Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome

Objective Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disorder characterized by debilitating fatigue accompanied by pain and impairments in memory, cognition, and concentration. Acetylcholine (ACh) has a plethora of roles in neuronal and neuromuscular transmission. There are two types of ACh receptors, muscarinic and nicotinic, comprising 17 different subunits of the nicotinic ACh receptor (nAChR) and five different subtypes of the muscarinic receptor (mAChR) that have been identified in humans. The purpose of this study was to determine the role of ACh receptor (nAChRs and mAChRs) single nucleotide polymorphisms (SNPs) in CFS/ME patients. Methods One-hundred and fifteen CFS/ME patients (age = 48.68 ± 1.06 years) and 90 nonfatigued controls (age = 46.48 ± 1.22 years) participated in this study, where CFS/ME patients were defined according to the 1994 Center for Disease Prevention and Control (CDC) criteria. A total of 464 SNPs for nine mammalian ACh receptor genes ( M1, M2, M3, M4, M5, alpha 2, 5, 7, and 10) were examined via the Agena Biosciences iPLEX Gold assay. Statistical analysis was performed using the PLINK analysis software. Results Seventeen SNPs were significantly associated with CFS/ME patients compared with the controls. Nine of these SNPs were associated with mAChRM3 (rs4463655; P = 0.00281, rs589962; P = 0.00348, rs1072320; P = 0.00371, rs7543259; P = 0.00513, rs6661621; P = 0.00536 rs7520974; P = 0.0167, rs726169; P = 0.02349, rsrs6669810; P = 0.02361, rsrs6429157; P = 0.0375), while the remainder were associated with nAChR alpha 10 (rs2672211; P = 0.0107, rs2672214; P = 0.0108, rs2741868; P = 0.01185, rs2741870; P = 0.01281, rs2741862; P = 0.03043), alpha 5 (rs951266; P = 0.01153; rs7180002, P = 0.03682), and alpha 2 (rs2565048; P = 0.01403). Conclusion The data from this pilot study suggest an association between ACh receptors, predominantly M3 and CFS. ACh receptor SNPs may contribute to the pathomechanism of CFS/ME.

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Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients

Journal of International Medical Research ◽

10.1177/0300060516671622 ◽

2016 ◽

Vol 44 (6) ◽

pp. 1381-1394 ◽

Cited By ~ 9

Author(s):

Sonya Marshall-Gradisnik ◽

Samantha Johnston ◽

Anu Chacko ◽

Thao Nguyen ◽

Peter Smith ◽

...

Keyword(s):

B Cells ◽

Chronic Fatigue Syndrome ◽

Single Nucleotide Polymorphisms ◽

Ion Channel ◽

B Cell ◽

Chronic Fatigue ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Fatigue Syndrome ◽

Trp Ion Channel

Objective The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca2+) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients. Methods A total of 11 CFS/ME patients (aged 31.82 ± 5.50 years) and 11 non-fatigued controls (aged 33.91 ± 5.06 years) were included. Flow cytometric protocols were used to determine B cell purity, followed by SNP and genotype analysis for 21 mammalian TRP ion channel genes and nine mammalian ACh receptor genes. SNP association and genotyping analysis were performed using ANOVA and PLINK analysis software. Results Seventy-eight SNPs were identified in nicotinic and muscarinic acetylcholine receptor genes in the CFS/ME group, of which 35 were in mAChM3. The remaining SNPs were identified in nAChR delta (n = 12), nAChR alpha 9 (n = 5), TRPV2 (n = 7), TRPM3 (n = 4), TRPM4 (n = 1) mAChRM3 2 (n = 2), and mAChRM5 (n = 3) genes. Nine genotypes were identified from SNPs in TRPM3 (n = 1), TRPC6 (n = 1), mAChRM3 (n = 2), nAChR alpha 4 (n = 1), and nAChR beta 1 (n = 4) genes, and were located in introns and 3′ untranslated regions. Odds ratios for these specific genotypes ranged between 7.11 and 26.67 for CFS/ME compared with the non-fatigued control group. Conclusion This preliminary investigation identified a number of SNPs and genotypes in genes encoding TRP ion channels and AChRs from B cells in patients with CFS/ME. These may be involved in B cell functional changes, and suggest a role for Ca2+ dysregulation in AChR and TRP ion channel signalling in the pathomechanism of CFS/ME.

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Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome

The Application of Clinical Genetics ◽

10.2147/tacg.s99405 ◽

2016 ◽

pp. 39 ◽

Cited By ~ 17

Author(s):

Sonya Marshall-Gradisnik ◽

Teilah Huth ◽

Anu Chacko ◽

Pete Smith ◽

Donald Staines ◽

...

Keyword(s):

Ion Channels ◽

Natural Killer Cells ◽

Chronic Fatigue Syndrome ◽

Single Nucleotide Polymorphisms ◽

Natural Killer ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Fatigue Syndrome

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Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients

Immunology and Immunogenetics Insights ◽

10.4137/iii.s25147 ◽

2015 ◽

Vol 7 ◽

pp. III.S25147 ◽

Cited By ~ 8

Author(s):

Sonya M. Marshall-Gradisnik ◽

Peter Smith ◽

Ekua W. Brenu ◽

Bernd Nilius ◽

Sandra B. Ramos ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Single Nucleotide Polymorphisms ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Chronic Fatigue ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Fatigue Syndrome ◽

