Background/Purpose: Stress is recognized as an important risk factor in the pathogenesis of rheumatoid arthritis (RA). However, it is still incompletely understood how the stress response and interactions between the autonomic nervous system, the hypothalamus-pituitary-adrenal axis and the immune system contributes to the pathogenesis of RA. The purpose of our study was to characterise neuroimmune interactions common variants in the genes of the beta2-adrenergic receptor (beta2AR) and corticotropin releasing hormone (CRH) together with functional stress responses in RA patients and controls.

Methods: An allele-specific polymerase chain reaction was used to determine the polymorphisms of the beta2AR at position 16, 27, and 164, as well as the polymorphic sequences in the 5′ flanking region of the human CRH gene in patients with RA (n = 310) and ethnically matched healthy controls (n = 305). In a subgroup of RA patients (n = 100) the autonomic response upon various standardised stressors was performed by utilising the heart rate variability (HRV) test (ProSciCard III, Version 2.2a, Medi-Syst GmbH, Germany) and compared to 45 age and sex matched osteoarthritis patients. To evaluate the impact of CRH promoter polymorphisms on the stress response in a subgroup of RA patients (n=18) an insulin hypoglycaemia test (IHT) was performed studying the dynamics of blood glucose levels, CRH, adrenocorticotropin (ACTH) and cortisol production.

Results: There was a highly significant distortion in the distribution of the beta2AR polymorphism at codon 16 between RA patients and controls, contributing to the genetic background of RA. Arginine (Arg) at codon 16 was present in 89.7 % of RA patients compared to 66.2 % controls (OR 4.43, 95 % CI 2.81 to 7.02, p = 0.00001). Stratifying RA patients for the amino acid sequence at position 16 and their autonomic reactivity revealed a statistically significant decrease of parasympathetic activity, in particular for the deep breathing test, in patients with homozygosity for Glycine (Gly) 16 compared to RA patients being heterozygous (Arg16Gly). However, RA patients with homozygosity for Glycine 16 showed a normalisation of the sympathetic reactivity upon mental stress test. On the other hand, polymorphisms of CRH 5’regulating region are differentially distributed in RA patients and healthy subjects. The CRH promoter polymorphisms exerted a significant influence on the stress response of RA patients undergoing an IHT. The integrated cortisol response to hypoglycaemia expressed as area under the curve was significantly lower in RA patients bearing the A1B1 allele (64154 ± 5768 nmol/l) compared to the A2B2 allele (91273 ± 7298 nmol/l, p=0.016).

Conclusion: Polymorphisms of the beta2AR and CRH contribute to the genetic background of RA and is associated with disturbed functional stress reactivity on various levels in these patients. Further studies are warranted to determine the role of genetic factors on stress response in the disease process of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-markers-of-functional-stress-response-in-patients-with-rheumatoid-arthritis/