genomic polymorphism – American ME and CFS Society

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

Abstract:

It 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.

Source: Felice L. Bedford, Bastian Greshake Tzovaras. Re-analysis of genetic risks for Chronic Fatigue Syndrome from 23andMe data finds few remain. medRxiv 2020.10.27.20220939; doi: https://doi.org/10.1101/2020.10.27.20220939
Now published in Frontiers in Pediatrics doi: 10.3389/fped.2021.590040 https://www.medrxiv.org/content/10.1101/2020.10.27.20220939v2.full-text (Full text)

Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis, also known as chronic fatigue syndrome or ME/CFS, is a multifactorial and debilitating disease that has an impact on over 4 million people in the United States alone. The pathogenesis of ME/CFS remains largely unknown; however, a genetic predisposition has been suggested.

In the present study, we used a DNA single-nucleotide polymorphism (SNP) chip representing over 906,600 known SNPs to analyze DNA from ME/CFS subjects and healthy controls. To the best of our knowledge, this study represents the most comprehensive genome-wide association study (GWAS) of an ME/CFS cohort conducted to date.

Here 442 SNPs were identified as candidates for association with ME/CFS (adjusted P-value<0.05). Whereas the majority of these SNPs are represented in non-coding regions of the genome, 12 SNPs were identified in the coding region of their respective gene. Among these, two candidate SNPs resulted in missense substitutions, one in a pattern recognition receptor and the other in an uncharacterized coiled-coil domain-containing protein. We also identified five SNPs that cluster in the non-coding regions of T-cell receptor loci.

Further examination of these polymorphisms may help identify contributing factors to the pathophysiology of ME/CFS, as well as categorize potential targets for medical intervention strategies.

Source: Schlauch KA, Khaiboullina SF, De Meirleir KL, Rawat S, Petereit J, Rizvanov AA, Blatt N, Mijatovic T, Kulick D, Palotás A, Lombardi VC. Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome. Transl Psychiatry. 2016 Feb 9;6:e730. doi: 10.1038/tp.2015.208. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872418/ (Full article)

Supervised selection of single nucleotide polymorphisms in chronic fatigue syndrome

Abstract:

INTRODUCTION: The different ways for selecting single nucleotide polymorphisms have been related to paradoxical conclusions about their usefulness in predicting chronic fatigue syndrome even when using the same dataset.

OBJECTIVE: To evaluate the efficacy in predicting this syndrome by using polymorphisms selected by a supervised approach that is claimed to be a method that helps identifying their optimal profile.

MATERIALS AND METHODS: We eliminated those polymorphisms that did not meet the Hardy-Weinberg equilibrium. Next, the profile of polymorphisms was obtained through the supervised approach and three aspects were evaluated: comparison of prediction accuracy with the accuracy of a profile that was based on linkage disequilibrium, assessment of the efficacy in determining a higher risk stratum, and estimating the algorithm influence on accuracy.

RESULTS: A valid profile (p<0.01) was obtained with a higher accuracy than the one based on linkage disequilibrium, 72.8 vs. 62.2% (p<0.01). This profile included two known polymorphisms associated with chronic fatigue syndrome, the NR3C1_11159943 major allele and the 5HTT_7911132 minor allele. Muscular pain or sinus nasal symptoms in the stratum with the profile predicted V with a higher accuracy than those symptoms in the entire dataset, 87.1 vs. 70.4% (p<0.01) and 92.5 vs. 71.8% (p<0.01) respectively. The profile led to similar accuracies with different algorithms.

CONCLUSIONS: The supervised approach made it possible to discover a reliable profile of polymorphisms associated with this syndrome. Using this profile, accuracy for this dataset was the highest reported and it increased when the profile was combined with clinical data.

Source: Cifuentes RA, Barreto E. Supervised selection of single nucleotide polymorphisms in chronic fatigue syndrome. Biomedica. 2011 Oct-Dec;31(4):613-21. doi: 10.1590/S0120-41572011000400017. http://www.scielo.org.co/pdf/bio/v31n4/v31n4a17.pdf (Full article)

Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome

Abstract:

AIM: To explore the frequency of polymorphisms in adrenergic cardiovascular control genes in adolescent with chronic fatigue syndrome (CFS) and the relation of such polymorphisms to cardiovascular variables.

