Sex-stratified autosomal association analysis reveals dimorphic genetic risk factors in non-systemic juvenile idiopathic arthritis

Objectives

Juvenile idiopathic arthritis (JIA) is a collection of childhood onset rheumatic conditions that more frequently occur in females in most subtypes. Sex influences disease biology, treatment trajectories, and patient outcomes, however, no study to date has investigated the interaction of sex with autosomal genetic risk to JIA.

Methods

Genotype data from 3748 JIA cases (2551 female, 1197 male) and 9196 controls (5136 female, 4060 male) were analysed using a sex-stratified genome-wide association analysis. Systemic JIA was excluded. HLA imputation and fine-mapping were performed using SNP2HLA. Sexspecific effects were assessed using an omnibus sex-interaction test for multi-allelic amino acid positions. A subtype specific analysis was repeated in rheumatoid factor (RF) negative polyarthritis and oligoarthritis (1862 female, 718 male).

Results

A sex-combined analysis identified genome-wide significant (P<5x10 ^-8 ) loci across the HLA region and nine loci outside the HLA region, including a novel association at rs231977 ( NUPR1) . Markers within the HLA region were significantly sex-dimorphic (P<5x10 ^-8 ) and nine loci outside of the HLA region were suggestive for sex dimorphism (P<5x10 ^-6 ), including SPRY2. HLA fine-mapping identified lysine at position 70 of HLA-B conferring greater male JIA risk, and tyrosine at position 10 of HLA-DRB1 conferring greater female JIA risk. Subtype specific analysis strengthened the association of tyrosine at position 10 of DRB1 in females.

Conclusions

This study provides the first evidence that autosomal genetic risk factors contribute to JIA risk in a sex-dimorphic manner, mirroring known clinical observations, and highlighting the importance of incorporating sex-stratified methods in future JIA studies.

Key Messages

What is already known on this topic

• Sex dimorphism is well-established in non-systemic juvenile idiopathic arthritis (JIA) presentation, with females more frequently affected. Genetic studies have defined genetic susceptibility loci for JIA, however the contribution of genetic risk factors for sex dimorphism remains unknown.

• This is the first sex-stratified autosomal genetic study of JIA, revealing that markers within the HLA region are sex-dimorphic in their association to JIA susceptibility. Specifically, lysine at position 70 of HLA-B presented a greater risk to JIA in males. Tyrosine at position 10 of HLA-DRB1 presented a greater risk to JIA in females.

• In defining autosomal genetic risk that significantly differs between males and females with non-systemic, this study advances understanding of the biological mechanisms underlying sex dimorphism in JIA presentation. These findings highlight the importance of incorporating sex-stratification into future JIA genetic studies and may inform future research of JIA classification. Further validation is required before clinical translation of these findings.