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

Abstract

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.

Keywords

• 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

Abstract

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. 

Keywords

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

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