In this prospective study, the effect of X and Y single nucleotide polymorphisms in HIF-1α (C/T SNP [11549465] ve PHD2 genes (C/T SNP [480902] ve [516651] on 30-day mortality and morbidity in patients with ARDS due to COVID 19 was investigated. Considering the HIF-1α HIF-1α (C/T SNP [11549465] polymorphism, it was revealed that 30-day mortality rates were lower in homozygous TT and heterozygous CT genotypes compared to the wild-type CC genotype. Besides, mechanical ventilator support and vasopressor drug use were also less in variants containing the T allele. It was observed that the studied polymorphisms (rs 480902 and rs 516651) in the PHD2 gene did not affect clinical parameters and mortality.
Acute lung injury, ARDS, and severe coronavirus disease 2019 are examples of inflammatory lung conditions characterized by pulmonary hypoxia at the tissue and cell levels. Damage to the lung vascular structure in ARDS patients causes hypoxia and defects in vascular permeability.9–11 Apoptosis occurs in alveolar epithelial cells and lung endothelial cells in ARDS. Weakening of the connections between lung endothelial cells and leukocyte infiltration causes vascular leakage and pulmonary edema.12 The HIF signaling pathway controls key processes that govern inflammatory lung injury and vascular repair, including maintenance of lung endothelial cell viability, proliferation of alveolar epithelial cells, repair of damaged areas, and establishment of intercellular connections. Different results have been obtained in studies investigating the effects of the HIF-1α signaling pathway in acute lung injury/ARDS. A study of ventilation-induced lung injury in rats demonstrated a role for HIF-1α in the lung protection conferred by adenosine. 13 However, studies have demonstrated that HIF-1α can promote acute lung injury and inflammation. Use of YC-1, a HIF inhibitor, reduced lung injury in a rat model of trauma-hemogenic shock.14 Another study using the hypoxic ischemia/reperfusion model reported that increased pulmonary HIF-1α level was associated with higher VEGF level and more vascular damage.15 In an endotoxin-induced lung inflammation model with endothelial cell-specific PHD2 knockout rats, reduction of PHD2 reduced lung vascular permeability, edema, and inflammatory cell infiltration. Furthermore, it was indicated that endothelial barrier function and intercellular junction integrity are improved.16 However, in a model created by incubation with a septic lymph node, the HIF-1α gene deleted (HIF-1α gene silencing) increased cell viability and decreased inflammatory cytokine expression.17 These results have revealed that the HIF-1α signaling pathway can produce different effects according to the stage of acute lung injury/ARDS disease (injury or recovery period) and the cell type studied (alveolar epithelium, lung endothelium, or leukocytes).
Although studies have reported how the HIF-1α signaling pathway affects the ARDS symptoms, there is not enough information about how the variations seen in the HIF-1α gene affect these symptoms. Single nucleotide polymorphism is the most common genetic variation. The HIF-1α rs 11549465single nucleotide polymorphism examined in this study is located in the coding region of the gene and results in the replacement of the amino acid proline at position 582 of HIF-1α with serine. It has been reported that this variation causes various cancers, such as prostate, breast, and colon cancer, to progress more aggressively. 18, 19 It is claimed that HIF-1α expression is increased in cells with HIF-1α rs747465 mutation, that increased HIF-1α level increases vascularization in tumor tissue under hypoxic conditions, resulting in accelerated tumor growth and spread. 18, 20 The HIF-1α rs 11549465 polymorphism may be a risk factor for the development of diabetic complications, chronic obstructive pulmonary disease, and skin disease other than cancer. 21–23 It is considered that single nucleotide polymorphism may cause disease by affecting the promoter and enhancer activity in the gene, the stability of messenger RNA, and the subcellular localization of messenger RNA and/or proteins.24In a prospective observational study involving 241 patients hospitalized for acute kidney injury, the HIF-1α rs 11549465 polymorphism was studied, and individuals with the T allele had higher adverse outcomes such as dialysis, mechanical ventilation need, and in-hospital mortality.25 However, this result contrasts with the results obtained from experimental studies in which the kidney was exposed to hypoxia. In experimental studies, it was determined that increased HIF-1α activation has a protective effect against ischemic damage. 26, 27
In this study, the effect of rs 11549465 single nucleotide polymorphism seen in the HIF-1α gene on ARDS clinic was investigated, and as a result, it was demonstrated that patients with the polymorphic form had better survival compared to the wild type. The cause-effect relationship underlying this survival advantage remains to be determined and may be the subject of further studies. During ARDS, epithelial cells, primarily alveolar Type I, die and are shed. During healing, Type II alveolar cells proliferate and spread to fill the spaces emptied by Type I cells on the basement membrane. 12 Repair of the alveolar epithelium is critical to clinical recovery. An experimental study by McClendon et al. reported that HIF-1α was activated in ATII cells after lung injury, and increased HIF-1α level supported epithelial cell proliferation and migration during the repair period. In summary, the HIF-1α signaling pathway accelerates alveolar epithelial repair after acute lung injury.28 The fact that the level of HIF-1α was not determined (due to cost) is a critical limitation of our study. We know from previous studies that HIF-1α levels are increased in groups containing the T allele.29 From this point of view, if we accept the high level of HIF-1α in groups containing the T allele in our study, it may be possible to explain the better survival rates observed in T allele groups.