutamic acid was associated with increased risk (OR 1.7, 95% CI 1.4-2.0).

Conclusion 

This is the largest genetic study of HLA regions in JIAU and further resolves the genetic risk factors in this key susceptibility region. The analysis in this study has independently validated the association signal at position 13 of HLA-DRB1 (highly correlated with position 11) that had been reported in a previous study. Conditional analysis of HLA-DRB1 revealed a novel secondary association signal at DRB1 to amino acid position 67. Conditional analysis on all DRB1 alleles confirmed association to position 69 of HLA-DPB1 where previous reports of this signal had been only modestly associated.

Disclosure 

M. Tordoff: None. S.L. Smith: None. E. Lopez-Isac: None. A. Morris: None. S. Eyre: None. W. Thomson: None. J. Bowes: None.