Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome

Abstract

Background: Chronic fatigue syndrome (CFS) is considered as a neuroimmunological disease but the etiology and pathophysiology is poorly understood. Patients suffer from sustained exhaustion, cognitive impairment and an increased sensitivity to pain and sensory stimuli. A subset of patients has frequent respiratory tract infections (RRTI). Dysregulation of the sympathetic nervous system and an association with genetic variations in the catechol-O-methyltransferase (COMT) and glucocorticoid receptor genes influencing sympathetic and glucocorticoid metabolism were reported in CFS. Here, we analyzed the prevalence of SNPs of COMT and glucocorticoid receptor-associated genes in CFS patients and correlated them to immunoglobulin levels and susceptibility to RRTI.

Methods: We analyzed blood cells of 74 CFS patients and 76 healthy controls for polymorphisms in COMT, FKBP5 and CRHR1 by allelic discrimination PCR. Serum immunoglobulins were determined by immunoturbidimetric technique, cortisol levels by ECLIA.

Results: Contrary to previous reports, we found no difference between CFS patients and healthy controls in the prevalence of SNPs for COMT, FKBP5 and CRHR1. In patients with the Met/Met variant of COMT rs4680 we observed enhanced cortisol levels providing evidence for its functional relevance. Both enhanced IgE and diminished IgG3 levels and an increased susceptibility to RRTI were observed in CFS patients with the Met/Met variant. Such an association was not observed in 68 non-CFS patients with RRTI.

Conclusion: Our results indicate a relationship of COMT polymorphism rs4680 with immune dysregulation in CFS providing a potential link for the association between stress and infection susceptibility in CFS.

Fig. 1

Cortisol levels in CFS patients. Serum of 55 CFS patients was analyzed for cortisol levels. Patients were grouped in the respective haplotypes of the SNPs for a rs4680 for COMT, b rs1360780 for FKBP5, and c rs12944712 for CRHR1. Statistic analysis was performed with the Kruskal–Wallis test followed by post hoc testing via two-tailed Mann–Whitney U test with Bonferroni adjustment for multiple testing with ***p < 0.00033 (0.001/3 comparisons) as significant, ns not significant.

Fig. 2

IgG₃ and IgG₄ levels in CFS patients with COMT, FKBP5, and CRHR1 SNP. a Levels of immunoglobulin subclasses IgG₃ and IgG₄ were determined in serum of CFS patients and grouped according to their genotype for rs4680 for COMT, b rs1360780 for FKBP5, and c rs12944712 for CRHR1, respectively. Statistic analysis was performed with the Kruskal–Wallis test followed by post hoc testing via two-tailed Mann–Whitney U test with Bonferroni adjustment for multiple testing with *p < 0.017 (0,05/3 comparisons) as significant.

Fig. 3

Correlation of IgE levels with COMT SNP rs4680. Serum of 54 CFS patients was analyzed for IgE. Patients were group in either Met/Met, Met/Val, or the wild type variant Val/Val. Enhanced IgE levels are defined >100 U/ml (dashed line). Statistic analysis was performed with two-tailed Chi-Square/Fisher’s exact test with *p < 0.05 between Met/Met or Met/Val and the variant Val/Val.

Fig. 4

Distribution of variants for COMT rs4680 in 34 CFS patients with RRTI and 40 CFS patients without RRTI. As control 68 non-CFS patients with RRTI were analysed. Statistic analysis was performed with two-tailed Chi-Square/Fisher’s exact test with *p < 0.05 between the variant Met/Met and Met/Val, and the major variant Val/Val.

Fig. 5

IgG₃ and IgG₄ levels in 68 non-CFS patients with RRTI with COMT and FKBP5 SNP. Statistic analysis was performed with the Kruskal–Wallis test followed by post hoc testing via two-tailed Mann–Whitney U test with Bonferroni adjustment for multiple testing.