METHODS: DNA from 53 patients with CFS, 12-18 years old, was analysed for five single nucleotide polymorphisms (SNPs) in the genes catechol-O-methyltransferase (COMT), the β₂ -adrenergic receptor (two SNPs), the β₁ -adrenergic receptor and the α₂(a) -adrenergic receptor. Frequencies were compared to a reference population constructed from the National Center for Biotechnology Information (NCBI) database, and associations between frequencies and autonomic cardiovascular responses during a 20° head-up tilt-test were explored.

RESULTS: For the COMT SNP Rs4680, patients with CFS had a higher frequency of the AA genotype and a lower frequency of the G containing genotypes (AG and GG), when compared to the reference sample (p = 0.046). Also, the AA genotype was associated with a smaller increase in LF/HF ratio (low-frequency:high-frequency heart rate variability ratio, an index of cardiac sympathovagal balance) during head-up tilt when compared to the AG/GG genotypes. For the β₂ -adrenergic receptor SNP Rs1042714, patients with CFS had a lower frequency of the GG genotype and a higher frequency of the genotypes containing C (CG and CC) (p = 0.044).

CONCLUSIONS: CFS might be related to polymorphisms of COMT and the β₂ -adrenergic receptor. More details of the molecular mechanisms remain to be investigated.

Source: Sommerfeldt L, Portilla H, Jacobsen L, Gjerstad J, Wyller VB. Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome. Acta Paediatr. 2011 Feb;100(2):293-8. doi: 10.1111/j.1651-2227.2010.02072.x. Epub 2010 Nov 18. https://www.ncbi.nlm.nih.gov/pubmed/21059181

Molecular study of receptor for advanced glycation endproduct gene promoter and identification of specific HLA haplotypes possibly involved in chronic fatigue syndrome

Abstract:

The receptor for advanced glycation end product (RAGE) is thought to play an important role in inflammation. Chronic fatigue syndrome (CFS) is a long-lasting fatigue that compromises at least 50% of a subject’s daily activities without other known cause. Immune dysfunction has been implicated and an association with a peculiar genetic cytokine profile, predisposing to an immunomodulatory response of inflammatory nature, was found.

The aim of this study is to analyse RAGE polymorphisms and HLA-DRB1 alleles in seventy-five Italian CFS patients and 141 controls matched for age, sex and ethnicity. These two groups underwent genomic study for RAGE 374T/A and 429C/T promoter polymorphisms; moreover, 46 patients and 186 controls were typed for HLA-DRB1 at low resolution molecular level. Of these, 31 patients and 99 controls also underwent high resolution analysis to define the HLA-DRB1*11 and DRB1*13 alleles.

The haplotypes RAGE-374T, DRB1*04; RAGE-374T, DRB1*09; RAGE-374T, DRB1*11; RAGE-374A, DRB1*13; RAGE-429T, DRB1*04 and RAGE-429C, DRB1*11 were significantly more frequent in CFS patients, whereas RAGE-429C, DRB1*07 would seem protective. A significantly lower frequency of DRB1*1104 (5.4% vs 12.9% p=0.04, OR=0.39) and a significantly higher frequency of HLA-DRB1*1301 (13.0% vs 5.1% p=0.006, OR= 2.79) were found in CFS patients. A synergic effect was observed with RAGE polymorphism.

The OR values strengthened in the following cis combinations: RAGE-374A, HLA-DRB1*1104 (OR=0.27) and RAGE-374A, HLADRB1*1301 (OR=6.23). HLA haplotypes rather than single alleles of RAGE or of DRB1 genes seem to be involved in CFS, probably including a subregion of major interest.

Source: Carlo-Stella N, Bozzini S, De Silvestri A, Sbarsi I, Pizzochero C, Lorusso L, Martinetti M, Cuccia M. Molecular study of receptor for advanced glycation endproduct gene promoter and identification of specific HLA haplotypes possibly involved in chronic fatigue syndrome. Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):745-54. https://www.ncbi.nlm.nih.gov/pubmed/19822091

Autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen class II alleles in chronic fatigue syndrome: are they associated with age at onset and specific symptoms?

