Evaluation of the poly(ADP‐ribose) polymerase‐1 gene variants in Alzheimer's disease

Abstract

Amyloid peptide is thought to play a critical role in neuronal death in Alzheimer's disease (AD), most likely through oxidative stress. Free radical-related injury leads to DNA breaks, which subsequently activates the repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1). In this study, the relationship between genetic variants situated at the PARP-1 gene and AD development was investigated. We performed a case and control study from a Taiwanese population enrolled 120 AD patients and 111 healthy controls by using a polymerase chain reaction restriction fragment length polymorphism approach for two PARP-1 exonic polymorphisms, 414C/T (rs1805404) and 2456T/C (rs1136410), corresponding to protein residues at positions 81Asp/Asp and 762Val/Ala. There were no significant differences in allele or genotype frequencies for either PARP-1 gene variant between the case and control groups; however, upon analysis of the haplotype distribution, four haplotypes (Hts) were identified. We found that the distributions of Ht3-TT and Ht4-CC were significantly associated with an increased risk of AD (P<0.0001), whereas the Ht1-TC haplotype showed a protective effect for cases compared with the control group (P<0.05). These results reveal that the PARP-1 gene is highly associated with AD susceptibility and might contribute to a critical mechanism that mediates cell survival or death as a response to cytotoxic stress.

Variants of Base Excision Repair Genes <b><i>MUTYH</i></b>, <b><i>PARP1</i></b> and <b><i>XRCC1</i></b> in Alzheimer's Disease Risk

“…Postmortem studies observed decreases in DNA glycosylase activity: UDG (uracil DNA glycosylase) and hOGG1, DNA polymerase β, as well as the overall BER in brain cells of AD patients compared to brain cells of patients with mild cognitive impairment, suggesting a relationship between BER performance and degree of neurodegeneration in these cells [11]. Polymorphisms of the BER gene PARP may also play a role in the pathogenesis of AD [12]. In the case of Parkinson's disease (PD), which is another neurodegenerative disorder, there is a positive association of apurinic/apirimidinic site endonuclease ( APE1; g.20456995T>G), X-ray repair cross-complementing protein 1 encoding XRCC1 protein (c.1196A>G), and XRCC3 (g.103699416G>A) DNA repair gene polymorphisms and increased PD risk [13].…”

Variants and Polymorphisms of DNA Repair Genes and Neurodegenerative Diseases

“…Again, none of the polymorphisms resulted independently associated with increased AD risk (Table 2). However, authors found that the distributions of haplotype 3-TT and haplotype 4-CC were significantly associated with an increased risk of AD, whereas the haplotype 1-TC showed a protective effect, with OR of 12.2 and 0.52, respectively (Liu et al, 2010). Overall, both studies support the hypothesis that PARP1 haplotypes might affect AD risk.…”

“…Particularly, haplotypes 2-1 and 1-2 were significantly overrepresented in AD individuals and associated with an increased risk for the disease with an adjusted OR of 1.42 and 5.38, respectively . More recently two PARP-1 exonic polymorphisms, 414C>T (rs1805404) and 2456T>C (rs1136410), have been evaluated in 120 Chinese AD patients and 111 matched controls (Liu et al, 2010). Again, none of the polymorphisms resulted independently associated with increased AD risk (Table 2).…”

The C Allele of a Synonymous SNP (rs1805414, Ala284Ala) in PARP1 is a Risk Factor for Susceptibility to Breast Cancer in Saudi Patients

“…Although many studies have searched for the association between PARP-1 polymorphisms and the risk of malignancy, the results are inconsistent in different organs and in different ethnic groups. Few studies have reported positive associations between the SNP's rs1805404 and rs1805414 at position 81 and 284, have been reported to be significantly associated with an increased risk of Alzheimer's disease (Liu et al, 2010), Glioblastoma (Keller et al, 2011), protectively associated with Colorectal cancer (Berndt et al, 2007;Ogino et al, 2010). rs1805404 reported be strongly associated with Tourette syndrome risk (Wu et al, 2013).…”