Impact of the abcb1 drug resistance gene on complications associated with covid-19

ABSTRACT

Background: Overexpression of the ABCB1 gene has been associated with a poor prognosis in various hemato-oncological diseases due to resistance to different chemotherapy types. Usually, the gene expression is low, but drugs like steroids can stimulate it. The COVID-19 infection has affected much of the world, especially Latin America, where mortality is higher than expected, mostly due to hypertension, diabetes, and obesity. Since the beginning of the pandemic, different combinations (chloroquine, azithromycin, antivirals) have been used, some with a moderate benefit (Tocilizumab, convalescent plasma) but without establishing a group that could benefit. The ATP flow pump contributes to cell detoxification, including overdosing of drugs;some drugs are substrates of this pump and modify its operation Aims: Describe the impact of ABCB1 drug resistance gene expression on mortality and ventilatory support in critically ill patients with COVID-19 Methods: Sixty-one patients (23 women and 38 men) were diagnosed with COVID-19 and included in the study. Mononuclear cells were isolated by Ficoll-Paque (GE Healthcare).RNA isolation was performed using Trizol ™ reagent (Invitrogen, Carlsbad, CA). The RNA obtained's concentration and purity was measured using Nanodrop ™ 2000 (Nanodrop Technologies, Wilmington, ME, USA). cDNA was synthesized from 1 μg of RNA using oligo (dT) and MML-V enzyme from Promega Biotech AB. The expression levels of the ABCB1 gene were determined by qPCR using the TaqMan ™ system (Hs01069047, Applied Biosystems, Inc. Foster City, CA, USA) and normalizing with the endogenous GUSB gene (Hs00939627) (Gene expression = 2 - ΔCT, where ΔCT = CT of the gene of interest - CT of the reference gene.) The expression levels were classified according to the known values in healthy donors. Results: 61 patients diagnosed with COVID-19 with criteria for hospital care and supplemental oxygen. The majority were men (n = 36, 59%), obesity was the most frequent comorbidity (n = 28.45.9%), followed by diabetes (n = 22, 36.1%) and hypertension (n = 18, 29.5%). Treatment for COVID-19 included high-flow oxygen in combination with the best available therapy;8.2% (n = 5) started with hydroxychloroquine, 44.3% (n = 27) were treated with metformin hydrochloride, 36.1% with azithromycin, 55.7% (n = 34) with atorvastatin and 95.2% (n = 58) with low molecular weight heparin. During the hospital period. 49.2% (n = 30) required ventilatory support. When analyzing the expression of ABCB1, 63.9% (n = 39) had a high or absent expression, 36.1% showed a low expression. Cases with high / absent expression showed a worse prognosis compared to low expression (Log Rank = 0.000). When comparing the different risk variables, the high / absent expression of ABCB1 was a significant risk factor for death (OR 3.08, [1.02-9.26], p = 0.045) and ventilatory support (OR 2.8, [0.98-8.5], p = 0.054). Other factors such as male gender (OR 2.54 [0.89-7.27], p = 0.081) and older age (OR 5.19, [1.48-18.2] p = 0.010) were associated with a poor prognosis. Diabetes had low impact (OR 1.11, [0.38-3.22], p=0838) on prognosis Summary/Conclusion: Similar to cancer treatment, the modification of the expression of the ABCB1 gene (high or absent) impacts the prognosis of patients with severe COVID-19 disease due to the overuse of drugs.