Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome, 2015, Rajeevan et al

forestglip

forestglip

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2015 study

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

Mangalathu S. Rajeevan, Irina Dimulescu, Janna Murray 1, Virginia R. Falkenberg, Elizabeth R. Unger

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 11 K 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.

Link | PDF (Human Immunology) [Open Access]
 
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This study found some variants in a gene that codes for complement factor H (CFH) which were more common in ME/CFS. This molecule was found to be higher in ME/CFS in this study: Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity, 2024, Beentjes, Ponting et al

From this paper:
For CFH, four SNPs, rs1061147 (G/T polymorphism), rs7529589 (C/T polymorphism), rs1061170 (T/C polymorphism) and rs10801555 (G/A polymorphism), were in high LD (Fig. 1B). Their respective major alleles G, C, T and G were associated with CFS in both allele (72–73% CFS vs 56% NF; p = 4.81–6.5 × 10−3) and haplotype analyses. Haplotype GCTG was 2 times more likely to be associated with CFS than NF (OR = 2.07; CI = 1.24–3.45; p = 4.8 × 10−3).
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forestglip said:
2015 study

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

Mangalathu S. Rajeevan, Irina Dimulescu, Janna Murray 1, Virginia R. Falkenberg, Elizabeth R. Unger

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 11 K 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.

Link | PDF (Human Immunology) [Open Access]
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It’s an interesting finding, but 50 patients is a tiny sample for genetic studies of this type. DecodeME data should be available sometime next year on 20,000 people and around 900,000 SNP‘s. I suspect that will include at least 10,000 immune genes
 
Jonathan Edwards said:
Yet they did pick out factor H again!
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They did!

– if that replicates in decodeme data, that will be quite something. If it doesn’t, it’s more questionable. Note that GWAS does not use pathway analysis so wouldn’t be expected to make the same findings as we see here. But someone else can apply pathway analysis to immune pathway SNPs

Added;, that should (and was always intended to) be a general benefit of decodeme. Got a hypothesis supported by study? See how it holds up in a huge and representative data set.
 
The Beentjes paper found several other complement proteins upregulated as well, including complement factor B (CFB) and complement component 2 (C2), whose genes were also associated with ME/CFS here.

Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity, 2024, Beentjes, Ponting et al
Considering all cases combined, 54 proteins are significant. Among these are 7 complement proteins (C1RL, C2, CFB, CFH, CFI, CFP and CR2) of the innate immune system, whose levels are all elevated in ME/CFS cases, including CR2 (complement C3d receptor 2), the receptor for Epstein-Barr virus (EBV) binding on B and T lymphocytes.
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This paper
For C2/CFB, two SNPs, rs9332739 (G/C polymorphism) and rs4151667 (T/A polymorphism) were in high LD (Fig. 1A). Their respective minor alleles C and A were associated with CFS in both allele and haplotype analyses. Haplotype CA was nearly 4 times more likely to be associated with CFS than NF (OR = 3.73; CI = 1.38–10.10; p = 6.0 103 ).
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Both CFH and CFB play pivotal but opposing roles in the alternate pathway. CFB activates the complement cascade by contributing to the formation C3 convertase and CFH inhibits the same pathway by accelerating the decay of C3 convertase [37]. C2 is similar to CFB, but contributes to the formation of C3 convertase through the classical pathway.

Interestingly two CFS-associated missense variants in genes of complement activation, [rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH] have previously been associated with age-related macular degeneration (AMD). The haplotype analysis that included the rs9332739 (E318D) in C2, a SNP that is in high LD with rs4151667 in CFB, reported to be associated with AMD, was also associated with CFS in our study; however, the risk and protective variants were switched (i.e. alleles protective for AMD were associated with risk for CFS).

A recent report indicates that protective alleles of CFH and CFB for AMD associate with lower levels of complement activation [40]. Since the same alleles are associated with risk for CFS in this study, we hypothesize lower levels of complement activation may be associated with at least a subset of CFS subjects.
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