Researchers investigated the inflammation outcomes of three different Interleukin-1 receptor antagonist gene (IL1RN) single-nucleotide variants (SNVs) in acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection patients. Their retrospective study included almost 2,600 confirmed severe coronavirus disease 2019 (COVID-19) patients and showed that the IL1RN CTA haplotype and its rs419598 C/C SNV dramatically attenuated COVID-19-associated hyperinflammation, a characteristic of severe SARS-CoV-2 infections.
Observed outcomes were substantially improved in men compared to women, with men depicting 15% reduced mortality over women with the same SNV. These findings were most extreme for older men, with patients with the rs419598 C/C SNV above the age of 74 presenting 80% less mortality risk than their non-SNV-expressing age-matched counterparts. This study is one of the first to elucidate the genetic determinants of COVID-19 pathology and may form the basis for personalized future interventions against the disease.
Study
Previous research by the current group identified the associations of IL1RN genetic variants with osteoarthritis and rheumatoid arthritis outcomes. It revealed that three SNVs (rs419598, rs315952, and rs9005) improved disease outcomes via hyperinflammation reduction mechanisms. The present study aims to investigate if the same genetic variants could improve COVID-19 outcomes due to the central role of hyperinflammation in severe COVID-19 pathology.
The study is a retrospective, observational study comprising data from adult (19+) patients admitted to Tisch Hospital, New York, United States, between March 2010 and March 2021. The cytokine profiles of these patients were compared against healthy age, sex, and body mass index (BMI)-matched controls without a clinical history of COVID-19 exposure. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays were used to confirm COVID-19 status and severity. Data sources comprised sociodemographic (sex, age, race, and ethnicity) and medical data obtained from hospital records and discarded COVID-19 blood samples (for plasma extraction). Data generation included whole-genome sequences (low coverage) of participants’ blood. The gencove.org database was used to annotate common SNV genotypes for each sequenced sample.
Three IL1RN genotypes, namely rs419598, rs315952, and rs9005, formed the focus of this study and were extracted from patients’ plasma samples during routine COVID-19 care. However, since multiple cytokines of interest were not included in routine care, plasma samples from 359 randomly selected study participants and their demography-matched controls were additionally extracted and subjected to a multiplex enzyme-linked immunosorbent assay (ELISA) assay.
Summary statistics were used to collate and analyze demographic variables and mortality statuses categorized by sex, race/ethnicity, and age. Univariate parametric tests were computed to evaluate CRS and mortality outcomes for each category. Comparisons between the mortality risks of different genotypes were conducted using multivariate logistic regressions, adjusting for sex and age.
Results
The present study included records from 2,589 hospitalized patients and an equal number of age, sex, and BMI-matched controls. Study participants presented a mean age of 61.2 years, an average BMI of 30.43, and comprised 53.3% male individuals.
ELISA and cytokine analyses revealed that, compared to healthy control, COVID-19 patients displayed significantly elevated levels of cytokines (IL-1α, IL-5, IL-8, IL-17, IL-1β, IL-2, IL-1Ra, IL-6, tumor necrosis factor-α [TNF-α], interferon-α, and vascular endothelial growth factor [VEGF]). Alarmingly, levels of IL-6, IL-1Ra, IL-8, and IL-10 were found to be more than 10 times higher than baseline controls’ values. Inflammatory markers, including CRP, procalcitonin, D-dimer, and ferritin, were similarly heightened.
Of the included patients, 397 (15.3%) died during treatment, with age (direct), sex (male at higher risk), and BMI (direct) showing associations with COVID-19-associated mortality.
Surprisingly, carriers of the IL1RN CTA-1/2 haplotype (either or two copies of the CTA haplotype) displayed substantially reduced inflammatory marker concentrations (except IL-1Ra, which was increased in these patients) compared to patients without the genotype. Encouragingly, the CTA haplotype was found to confer a 40% reduction in COVID-19-associated mortality risk in men above the age of 74. However, no associations with BMI were revealed. When evaluating each IL1RN CTA SNV individually, rs419598 C/C SNV patients exhibited substantially reduced inflammatory marker concentrations compared to their C/T or T/T counterparts.
Comparison between men and women reveals that, while most biomarker and mortality outcomes are indistinguishable across the sexes, IL1RN rs419598 C/C SNV was found to be associated with a decreased trend in mortality in men of all included age groups. In men above the age of 74, especially, this genotype was associated with an 80% decline in mortality, highlighting the role of hyperinflammation in severe COVID-19 progression.
Conclusion
The present study highlights that the IL1RN CTA haplotype, especially in combination with the rs419598 C/C genotype, substantially reduced CRS in patients (irrespective of sex) in severe COVID-19 infections and substantially reduced mortality in men.
Source:
https://www.news-medical.net/news/20240319/Genetic-key-to-milder-COVID-Certain-genes-slash-severity-and-death-risk-in-older-men.aspx