Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset

Abstract

Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases. Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS. The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04-2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17-2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56-2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61-1.30, p = 0.268). This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.

Keywords: autoimmunity; chronic fatigue syndrome (CFS); cytotoxic T-lymphocyte-associated protein 4 (CTLA4); interferon regulatory factor 5 (IRF5); myalgic encephalomyelitis (ME); single nucleotide polymorphism (SNP); tumor necrosis factor (TNF); tyrosine phosphatase non-receptor type 22 (PTPN22).

Figure 1

Genotype distribution of CTLA4 and PTPN22 SNPs. Distribution of major (black), hetero (white), and minor (gray) genotypes of CTLA4 rs3087243 (A) and PTPN22 rs2476601 (B) in ME/CFS patients with (n = 232) and without infection triggered onset (n = 73), and healthy controls (n = 201). The risk allele G in rs3087243 and A in rs2476601 are underlined. Statistical analyses were performed using 2 × 3 contingency tables and χ²- test. A p ≤ 0.05 was considered as statistically significant. HC, healthy control; w/ ITO, with infection-triggered onset; w/o ITO, without infection-triggered onset.

Figure 2

Association of disease onset type (A), PTPN22 SNP (B), or CTLA4 SNP (C) in ME/CFS patients with immune marker. Median with range of C3 and C4 complement levels [mg/dl], CD19+ B cells [/nl], and CrP [mg/dl] is shown for the ME/CFS subgroups (A) with (w/) or without (w/o) infection-triggered onset (ITO). (B) without or with PTPN22 rs2476601 risk allele A or (C) without or with CTLA4 rs3087243 risk allele G. Statistical analysis was performed using Mann–Whitney U test. A p ≤ 0.05 was considered as statistically significant.