ÖZ
Amaç
Koroner arter hastalığı (KAH) küresel ölçekte önemli bir sağlık yükü olmaya devam etmektedir ve mevcut kan biyobelirteçleri erken tanı için yeterli duyarlılığa sahip değildir. Bu çalışmanın amacı, KAH ile ilişkili dolaşımdaki mRNA ve uzun kodlamayan RNA (lncRNA) biyobelirteçlerini tanımlamak ve doğrulamak, ayrıca öngörücü bir transkriptomik model geliştirmektir.
Gereç ve Yöntem
Stabil KAH hastaları ve sağlıklı kontrollerden elde edilen plazma RNA-sekanslama verileri (GSE208194) analiz edilmiş ve bulgular bağımsız bir periferik kan mikrodizi kohortunda (GSE113079) doğrulanmıştır. Diferansiyel gen ekspresyonu | |log2 kat değişimi| ≥1 ve yanlış keşif oranı <0,05 eşikleri kullanılarak değerlendirilmiştir. Gen ontolojisi ve Kyoto Genler ve Genomlar Ansiklopedisi yolakları için zenginleştirme analizleri yapılmıştır. Öngörücü model, lojistik regresyon modeli ile cezalandırılmış lojistik regresyon kullanılarak oluşturulmuş, hiperparametreler iç içe çapraz doğrulama çerçevesinde ayarlanmış ve bağımsız doğrulama kohortunda değerlendirilmiştir.
Bulgular
Toplam 182 transkript (177 mRNA, 5 lncRNA) diferansiyel olarak eksprese bulunmuş ve bunların %91’i KAH’de aşağı regüle edilmiştir. Zenginleştirme analizleri ribozomal biyogenez, sitoplazmik translasyon, mitokondriyal oksidatif fosforilasyon ve p53/NF-κB enflamatuvar yolaklarında eşgüdümlü düzensizlikleri ortaya koymuştur. Platformlar arası doğrulama 85 transkripti teyit ederek sağlam bir ekspresyon imzasına işaret etmiştir. Öngörücü model iki geni (NEUROD2 ve RPS27) seçmiş ve doğrulama kohortunda 0,820’lik harici eğri altında kalan alan değerine ulaşmıştır.
Sonuç
Kan transkriptomik profillemesi, KAH ile ilişkili, tekrarlanabilir bir gen ekspresyon imzası ortaya koymakta ve enflamasyon ile metabolik stres süreçlerini yansıtan iki genli, yalın bir sınıflandırıcının kullanılabileceğini göstermektedir. Bu bulgular, kan temelli transkriptomik biyobelirteçlerin geliştirilmesine yönelik önemli bir temel sağlamaktadır. Ancak klinik uygulamadaki değerinin ortaya konabilmesi için daha geniş ve farklı özelliklere sahip hasta popülasyonlarında doğrulanması gerekmektedir.
Anahtar Kelimeler:
Koroner arter hastalığı, transkriptom, biyobelirteçler, RNA, lojistik modeller
Kaynaklar
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