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. 2024 Mar 15;10(6):e27997.
doi: 10.1016/j.heliyon.2024.e27997. eCollection 2024 Mar 30.

Association of PADI2 and PADI4 polymorphisms in COVID-19 host severity and non-survival

Ilse Adriana Gutiérrez-Pérez  1 , Ivette Buendía-Roldán  2 , Oscar Zaragoza-García  1 , Gloria Pérez-Rubio  3 , José Rafael Villafan-Bernal  4 , Leslie Chávez-Galán  5 , Isela Parra-Rojas  1 , Rafael de Jesús Hernández-Zenteno  6 , Ingrid Fricke-Galindo  3 , Natividad Castro-Alarcón  1 , Brandon Bautista-Becerril  3 , Ramcés Falfán-Valencia  3 , Iris Paola Guzmán-Guzmán  1
Affiliations

Association of PADI2 and PADI4 polymorphisms in COVID-19 host severity and non-survival

Ilse Adriana Gutiérrez-Pérez et al. Heliyon. .

Abstract

Background: Enzymes of the peptidylarginine deiminase family (PADs) play a relevant role in the pathogenesis of COVID-19. However, the association of single nucleotide polymorphisms (SNPs) in their genes with COVID-19 severity and death is unknown.

Methodology: We included 1045 patients who were diagnosed with COVID-19 between October 2020 and December 2021. All subjects were genotyped for PADI2 (rs1005753 and rs2235926) and PADI4 (rs11203366, rs11203367, and rs874881) SNPs by TaqMan assays and their associations with disease severity, death, and inflammatory biomarkers were evaluated.

Results: 291 patients presented had severe COVID-19 according to PaO2/FiO2, and 393 had a non-survival outcome. Carriers of the rs1005753 G/G genotype in the PADI2 gene presented susceptibility for severe COVID-19, while the heterozygous carriers in rs11203366, rs11203367, and rs874881 of the PADI4 gene showed risk of death. The GTACC haplotype in PADI2-PADI4 was associated with susceptibility to severe COVID-19, while the GCACC haplotype was a protective factor. The GCGTG haplotype was associated with severe COVID-19 but as a protective haplotype for death. Finally, the GTACC haplotype was associated with platelet-to-lymphocyte ratio (PLR), the GCACC haplotype with neutrophil-to-hemoglobin and lymphocyte and the GCGTG haplotype as a protective factor for the elevation of procalcitonin, D-dimer, CRP, LCRP, NHL, SII, NLR, and PLR.

Conclusions: Our results suggest that the haplotypic combination of GTACC and some individual genotypes of PADI2 and PADI4 contribute to the subjects' susceptibility for severity and death by COVID-19.

Keywords: COVID-19; Inflammatory parameters; Outcome; PADI2; PADI4; Polymorphisms.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Linkage disequilibrium test of PADI2 and PADI4 polymorphisms. Haplotype frequencies and linkage disequilibrium (LD) were calculated using SHEsis software. Red area represents higher levels of LD. A D′ value of 100 indicates a complete LD between two markers and a D′ value of 0 indicates complete linkage equilibrium.
Fig. 2
Fig. 2
Association of the haplotypic combination of PADI2 and PADI4 polymorphisms with markers of inflammation in patients with COVID-19. The OR and 95% CI and p values were obtained by SHEsis test. p-value <0.05.
Fig. 3
Fig. 3
A hypothetical combination of the PADI2 and PADI4 polymorphisms contributing to the outcomes of COVID-19. The allele composition in PADs genes could promote a different level of citrullination mediated by PADs enzymes, favoring, or interfering with defense against infections. Allele composition might modulate early and acute activation of phagocytosis, neutrophil degranulation, and NET formation, influencing the control of the infectious processes or worsening the inflammatory response, causing endothelial damage, and progressing to severe COVID-19 or death.
See this image and copyright information in PMC

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