JIA is an inflammatory arthropathy in which T-cells with a pro-inflammatory cytokine profile play key roles in the perpetuation of immune responses. Alterations in the interactions between the autonomic nervous system and the immune system could be associated with autoimmune disorders. Autonomic dysfunction has been reported in several autoimmune disorders, including RA.[4
] Children with active JIA demonstrated higher resting heart rates than controls.[7
] This increase was not seen when JIA was inactive, suggesting that JIA is also associated with autonomic dysfunction.
The interaction between the nervous system and the immune system is critical to maintain immune homeostasis.[8
] The sympathetic nervous system influences the immune system through the release of norepinephrine. β2-ARs expressed on B-cells, naïve CD4 cells and Th1 cells mediate the interaction between the sympathetic nervous system and the immune system.[8
] In a study of β2-adrenergic mechanisms in experimental arthritis, Levine et al found that administration of specific β2-AR antagonists significantly retarded disease onset and reduced the severity of arthritis.[18
] This suggests that β2-ARs contribute to joint injury in experimental arthritis. Activation of the β2-ARs results in the production of cAMP, which regulates cellular processes such as production of cytokines. Children with JIA demonstrate altered responses to catecholamines and have decreased cAMP levels compared to healthy controls.[6
] Together, these observations suggest that β2-ARs could play important roles in inflammatory arthropathies, including JIA.
variants have been associated with RA in Swedish and German cohorts, [11
], as well as with myasthenia gravis [13
] and Graves disease.[14
] We undertook this study to investigate the same variants in JIA. Our results do not support a major role for these two functional ADRB2
variants in JIA or any of the JIA subtypes. A minor role for these cannot be excluded given that our cohort size was modest. Both RA studies suggest that the R16 variant is associated with increased RA risk, (OR:2-3 for the R allele).[11
] Myasthenia gravis also demonstrates an association with the R16 variant (OR:3.6, for the RR genotype).[13
] Our JIA cohort is adequately powered to detect an association with an OR of ~1.5 for both polymorphisms.
Lack of power can be a major limitation of case-control studies. Hence we performed a meta-analysis. The combined cohort of 1152 subjects has 80% power to detect an association with an OR of ~1.4, but a meta-analysis of the G16R variant did not find an association with JIA. Although our cohort was ascertained in the United States and that of Schubert et al., was from Germany, we felt a meta-analysis was justified because the population of Utah is genetically similar to other Northern European-derived populations.[19
] It should be noted that our RF-positive JIA cohort is small, and a larger cohort would be necessary to determine if there is an association with this or other JIA subsets. When we combined all polyarticular JIA subjects and repeated the analyses, we still did not find an association with either variant (data not shown). The minor departure from HWE at position 16 among cases is unlikely to be responsible for the observed lack of association.
JIA is a clinically and genetically heterogeneous disease.[3
] The lack of the association observed here might reflect the differences between the different subtypes of JIA. Thus, our cohort is underpowered to detect associations between the individual subtypes of JIA and these variants. While there are some examples of common genetic susceptibility factors between JIA and RA such as PTPN22
, others, like CCR5
, show conflicting results in different populations.[3
Although the associations between ADRB2 variants and RA appear to be validated, having been seen in two different cohorts, larger studies are necessary to confirm this association. Recent meta-analyses have failed to confirm several positive associations reported in small initial cohorts of patients with RA. Our results suggest that although RA and JIA share several clinical and pathological features, as well as some common genetic risk factors, ADRB2 variants do not appear to play a major role in susceptibility to JIA.