Genetic Variant in Surfactant Protein D May Shield Carriers From Severe COVID-19

One of the enduring puzzles of the COVID-19 pandemic has been the extraordinary variability in how people respond to infection with SARS-CoV-2. Some individuals carry the virus without ever developing symptoms, while others progress to life-threatening respiratory failure within days. Although age, comorbidities, and vaccination status explain much of this variation, host genetics has emerged as a powerful additional factor. A new study from the Czech Republic now adds an important piece to that picture, focusing on a gene that encodes a key molecule of the lung’s innate immune defense: surfactant-associated protein D, or SP-D, produced by the SFTPD gene.

The research, published in the journal Immunity, Inflammation and Disease, was conceived as a direct replication attempt of an earlier Iranian study that had reported a worrying association. That study, led by Kolsari and colleagues, found that carriers of the TT genotype at a specific variant in the SFTPD gene, known as rs721917, were more likely to be hospitalized and to suffer severe symptoms after SARS-CoV-2 infection. The TT genotype appeared more frequently among patients admitted to intensive care and cardiac care units than the CC genotype, and it was linked to higher overall hospitalization rates. If correct, the finding would have identified a common genetic variant, present in roughly a third of many populations, as a risk factor for severe disease.

To test this, a team at the Institute for Clinical and Experimental Medicine in Prague, led by Jaroslav A. Hubacek, analyzed the same polymorphism in a much larger Czech cohort. The variant rs721917 is a single-letter change in the DNA sequence, a C-to-T substitution that alters the amino acid at position 31 of the SP-D protein, replacing methionine with threonine. This region of the protein matters functionally, because SP-D is a collectin, a molecule that binds both pathogens and immune cells, helping to clear viruses and bacteria from the lungs while modulating inflammation. Genetic variation in this gene is therefore a biologically plausible candidate for influencing the course of a respiratory infection such as COVID-19.

The Czech researchers used a PCR-based restriction fragment length polymorphism assay to genotype 436 adults with confirmed SARS-CoV-2 infection, of whom 164 had remained completely asymptomatic and 272 had developed symptoms. They compared these patients with 467 adult population controls drawn from the Czech post-MONICA study, a long-running cardiovascular risk survey that provides a representative sample of the national population. Infection status was confirmed by PCR screening, and follow-up extended until December 2024, ensuring that participants’ infection histories were reliably documented. Statistical analyses were performed with SPSS Statistics 27.

The first reassuring observation was that genotype distributions in both patients and controls conformed to the Hardy-Weinberg equilibrium, the genetic baseline that indicates a population is mating randomly and that genotyping is technically sound. The equilibrium probabilities were p equals 0.80 for controls and p equals 0.24 for patients. When the researchers compared the entire group of SARS-CoV-2-positive individuals with the controls, they found no significant difference in genotype frequencies, with a p-value of 0.59. In other words, carrying any particular version of rs721917 did not appear to influence whether a person became infected in the first place.

The more interesting results emerged when the patients were stratified by disease course. Genotype frequencies differed significantly between asymptomatic subjects and population controls, with a p-value of 0.02, and between asymptomatic subjects and symptomatic patients, with a p-value of 0.01. The driving force behind these differences was a higher proportion of heterozygotes, individuals carrying one C and one T allele, among the asymptomatic group, where they made up 60.3 percent of subjects compared with 47.8 percent of controls and 45.6 percent of symptomatic patients. The researchers caution that such an excess of heterozygotes raises the possibility of an overdominant effect, in which having two different versions of the gene confers an advantage over having two identical copies.

A second pattern pointed in the same direction. The frequency of the CC genotype rose in a borderline, nonsignificant trend, with p equal to 0.08, from the asymptomatic group through the population controls to the symptomatic subjects. Consistent with this gradient, carriers of at least one T allele were slightly less likely to appear in the symptomatic COVID-19 group than CC homozygotes, with an odds ratio of 0.59 and a 95 percent confidence interval of 0.34 to 1.05, at a nominal p-value of 0.07. This is the opposite direction of association to that reported in the Iranian study, which had flagged the T-bearing TT genotype as a risk factor rather than a protective one.

The authors offer several explanations for the discrepancy. The original Iranian study was small, with only between 17 and 42 subjects in each severity category, spanning mild, moderate, severe, and critical courses of COVID-19. Samples of that size are notoriously prone to false positive results, particularly in genetic association studies where many variants are tested simultaneously. More troubling still, the genotype frequencies in the Iranian cohort deviated dramatically from the Hardy-Weinberg expectation, with a p-value below 0.0000001. Such a marked deviation complicates interpretation and may reflect ascertainment bias, hidden population structure, or genotyping inaccuracies, any of which could produce a spurious association. Interethnic differences in genetic susceptibility to SARS-CoV-2 infection are also well documented, providing a further possible reason why results from an Iranian population might not replicate in Central Europeans.

Crucially, the Czech findings align with the largest genetic evidence base available. A major meta-analysis of genome-wide association studies, published in Nature by Pairo-Castineira and colleagues, identified 49 genetic variants associated with critical COVID-19, and rs721917 was among them. In that analysis, the T allele was associated with approximately a 7 percent lower risk of critical disease, a result that supports the Czech case-control finding, where the T allele showed a nominal 4 percent decrease in risk of symptomatic illness. The convergence of an independent large-scale GWAS meta-analysis with a targeted replication study strengthens the conclusion that the T allele is not a risk factor, and may instead confer modest protection against severe or symptomatic COVID-19.

The picture is rounded out by studies of the protein itself. Two investigations measured circulating concentrations of SP-D and reached similar conclusions. No difference in plasma SP-D levels was observed between 141 convalescent COVID-19 patients examined ten weeks after infection and 98 uninfected subjects, and in a separate pediatric cohort of 325 children, SP-D levels were not associated with COVID-19 severity. In children, the SFTPD rs721917 polymorphism likewise showed no effect on disease severity. The authors also note, somewhat surprisingly, that despite the strong biological plausibility of SFTPD as a susceptibility gene, no further adult studies outside GWAS analyses have been published on this topic, underscoring how much remains to be learned. Taken together, the Czech results and the wider literature suggest that carriers of the T allele at rs721917 are potentially protected, rather than placed at increased risk, against symptomatic or severe forms of COVID-19, though the authors emphasize that further studies are needed to detect potential ethnic-specific effects of this variant across different populations.

Subject of Research: Association between the SFTPD rs721917 polymorphism and susceptibility to symptomatic and severe COVID-19 in the Czech population

Article Title: Surfactant‐Associated Protein D Polymorphism and Protection Against COVID‐19 in the Czech Population

Article References: Hubacek, J. A., Philipp, T., Ondrackova, M., Adamkova, V., & Dusek, L. (2026). Surfactant‐Associated Protein D Polymorphism and Protection Against COVID‐19 in the Czech Population. Immunity, Inflammation and Disease, 14(10), Article e70541. https://doi.org/10.1002/iid3.70541

Image Credits: AI Generated

DOI: 10.1002/iid3.70541

Keywords: SFTPD, surfactant protein D, rs721917, COVID-19, SARS-CoV-2, genetic polymorphism, host genetics, case-control study, Hardy-Weinberg equilibrium, GWAS meta-analysis, Czech population, innate immunity