Evaluation of PCSK9 E670G and N425S Gene Variations in Coronary Heart Disease in Turkish Population

Yıl 2018, Sayı: 4, 345 - 360, 20.04.2018

Ayşegül Başak Akadam Teker Erhan Teker Özlem Kurnaz Gömleksiz Hülya Yılmaz Aydoğan

Öz

Aim: Coronary artery disease (CAD) due to atherosclerosis
is a multifactorial disease resulting from the interaction of numerous genetic
and environmental factors. In developed
countries, it is among the diseases with highest rates of mortality and
morbidity. Proprotein convertase subtilisin/kexin 9 (PCSK9), plays an important
role for cholesterol homoeostasis via inducing post-transcriptional degradation
of Low-density lipoprotein-Receptor (LDLR).Since PCSK9’s first discovery
in 2003, studies focusing on PCSK9 continue without slowing down and now PCSK9
is a candidate as a new therapeutic target in atherosclerosis. However, little
is known about the genetic variants of PCSK9 and its influence on Low Density
Lipoprotein – cholesterol (LDL-C) in Turkish population. Mutations in the PCSK9
gene have been associated with both hypocholesterolemia and
hypercholesterolemia through ‘loss-of-function’ and ‘gain-of-function’
mechanisms, respectively. Our aim was to investigate PCSK9 N425S (rs28362261) and E670G
(23968A>G) (rs 505151) gene
polymorphisms in regard to their effects on serum lipoprotein level and
development of CHD.

Method: PCR-RFLP (Polymerase Chain Reaction-Restriction
Fragment Length Polymorphism) method is used for determination of PCSK9
variants.

Findings: In the patient group, frequency of PCSK9 E670G mutant T allele is higher than controls. Our findings indicate
that these variants might be an independent risk factors in development of CHD.
In the patient group, we observed the PCSK9
E670G normal A allele is associated with increased serum total-cholesterol
level.

Conclusion: In conclusion we suggest that the
PCSK9 gene variants might pose a
risk in susceptibility to CHD, since PCSK9 has detrimental effects on serum
lipids.

Anahtar Kelimeler

Proprotein convertase subtilisin/kexin-9 (PCSK9), coronary artery disease, lipoprotein, LDL-C, hypercholesterolemia

Koroner Kalp Hastalarında PCSK9 E670G ve N425S Gen Varyasyonlarının Etkisinin Türk Toplumunda Değerlendirilmesi

Öz

Amaç: Aterosklerozdan kaynaklanan Koroner Arter Hastalığı (KAH)
çeşitli genetik ve çevresel etmenlerin etkileşiminden kaynaklanan
multifaktöriyel bir hastalıktır. Gelişmiş ülkelerde en yüksek mortalite ve
morbidite nedenlerindendir. Proprotein subtilisin keksin tip-9 (PCSK9), Düşük
Yoğunluklu Lipoprotein Reseptörü (Low-density lipoprotein-Receptor / LDLR)'nün
post-transkripsiyonel degredasyonunu indükleyerek kolesterol hemostazında
önemli bir rol oynamaktadır. PCSK9'un ilk keşfedildiği 2003 yılından bu yana
çalışmalar hız kesmeden devam etmiş ve artık anti-PCSK9 monoklonal antikorları
ateroskleroz tedavisinde yeni bir hedef olarak sunulmuştur. Ancak Türk
popülasyonunda PCSK9'un genetik varyasyonları ve LDL-kolesterol (LDL-K)
üzerindeki etkisi hakkında çok az bilgi vardır. PCSK9 genindeki mutasyonlar
sırasıyla fonksiyon kaybı ve fonsiyon kazanımı mekanizmaları aracılığı ile hem
hipokolesterolemi hemde hiperkolesterolemi ile ilişkilidir. Çalışmamızda; PCSK9
fonksiyon kazanımı ile ilişkili N425S (rs28362261) ve E670G (23968A>G) (rs 505151) gen polimorfizmlerinin serum
lipoprotein düzeyi ve KAH gelişimindeki etkilerinin belirlenmesi amaçlanmıştır.

Yöntem: 64 hasta ve 50 kontrol’ün PCSK9 E670G ve N425S varyantının belirlenmesi için PCR-RFLP
(Polimeraz Zincir Reaksiyonu-Restriksiyon Parça Uzunluk Polimorfizmi) yöntemi
kullanılmıştır.

Bulgular: Koroner arter hastalarında PCSK9 E670G mutant T alleli frekansı kontrol grubuna göre daha yüksek gözlenmiştir. Verilerimiz bu varyantın
koroner kalp hastalığı gelişiminde bağımsız risk faktörü olabileceğini  önermektedir. Koroner arter hastalarında PCSK9 E670G normal A alleli yüksek serum
total-kolesterol düzeyi ile ilişkili bulunmuştur. PCSK9
N425S polimorfizmi dağılımlarında hasta ve kontrol gruplarında sadece NN normal
homozigot genotipi gözlenmiştir.

Sonuç: PCSK9 genindeki E670G varyantının serum lipid profili
üzerindeki olumsuz etkileriyle koroner kalp hastalığı gelişiminde risk oluşturabileceğini
göstermektedir. 

Anahtar Kelimeler

LDL-K, Proprotein konvertaz subtilisin keksin tip-9 (PCSK9), koroner arter hastalığı, lipoprotein, hiperkolesterolemi

Kaynakça

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