Associations between SE-encoding HLA-DRB1
alleles and RA have been well established. Previously, studies of small cohorts of children with “seropositive JRA” reported associations with HLA-DR4
). Many of these studies, dating back 20 years or more, used lower resolution HLA typing, and were limited to evaluating the presence or absence of SE (). In the work reported here, we not only confirmed the association between SE alleles and susceptibility to childhood onset of RA using the largest cohort of CORA patients yet assembled, but also demonstrated associations between individual HLA-DRB1
alleles and CORA for the first time.
Prior investigations of SE in NHW children with CORA.
In a study limited to 15 children with RA, Vehe et al observed that 11 (73%) children carried an SE-encoding HLA-DRB1
allele on both haplotypes, and speculated that gene dosage may contribute to the early disease onset that defines CORA (11
). In contrast, Barron et al, reported that none of their 13 cases with CORA had 2 copies of the SE (6
). Addressing this discrepancy in our larger dataset, we found that the proportion of children with CORA who have two copies of SE was significantly higher than in controls (33% versus 6%), a finding similar to what has been observed in well powered studies of adults with RA. Specifically, 28% of 1320 British adults with RA were found to have 2 SE alleles compared to 7% of controls (14
). Likewise in a separate study, 33% of 1275 adults with ACPA-positive RA carried 2 SE alleles, compared to 8% among 2405 controls (15
). The similarity between our findings in CORA and adult onset RA suggests that gene dosage at the HLA-DRB1
locus does not influence the age of onset of RA.
Investigating the allelic combinations present in our population, we found that heterozygosity for HLA-DRB1*0401/0404
confers a significantly excessive risk of CORA, consistent with findings previously reported in adults with severe RA (16
). Furthermore, the frequency of heterozygosity for S2/S3P alleles was higher in our cohort of CORA compared to that reported for the British cohort of RA reported by Morgan et al. (23.5 % in CORA versus 15.8% in RA were heterozygous for S2/S3P alleles; OR 1.64 (1.07-2.51), p <0.02). Also the genotypic ORs for SEs suggests that heterozygosity for S2/S3P confers a greater risk of CORA compared to RA (OR for S2/S3P versus L/L = 22.3 in CORA compared to 7.4 in RA). The differences between CORA and adult RA may reflect sampling variation from a relatively smaller number of pediatric cases. However, the excess risk conferred by individuals who carry the combination of S2/S3P alleles even beyond that expected based on the presence of two risk alleles suggests that children with HLA-DRβ1 chains containing both KRAA and Q/R-RRAA are especially prone to CORA.
Our study does have some limitations, notably the relatively small number of children who were of African American or Hispanic descent in the cohort. Despite the small sample size, there was an association between CORA and SE in Hispanic American children. There was also a trend towards association between SE and CORA in African American children, likely reflecting the small sample size. It should be noted that the frequency of SE-encoding HLA-DRB1
alleles among African American children with CORA is comparable to African American adults with early RA reported by Hughes et al (26.2% in CORA versus 25.2% in RA) (17
). Our control samples were limited to two sources, (Utah and Ohio), whereas the case samples came from a greater number of institutions, with ~ 70% of cases coming from Utah and Ohio. We do not believe this affected our results, given that the controls were broadly representative of the NHW population of the United States. This is further supported by almost identical frequencies of HLA alleles among controls used in our study and >7000 NHW controls from the NMDP Registry (13
). Another limitation was the lack of extensive phenotype information such as erosions or nodules, hence limiting our analyses to association between SE and susceptibility but not severity of disease. Finally, it would have been ideal to perform a meta-analysis using data from published studies. However, the published data spanned several years and lacked appropriate data. Control frequencies were not always available and the SE-encoding alleles included varied in these studies. These factors precluded a meta-analysis.
Important genetic discoveries have resulted from investigations of individuals with an earlier age-of-onset of several complex genetic traits, including inflammatory bowel disease and obesity (18
). We believe CORA is also a genetically enriched early-onset cohort that is a promising target for identification of additional genetic factors predisposing to RA. Furthermore, studying children minimizes the impact of environmental influences such as smoking, also known to confer susceptibility to RA (20
). Our results suggest that whereas SE-encoding HLA-DRB1
alleles confer a significant risk for developing CORA, HLA-DRB1
gene dosage does not appear to be a factor influencing the development of RA in childhood compared to adulthood. However, our results show that compared to adults with RA, children with CORA appear to have a greater frequency of S2/S3P alleles, suggesting that heterozygosity for HLA-DRB1
alleles encoding SE plays a role in early onset of disease. Investigating the role played by HLA and non-HLA loci, as well as rare variants in larger, well-characterized cohorts of children with CORA will likely yield further insights into the etiopathogenesis of RA.