SARS-CoV-2 Enfeksiyonuna Yatkınlıkta Rol Oynayan Genetik Varyasyonlar
Özet
SARS-CoV-2 enfeksiyonunun seyrindeki ve şiddetindeki bireysel farklılıkların temel nedenlerinden biri konakçı genetik varyasyonlarıdır. Virüsün konakçı hücreye girişi, Spike (S) glikoproteininin hücre yüzeyindeki anjiyotensin dönüştürücü enzim 2 (ACE2) reseptörüne bağlanması ve TMPRSS2 gibi proteazlar tarafından parçalanmasıyla başlar. ACE2 genindeki K26R ve S331F gibi varyantlar viral afiniteyi etkilerken, belirli SNP'lerin (S19P, I21V vb.) enfeksiyona duyarlılığı artırdığı, bazılarının ise koruyucu olduğu varsayılmaktadır. Virüsün hücreye girişinde rol oynayan TMPRSS2, Furin, ELANE ve CTSL proteaz genlerindeki polimorfizmler ile bağışıklık yanıtını düzenleyen IFN, IFITM3 (rs12252-C/C), APOE (ε4 alleli), CCR5, HLA (DRB1*08), TNF ve DDR1 (rs4618569) genlerindeki varyasyonların da hastalığın riskini, kuluçka süresini, solunum yetmezliği semptomlarını, klinik şiddetini ve ölüm oranlarını doğrudan etkilediği belirlenmiştir. Küresel çapta popülasyonlar arasında risk allellerinin dağılımı önemli farklılıklar göstermektedir. Sonuç olarak, bu genetik varyasyonların tanımlanması, COVID-19 başta olmak üzere viral enfeksiyonlarda kişiselleştirilmiş tedavi yöntemlerinin geliştirilmesi, tedavi yanıtının öngörülmesi ve hasta takibinin optimize edilmesi açısından kritik bir öneme sahiptir.
Host genetic variations constitute one of the primary reasons underlying individual differences in the course and severity of SARS-CoV-2 infection. Viral entry into host cells initiates with the binding of the Spike (S) glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface and its subsequent cleavage by host proteases such as TMPRSS2. While variants like K26R and S331F in the ACE2 gene alter viral affinity, certain SNPs (e.g., S19P, I21V) enhance susceptibility to infection, whereas others are hypothesized to provide a protective effect. Polymorphisms in protease genes involved in viral entry, such as TMPRSS2, Furin, ELANE, and CTSL, alongside variations in immune-regulatory genes including IFN, IFITM3 (rs12252-C/C), APOE (ε4 allele), CCR5, HLA (DRB1*08), TNF, and DDR1 (rs4618569), have been directly associated with modulating infection risk, incubation periods, respiratory symptoms, clinical severity, and mortality rates. Globally, the distribution of these risk alleles exhibits significant differences across various populations. Consequently, characterizing these genetic variations is of critical importance for developing personalized therapeutic modalities, predicting treatment response, and optimizing patient monitoring protocols in COVID-19 and other infectious diseases.
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