A Study of the Impact of Death Receptor 4 (DR4) Gene Polymorphisms in Alzheimer’s Disease

Abstract

Background: Excessive apoptosis is believed to play a role in many degenerative and non-degenerative neurological diseases including Alzheimer's disease (AD). Much recent data suggest that apoptotic mechanisms may represent the missing link between Aβ deposition and proteolysis of tau protein. However, there is emerging evidence that apoptotic mechanisms may play a role in Alzheimer's Disease pathogenesis in the absence of overt apoptosis. TNF-related apoptosis inducing ligand receptor 1 (Death Receptor 4, DR4) might impair the apoptotic signal transduction and lead to dysregulation of the homeostasis between cell survival and cell death. Aims: The aim of our study was to further investigate the relationship between genetic variants of DR4 and Alzheimer's Disease. Study Design: Case control study. Methods: Sixty-eight patients with AD were included in the study. The control group comprised 72 subjects without signs of neurodegenerative diseases, as evidenced by the examination.DNA was extracted from whole blood using the salting-out procedure. Genotypes were identified by restriction fragment length polymorphism analysis of polymerase chain reaction (PCR-RFLP) products. Results: We observed significant differences in the genotypic distribution of the rs6557634 polymorphism in AD patients compared with controls (p<0.05); our data suggest that the GA genotype in rs6557634 could be protective against AD (p<0.05). However, there were no significant differences between AD patients and control groups in terms of the DR4 rs20575 polymorphism (p>0.05) and the DR4 rs20576 polymorphism (p>0.05). According to haplotype analysis of the DR4 gene for rs6557634, rs20575 and rs20576 polymorphisms, GCA and GCC haplotypes might be a risk factor for AD. Also, we have shown that ACA, GGC and GGA haplotypes might be protective factors against AD. Conclusion: The present results indicate for the first time the possible contribution of the DR4 gene rs6557634, rs20575, rs20576 polymorphisms in Alzheimer's Disease, which may influence susceptibility to Alzheimer's Disease. Turkish Başlık: Ölüm Reseptör 4 (DR4) Geni Polimorfizmlerinin Alzheimer Hastalığına Etkisi Üzerine Bir Çalışma Anahtar Kelimeler: Alzheimer Hastalığı, Ölüm reseptörü 4, Genetik Polimorfizm Arkaplan: Yüksek oranda apoptozisin, Alzheimer hastalığı (AH) dahil olmak üzere birçok dejeneratif ve non-dejeneratif nörolojik hastalıklarda rol oynadığına inanılmaktadır. Elde edilen birçok yeni veri Aβ birikimi ve tau proteolizi arasındaki kayıp halkanın apoptotik mekanizmalar olabileceğini düşündürmektedir. Ancak açık apoptozun yokluğunda, Alzheimer Hastalığı patogenezinde apoptotik mekanizmaların rol oynayabileceği öne sürülmüştür. TNF-ilişkili apoptozisi indükleyen ligand reseptör 1 (Ölüm Reseptör 4, DR4) apoptotik sinyal transdüksiyonunu bozarak, hücre canlılığı ve hücre ölümü arasındaki dengesinin bozulmasına yol açabilir. Amaç: Çalışmamızın amacı, DR4 geni varyantları ve Alzheimer Hastalığı arasındaki ilişkiyi araştırmaktır. Çalışma Tasarımı: Altmış sekiz Alzheimer hastalısı çalışmaya dahil edildi. Kontrol grubu muayenesi yapılarak nörodejeneratif bir hastalığı olmadığı belirlenen 72 olgudan oluşturuldu. Yöntemler: Tuz çöktürme yöntemiyle DNA elde edildi. Genotipler, polimeraz zincir reaksiyonu ürünlerinin restriksiyon fragment uzunluk polimorfizmi analizi ile tespit edildi. Bulgular: DR4 geni rs6557634 polimorfizmi açısından kontrol grubu ile Alzheimer hastaları karşılaştırıldığında, genotipik dağılımında anlamlı bir fark gözlenmedi (p<0.05). Elde ettiğimiz veriler göre, rs6557634 polimorfizminde GA genotipinin Alzheimer hastalığına karşı koruyucu bir faktör olabileceği tespit edildi. (p<0.05). Ancak DR4 geni rs20575 polimorfizmi ve DR4 rs20576 polimorfizmi açısından Alzheimer hastaları ve kontrol grupları arasında anlamlı bir fark belirlenmedi (p> 0.05). DR4 geni haplotip analizine göre rs6557634, rs20575 ve rs20576 polimorfizmleri; GCA, GCC haplotipinin AH için bir risk faktörü olabileceği belirlendi. Ayrıca, ACA, GGC ve GGA haplotiplerinin AH karşı koruyucu faktörler olabileceği gösterilmiştir. Sonuç: Elde ettiğimiz verilerimiz ile DR4 geni rs6557634, rs20575 ve rs20576 polimorfizmlerinin Alzheimer Hastalığına duyarlılığı etkileyebileceği ilk kez, tespit edilmiştir.

Keywords

• Alzheimer’s disease, death receptor 4, genetic polymorphism

A Study of the Impact of Death Receptor 4 (DR4) Gene Polymorphisms in Alzheimer’s Disease

Öz

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