Seasonal variation in the associations between self-reported long-COVID symptoms and IL-6 signalling-related factors [...], 2025, Rees et al

[forestglip]

Seasonal variation in the associations between self-reported long-COVID symptoms and IL-6 signalling-related factors (particularly the rs2228145 variant of the IL-6R gene): A clinical study.

Katie Rees, Rebecca Aicheler, Lee Butcher, Alan Dodd, John Geen, Ceri Lynch, Isabel Massey, Keith Morris, Brian Tennant, Richard Webb

Highlights

• 175 patients who'd previously had acute COVID-19 reported their long-COVID symptoms.
• Patients' IL-6R genotype, IL-6 and sIL-6R levels were measured in DNA/blood samples.
• Cohort was stratified on basis of sampling date, to account for seasonal variations.
• Long-COVID sufferers had higher IL-6 levels than those who had regained full health.
• In summer sub-cohort, patients with IL-6R AA genotype had higher risk of long-COVID.

Abstract
This observational study focused on the impact of Interleukin-6 (IL-6)-related factors (notably the IL-6 receptor (IL-6R) gene's rs2228145 polymorphism) on long-COVID risk in individuals who had previously experienced COVID-19 infection(s). The purpose of the study was to better understand such factors' contribution to long-COVID risk, and thus possibly initiate future strategies for using IL-6-related factors as biomarkers predictive of risk (while also obtaining data that may influence long-COVID management and treatment more generally).

DNA and blood samples, plus questionnaire responses regarding long-COVID symptoms (including chronic fatigue and cognitive impairment), were collected from 175 participants who had previously experienced COVID-19 infection(s). Potential associations between self-reported long-COVID symptoms and participants' rs2228145 genotypes (determined using TaqMan-based genotyping assays) and/or their circulating IL-6, sIL-6R and sgp130 levels (determined using ELISA) were evaluated.

Univariate-regression analyses demonstrated that odds of exhibiting long-COVID symptoms increased with severity/number of previous COVID-19 infection(s) and with hypertension as a co-morbidity, while vaccination decreased the likelihood of developing long-COVID. While long-COVID sufferers exhibited higher IL-6 signalling activity than healthy control individuals, rs2228145 genotype was not associated with long-COVID odds-ratios in- the entire-study cohort. Following identification of significant seasonal variations within our dataset, the entire-study cohort was stratified depending on when samples/questionnaire responses were obtained. In the resulting ‘summer’ sub-cohort (but not the ‘winter’ sub-cohort), the rs2228145 AA genotype was significantly over-represented amongst those exhibiting long-COVID symptoms, and long-COVID odds-ratios were significantly reduced for the CC and AC genotypes.

While interpretation is complicated by seasonal variations, these findings may be of medical/biomedical value. Importantly, as IL-6 was higher in long-COVID sufferers than healthy controls, and rs2228145 AA genotype-bearing individuals within our ‘summer’ sub-cohort were at elevated risk of developing long-COVID, these findings point towards possible future use of IL-6 and/or rs2228145 genotype as biomarkers predictive of long-COVID risk, which may bring advantages regarding management and treatment of long-COVID.

Link (Cytokine) [Paywall]

 

[SNT Gatchaman]

See also Long-term increase in soluble interleukin-6 receptor levels in convalescents after mild COVID-19 infection (2025, Frontiers in Immunology) which states —

Our most important finding is a significant increase in sIL-6R in the MC [Mild Covid Convalescent] group, which points to long lasting responses of the protease/cytokine receptor system even after the underlying SARS-CoV-2 infection has been resolved. […] Importantly, this appears not a general phenomenon seen for all cytokine receptors, as we did not observe such a long lasting effect on sCD25, which is generated by the same proteases as the sIL-6R. From our data, we cannot definitely determine the molecular mechanism behind this. We could not detect a major transcriptional up-regulation of the IL6R mRNA in immune cells from COVID-19 patients, and as the major mechanism of sIL-6R generation is proteolysis, the increase in sIL-6R in both patient groups is therefore most likely due to enhanced proteolysis, which is in line with a previous study showing more IL-6R shedding induced by the SARS-CoV-2 spike protein.

It is unclear which functional consequences the long-term elevated sIL-6R levels have in addition to the increased buffer capacity mentioned above. The single nucleotide polymorphism rs2228145, which results in the exchange of amino-acid residue Asp-358 to Ala-358 of the IL-6R and which makes the IL-6R more susceptible to proteolysis by the protease ADAM17, results in increased sIL-6R serum levels in individuals which are homozygous for the minor allele. These individuals have reduced C-reactive protein concentrations and decreased odds of coronary heart disease events. This example underlines the antiinflammatory effect of increased sIL-6R levels.

 

[SNT Gatchaman]

This paper concludes (reformatting and adding line breaks) —

several of the study’s findings yield insights of significant medical/biomedical value:

i) long-COVID sufferers appear to exhibit higher IL-6 signalling activity than healthy control individuals

ii) number/severity of previous COVID-19 infections, and hypertension as a co-morbidity, increase risk of developing long-COVID

iii) vaccination pre-infection decreases risk of developing long-COVID

iv) within our ‘summer’ cohort bearers of the rs2228145 AA genotype appear to be at greater risk of developing long-COVID symptoms (including neuropsychiatric symptoms such as chronic fatigue and cognitive impairment) than those who have inherited one or more C allele at the rs2228145 locus.

Further work is required to fully elucidate the source and impact of the seasonal variation mentioned above, and develop tools to discriminate between long-COVID symptoms and seasonal non-COVID conditions. If this can be achieved, our findings point towards possible future use of IL-6 and/or rs2228145 genotype as biomarkers predictive of long-COVID risk; in particular, the exciting prospect emerges that rs2228145 genotypescreening (using a simple mouthswill-DNA extraction-PCR procedure) may be of use in identifying at-risk individuals, facilitating rapid signposting towards treatment options that can combat the relevant symptoms, and bringing advantages regarding the management and treatment of long-COVID.​