Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome

Abstract

Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS. Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11K single nucleotide polymorphisms (SNPs) following the manufacturer's protocol. Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs. CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4). Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5' UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms. This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study.

A systematic review of the association between fatigue and genetic polymorphisms

“…In addition, the cytokine SNP TNF-308 was found to be highly associated with CFS (Carlo-Stella et al, 2006). This relationship was further supported by another study that demonstrated associations between 32 inflammation and immune-related SNPs and CFS (Rajeevan et al, 2015). …”

“…These mechanisms primarily included neurotransmitter dysregulation (five studies) (Fukuda et al, 2013; Narita et al, 2003; Smith et al, 2008, 2011; Sommerfeldt et al, 2011), hypothalamic-pituitary adrenal (HPA) axis regulation (two studies) (Lee et al, 2009; Rajeevan et al, 2007), inflammatory/immunomodulatory responses (four studies) (Carlo-Stella et al, 2006, 2009; Rajeevan et al, 2015; Smith et al, 2005), and other mechanisms involving metabolism and endurance (one study) (Vladutiu and Natelson, 2004)…”

Genome-epigenome interactions associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…The earliest study by Smith et al [22] evaluated 116,204 SNPs (n = 40 CFS, n = 40 non-ME/CFS) using the Affymetrix GeneChip Mapping 100K array, and found 65 SNPs associated with ME/ CFS (p < 0.001). Rajeevan et al [21] used the Affymetrix Immune and Inflammation Chip to focus on~11,000 SNPs located in genes involved in immune and inflammation pathways (n = 121 ME/ CFS, n = 50 non-ME/CFS). Of these, 32 were associated with ME/CFS (p < 0.05).…”

“…There were no other overlaps in the SNPs or genes associated with ME/CFS between this study and previous genetic association studies. This observation may be confounded by a combination of multiple factors, including: 1) Differences in the types of arrays utilized in each study (our study, with the largest genetic coverage to date, evaluated two-orders of magnitude more SNPs than the Rajeevan et al [21] study); 2) Differences among cohorts due to the heterogeneity of ME/CFS; 3) Reduced statistical power to discriminate the effects of multiple small-effect variants due to relatively small sample sizes in each of these studies; and 4) Interactions with environmental and epigenetic factors. Additional larger-scale genomewide association studies with overlapping SNP probes and larger sample sizes will further our understanding of the interaction between genetic factors and ME/CFS.…”

“…Multiple studies point to disruptions in the immune and neuroendocrine systems in ME/CFS patients [8][9][10][11][12][13][14][15][16][17][18][19]. ME/CFS appears to be associated with specific genetic polymorphisms [20][21][22], as well as with alterations of the DNA methylome in lymphocytes [11,23,24]. Understanding the contribution of genetic background in ME/CFS patients as a predisposing factor for epigenetic abnormalities associated with the disease is a fundamental step to elucidate its causes.…”