Abstract:

This study aimed to determine the influence of autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen (HLA) class II genes on age at chronic fatigue syndrome (CFS) onset and symptoms.

Eighty-one CFS patients were enrolled, and clinical data were recorded. Autoantibodies to different components of the central nervous system were tested. Polymorphisms in the promoter of the serotonin transporter gene (l/s) and a single nucleotide polymorphism in the serotonin receptor-2A gene (A/G) as well as HLA class II alleles were determined. Multivariate logistic-regression analyses were carried out.

The mean age at CFS onset +/- SD was 33.5 +/- 12.5 years. An age at CFS onset (ACFSO) during the third decade of life was associated with the serotonin receptor AA genotype and the HLA-DRB1*03 allele. An ACFSO during the fourth decade of life was associated with the HLA-DRB1*07 allele, whereas an ACFSO > or = 43 years was associated with having at least one copy of the serotonin G allele.

Concerning CFS symptoms, the serotonin AG genotype was protective against depressive symptoms. Although having at least one copy of the serotonin A allele and being female were associated with risk for arthralgia, the presence of antineuronal cell antibodies was protective against this. Episodes of unexplained fever were associated with the HLA-DRB1*11 allele. None of the genetic or serological features was associated with myalgia. None of the antibodies determined correlated with any ACFSO or other symptoms.

Our results reveal that in CFS, like other autoimmune diseases, different genetic features are related to age at CFS onset and symptoms.

Source: Ortega-Hernandez OD, Cuccia M, Bozzini S, Bassi N, Moscavitch S, Diaz-Gallo LM, Blank M, Agmon-Levin N, Shoenfeld Y. Autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen class II alleles in chronic fatigue syndrome: are they associated with age at onset and specific symptoms? Ann N Y Acad Sci. 2009 Sep;1173:589-99. doi: 10.1111/j.1749-6632.2009.04802.x. https://www.ncbi.nlm.nih.gov/pubmed/19758204

Genomic polymorphism, growth properties, and immunologic variations in human herpesvirus-6 isolates

Abstract:

Fifteen human herpesvirus-6 (HHV-6) isolates from normal donors and patients with AIDS, systemic lupus erythematosis, chronic fatigue syndrome, collagen-vascular disease, leukopenia, bone marrow transplants, Exanthem subitum (roseola), and atypical polyclonal lymphoproliferation were studied for their tropism to fresh human cord blood mononuclear cells, growth in continuous T cell lines, reactivity to monoclonal antibodies, and by restriction enzyme banding patterns. All isolates replicated efficiently in human cord blood mononuclear cells, but mitogen stimulation of the cells prior to infection was required. The ability to infect continuous T-cell lines varied with the isolates. Isolates similar to GS prototype infected HSB2 and Sup T1 cells and did not infect Molt-3 cells, whereas isolates similar to Z-29 infected Molt-3 cells but not HSB2 and Sup T1 cells. Some of the monoclonal antibodies directed against the HHV-6 (GS) isolate showed reactivity with all isolates tested, but others only reacted with HHV-6 isolates similar to the GS isolate and not with those similar to Z-29 isolate. Restriction enzyme analysis using EcoRI, BamHI, and HindIII revealed that HHV-6 isolates from roseola, bone marrow transplant, leukopenia, and an HIV-1-positive AIDS patient from Zaire (Z-29) were closely related but distinct from GS type HHV-6 isolates. Based on the above findings, we propose that, like herpes simplex virus types 1 and 2, the 15 HHV-6 isolates analyzed can be divided into group A (GS type) and group B (Z-29 type).

Source: Ablashi DV, Balachandran N, Josephs SF, Hung CL, Krueger GR, Kramarsky B, Salahuddin SZ, Gallo RC. Genomic polymorphism, growth properties, and immunologic variations in human herpesvirus-6 isolates. Virology. 1991 Oct;184(2):545-52. http://www.ncbi.nlm.nih.gov/pubmed/1653487