Trp Ion Channels ◽

Transient Receptor

Background The transient receptor potential (TRP) superfamily in humans comprises 27 cation channels with permeability to monovalent and divalent cations. These channels are widely expressed within humans on cells and tissues and have significant sensory and regulatory roles on most physiological functions. Chronic fatigue syndrome (CFS) is an unexplained disorder with multiple physiological impairments. OBJECTIVES The purpose of this study was to determine the role of TRPs in CFS. Methods The study comprised 115 CFS patients (age = 48.68 ± 1.06 years) and 90 nonfatigued controls (age = 46.48 ± 1.22 years). CFS patients were defined according to the 1994 Center for Disease Prevention and Control criteria for CFS. A total of 240 single nucleotide polymorphisms (SNPs) for 21 mammalian TRP ion channel genes ( TRPA1, TRPC1, TRPC2, TRPC3, TRPC4, TRPC6, TRPC7, TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) were examined via the Agena Biosciences iPLEX Gold assay. Statistical analysis was performed using the PLINK analysis software. Results Thirteen SNPs were significantly associated with CFS patients compared with the controls. Nine of these SNPs were associated with TRPM3 (rs12682832; P < 0.003, rs11142508; P < 0.004, rs1160742; P < 0.08, rs4454352; P < 0.013, rs1328153; P < 0.013, rs3763619; P < 0.014, rs7865858; P ≤ 0.021, rs1504401; P ≤ 0041, rs10115622; P ≤ 0.050), while the remainder were associated with TRPA1 (rs2383844; P ≤ 0.040, rs4738202; P ≤ 0.018) and TRPC4 (rs6650469; P ≤ 0.016, rs655207; P ≤ 0.018). Conclusion The data from this pilot study suggest an association between TRP ion channels, predominantly TRPM3 and CFS. This and other TRPs identified may contribute to the etiology and pathomechanism of CFS.

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Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

Journal of Clinical Pathology ◽

10.1136/jclinpath-2014-202597 ◽

2014 ◽

Vol 67 (12) ◽

pp. 1078-1083 ◽

Cited By ~ 9

Author(s):

Nana Shimosako ◽

Jonathan R Kerr

Keyword(s):

Gene Expression ◽

Chronic Fatigue Syndrome ◽

Chronic Fatigue ◽

Endogenous Depression ◽

Myalgic Encephalomyelitis ◽

Snp Analysis ◽

Nucleotide Polymorphisms ◽

Goldengate Assay ◽

Single Nucleotide ◽

Fatigue Syndrome

AimsWe have reported gene expression changes in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and the fact that such gene expression data can be used to identify subtypes of CFS/ME with distinct clinical phenotypes. Due to the difficulties in using a comparative gene expression method as an aid to CFS/ME disease and subtype-specific diagnosis, we have attempted to develop such a method based on single-nucleotide polymorphism (SNP) analysis.MethodsTo identify SNP allele associations with CFS/ME and CFS/ME subtypes, we tested genomic DNA of patients with CFS/ME (n=108), patients with endogenous depression (n=17) and normal blood donors (n=68) for 504 human SNP alleles located within 88 CFS-associated human genes using the SNP Genotyping GoldenGate Assay (Illumina, San Diego, California, USA). 360 ancestry informative markers (AIM) were also examined.Results21 SNPs were significantly associated with CFS/ME compared with depression and normal groups. 148 SNP alleles had a significant association with one or more CFS/ME subtypes. For each subtype, associated SNPs tended to be grouped together within particular genes. AIM SNPs indicated that 4 subjects were of Asian origin while the remainder were Caucasian. Hierarchical clustering of AIM data revealed the relatedness between 2 couples of patients with CFS only and confirmed the overall heterogeneity of all subjects.ConclusionsThis study provides evidence that human SNPs located within CFS/ME associated genes are associated with particular genomic subtypes of CFS/ME. Further work is required to develop this into a clinically useful subtype-specific diagnostic test.

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Re-analysis of genetic risks for Chronic Fatigue Syndrome from 23andMe data finds few remain

10.1101/2020.10.27.20220939 ◽

2020 ◽

Author(s):

Felice L. Bedford ◽

Bastian Greshake Tzovaras

Keyword(s):

Chronic Fatigue Syndrome ◽

Chronic Fatigue ◽

Initial Study ◽

Major Advance ◽

Nucleotide Polymorphisms ◽

Direct To Consumer ◽

Fatigue Syndrome ◽

Commercial Company ◽

Genetic Risks ◽

Reference Databases

AbstractIt is tempting to mine the abundance of DNA data that is now available from direct-to-consumer genetic tests but this approach also has its pitfalls A recent study put forth a list of 50 single nucleotide polymorphisms (SNPs) that predispose to Chronic Fatigue Syndrome (CFS), a potentially major advance in understanding this still mysterious condition. However, only the patient cohort data came from a commercial company (23andMe) while the control was from a genetic database. The extent to which 23andMe data agree with genetic reference databases is unknown. We reanalyzed the 50 purported CFS SNPs by comparing to control data specifically from 23andMe which are available through public platform OpenSNP. In addition, large high-quality database ALFA was used as an additional control. The analysis lead to dramatic change with the top of the leaderboard for CFS risk reduced and reversed from an astronomical 129,000 times to 0.8. Errors were found both within 23andMe data and the original study-reported Kaviar database control. Only 3 of 50 SNPs survived initial study criterion of at least twice as prevalent in patients, EFCAB4B, involved in calcium ion channel activation, LINC01171, and MORN2 genes. We conclude that the reported top-50 deleterious polymorphisms for Chronic Fatigue Syndrome were more likely the top-50 errors in the 23andMe and Kaviar databases. In general, however, correlation of 23andMe control with ALFA was a respectable 0.93, suggesting an overall usefulness of 23andMe results for research purposes but only if caution is taken with chips and SNPs.

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