Štampar Patricija, Blagus Tanja, Goričar Katja, Bogovič Petra, Turel Gabriele, Strle Franc, Dolžan Vita
Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Department of Infectious Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Front Pharmacol. 2024 Jul 29;15:1418567. doi: 10.3389/fphar.2024.1418567. eCollection 2024.
Corticosteroids are widely used for the treatment of coronavirus disease (COVID)-19. Genetic polymorphisms of the glucocorticoid receptor, metabolizing enzymes, or transporters may affect treatment response to dexamethasone. This study aimed to evaluate the association of the glucocorticoid pathway polymorphisms with the treatment response and short-term outcomes in patients with severe COVID-19. Our pilot study included 107 hospitalized patients with COVID-19 treated with dexamethasone and/or methylprednisolone, genotyped for 14 polymorphisms in the glucocorticoid pathway. In total, 83% of patients had severe disease, 15.1% had critical disease and only 1.9% had moderate disease. rs35599367 was the major genetic determinant of COVID-19 severity as carriers of this polymorphism had higher risk of critical disease (OR = 6.538; 95% confidence interval = 1.19-35.914: = 0.031) and needed intensive care unit treatment more frequently (OR = 10; 95% CI = 1.754-57.021: = 0.01). This polymorphism was also associated with worse disease outcomes, as those patients had to switch from dexamethasone to methylprednisolone more often (OR = 6.609; 95% CI = 1.137-38.424: = 0.036), had longer hospitalization ( = 0.022) and needed longer oxygen supplementation ( = 0.040). Carriers of rs6198 polymorphic allele required shorter dexamethasone treatment ( = 0.043), but had higher odds for switching therapy with methylprednisolone (OR = 2.711; 95% CI = 1.018-7.22: = 0.046). Furthermore, rs6198 was also associated with longer duration of hospitalization ( = 0.001) and longer oxygen supplementation ( = 0.001). rs33388 polymorphic allele was associated with shorter hospitalization ( = 0.025) and lower odds for ICU treatment (OR = 0.144; 95% CI = 0.027-0.769: = 0.023). rs1695 was associated with duration of hospitalization ( = 0.015), oxygen supplementation and ( = 0.047) dexamethasone treatment ( = 0.022). Our pathway-based approach enabled us to identify novel candidate polymorphisms that can be used as predictive biomarkers associated with response to glucocorticoid treatment in COVID-19. This could contribute to the patient's stratification and personalized treatment approach.
皮质类固醇被广泛用于治疗冠状病毒病（COVID）-19。糖皮质激素受体、代谢酶或转运蛋白的基因多态性可能会影响对地塞米松的治疗反应。本研究旨在评估糖皮质激素途径多态性与重症COVID-19患者的治疗反应及短期预后之间的关联。我们的初步研究纳入了107例接受地塞米松和/或甲泼尼龙治疗的COVID-19住院患者，对糖皮质激素途径中的14种多态性进行了基因分型。总体而言，83%的患者患有重症疾病，15.1%患有危重症，仅有1.9%患有中度疾病。rs35599367是COVID-19严重程度的主要遗传决定因素，因为该多态性的携带者患危重症的风险更高（比值比[OR]=6.538；95%置信区间=1.19-35.914：P=0.031），且更频繁地需要重症监护病房治疗（OR=10；95%置信区间=1.754-57.021：P=0.01）。这种多态性还与更差的疾病预后相关，因为这些患者更常需要从地塞米松换用甲泼尼龙（OR=6.609；95%置信区间=1.137-38.424：P=0.036），住院时间更长（P=0.022）且需要更长时间的吸氧（P=0.040）。rs6198多态性等位基因的携带者需要更短的地塞米松治疗时间（P=0.043），但换用甲泼尼龙治疗的几率更高（OR=2.711；95%置信区间=1.018-7.22：P=0.046）。此外，rs6198还与更长的住院时间（P=0.001）和更长的吸氧时间（P=0.001）相关。rs33388多态性等位基因与更短的住院时间（P=0.025）和更低的重症监护病房治疗几率相关（OR=0.144；95%置信区间=0.027-0.769：P=0.023）。rs1695与住院时间（P=0.015）、吸氧时间（P=0.047）和地塞米松治疗时间（P=0.022）相关。我们基于途径的方法使我们能够识别新的候选多态性，这些多态性可作为与COVID-19中糖皮质激素治疗反应相关的预测生物标志物。这可能有助于患者分层和个性化治疗方案的制定。
