Immune receptor gene variant linked to higher COVID-19 death risk in Iranian patients

Host genetic variation may help explain why some patients with COVID-19 die while others recover from what appears to be the same infection. A new case-control study from Iran reports that a specific variant in the gene encoding the interleukin-8 receptor is associated with a markedly higher risk of death among hospitalized patients, adding to growing evidence that inherited differences in inflammatory signaling shape the course of severe disease. The work, published in the Egyptian Journal of Medical Human Genetics, examined three polymorphisms across the interleukin-8 pathway and found that only one, a coding change in the receptor gene IL-8R1, showed a statistically robust association with fatal outcomes.

The research team, led by Mohadeseh Sadat Sajadi, Farzaneh Hossini, and Pooneh Rahimi, enrolled 328 hospitalized patients with confirmed COVID-19 during the early phase of the pandemic. Of these, 178 patients recovered and 150 died, a mortality proportion of 45.8 percent within the studied cohort. All participants were adults, most between 20 and 60 years of age, and the eligibility criteria deliberately excluded individuals with chronic respiratory diseases, asthma, allergies, cardiovascular disease, diabetes, or cancer. Patients also had to have received no medication before sample collection, and blood samples were drawn during the second week of illness following a positive PCR test taken at least one week after symptom onset.

The investigators focused on the IL-8/CXCR1 axis, a signaling pathway central to neutrophil-driven inflammation. Interleukin-8, also known as CXCL8, is a potent chemoattractant and activator of neutrophils, and it exerts its biological effects primarily through the G-protein-coupled receptors CXCR1 and CXCR2 on the surface of these cells. In severe COVID-19, excessive IL-8-associated neutrophil activation and the formation of neutrophil extracellular traps have been implicated in pulmonary tissue injury and thrombo-inflammatory complications. Elevated circulating IL-8 levels have previously been associated with prolonged illness and adverse outcomes, including mortality, in patients with severe disease, providing the biological rationale for interrogating genetic variants in this pathway.

Three polymorphisms were genotyped: IL-8 rs4073, located in the promoter region of the CXCL8 gene; IL-8 rs2227306, situated in intron 1 of the same gene; and IL-8R1 rs2234671, a coding variant in the CXCR1 receptor gene that produces a serine-to-threonine substitution at amino acid position 276. The promoter variant has been linked in prior experimental and clinical studies to differences in IL-8 expression, with the −251 A allele associated with increased expression under inflammatory stimulation in some settings. The intronic variant has also been investigated in relation to IL-8 expression and inflammatory phenotypes, though its functional effect remains less clearly established. The receptor variant, by contrast, may directly alter receptor properties or downstream IL-8 signaling, although direct functional evidence remains limited.

Genotyping was performed using polymerase chain reaction–restriction fragment length polymorphism, a technique in which PCR-amplified DNA fragments are cut by specific restriction enzymes and the resulting banding patterns on agarose gels reveal which alleles are present. For the IL-8R1 rs2234671 polymorphism, digestion with AluI produced distinct fragment profiles for the CC, CG, and GG genotypes, with the heterozygous CG genotype yielding fragments of 203, 157, 102, and 66 base pairs. Representative samples from each genotype were then confirmed by Sanger sequencing, with chromatograms aligned against NCBI reference sequences and double peaks in heterozygous samples verifying the presence of both alleles. The authors report that these sequencing findings were fully consistent with the restriction-digestion patterns, strengthening confidence in the genotyping accuracy.

The central result concerned IL-8R1 rs2234671. Carriers of the G allele exhibited an increased risk of death compared with CC homozygotes under codominant, dominant, overdominant, and log-additive inheritance models, all with P values below 0.05. The strongest association emerged under the dominant model, yielding an odds ratio of 3.29 with a 95 percent confidence interval of 1.55 to 6.99 and a P value of 0.0014. In terms of raw frequencies, 85 percent of recovered patients carried the CC genotype, compared with 64 percent of deceased patients, while the GG genotype appeared in only 2 percent of survivors but 9 percent of those who died. At the allele level, the G allele was present in 8 percent of recovered individuals and 23 percent of deceased patients. Hardy–Weinberg equilibrium testing showed no significant deviation for any of the investigated polymorphisms.

In contrast to the receptor variant, neither IL-8 polymorphism showed a statistically significant association with mortality when analyzed individually. For rs4073, the overall genotype distribution was 21 percent AA, 48 percent AT, and 32 percent TT across the cohort, with the TT genotype yielding an odds ratio of 1.00 in the mortality analysis. The rs2227306 variant likewise failed to reach significance on its own, despite the C allele being somewhat more prevalent among deceased patients at 57 percent versus 65 percent among recovered individuals. A previous study had reported a higher frequency of the rs2227306 CC genotype and C allele among patients with severe COVID-19, but the authors note that the direction and strength of such associations may vary across populations and study designs.

Beyond single-variant analysis, the team conducted a multilocus genotype combination analysis to evaluate joint effects of the three polymorphisms. Because the variants reside in different genes on different chromosomal regions, the authors emphasize that these combinations should not be interpreted as true haplotypes but rather as multilocus genotype combinations. Certain combinations showed differences between recovered and deceased patients. Notably, a combination involving the G allele of rs2234671 together with the A allele of rs4073 and the T allele of rs2227306 was associated with a reduced recovery rate, suggesting a possible unfavorable clinical outcome. Another combination containing the G allele of rs2234671 with the A allele of rs4073 and the C allele of rs2227306 showed only a trend toward association that did not reach statistical significance. Stratified analysis by sex revealed no significant differences in the distribution or clinical impact of these multilocus combinations.

The authors are careful to frame their findings within the limits of the study design. The sample size, particularly for less frequent genotypes, may have limited statistical power in some analyses. The study was conducted in a single Iranian population, which may restrict generalizability to other ethnic groups and geographic regions. Critically, circulating IL-8 concentrations, CXCR1 expression levels, and other inflammatory biomarkers were not measured, and no functional assays were performed to validate the biological effects of the identified variants. The proposed mechanism, in which the Ser276Thr substitution alters receptor binding efficiency and downstream signaling to modulate inflammatory responses, remains biologically plausible but experimentally unconfirmed. SARS-CoV-2 variant determination was also not performed, so the results should not be considered variant-specific, and residual confounding from demographic or clinical factors cannot be completely ruled out despite the exclusion of major chronic comorbidities.

The study adds a piece to the larger puzzle of why COVID-19 outcomes vary so dramatically between individuals infected with the same virus. The findings support the potential role of the IL-8/CXCR1 signaling axis in the dysregulated inflammatory responses that characterize severe disease, and they underscore the potential importance of considering combined genetic effects rather than single polymorphisms alone when evaluating host susceptibility. However, the clinical applicability of these variants remains uncertain. The authors call for larger, multi-center, and multi-ethnic studies incorporating functional analyses and biomarker measurements to confirm these results and to assess whether such genetic information could eventually contribute to risk stratification or personalized management of COVID-19 patients.

Subject of Research: Association of IL-8 and IL-8R1 gene polymorphisms with COVID-19 mortality in an Iranian population

Article Title: Association of IL-8 and IL-8R1 gene polymorphisms with COVID-19 mortality

Article References: Sajadi, M. S., Hossini, F., & Rahimi, P. (2026). Association of IL-8 and IL-8R1 gene polymorphisms with COVID-19 mortality. Egyptian Journal of Medical Human Genetics, 27(1), Article 91. https://doi.org/10.1186/s43042-026-00910-z

Image Credits: AI Generated

DOI: 10.1186/s43042-026-00910-z

Keywords: COVID-19, IL-8, IL-8R1, CXCR1, genetic polymorphism, rs2234671, mortality, PCR-RFLP, case-control study, Iranian population, cytokine, host genetics