Genetic association of TNF-α-308 G/A and -863 C/A polymorphisms with late onset Alzheimer's disease in Azeri Turk population of Iran

Abstract

Background: Recent findings suggest that production of pro-inflammatory cytokines, such as Tumour Necrosis Factor-alpha (TNF-α), is increased in the brain tissue of patients suffering late-onset Alzheimer's disease (LOAD) and play an important role in the pathogenesis of this disease. Several epidemiological studies also suggest that patients taking anti-inflammatory drugs have a decreased risk of developing AD. TNF-α is an important pro inflammatory cytokine that is unregulated in Alzheimer's patients. Functional polymorphisms in tumor necrosis factor alpha (TNF-α) can affect immune response, inflammation, tissue injury and possibly the susceptibility to Alzheimer disease (AD).

Methods: We used the polymorphic DNA markers (-308G/A) and (-863C/A) to study the association of TNF-α gene mutations with Late-onset Alzheimer's disease (LOAD) and the relation between clinical features and genotypes in affected individuals. A total of 160 patient samples and 163 healthy controls from west northern Iran (Eastern Azerbaijan) were genotyped for the two polymorphisms by the PCR-RFLP method and genotype frequencies were statistically determined.

Results: Our data showed significant difference in TNF-α-308 G/A genotype and pro inflammatory cytokine allele frequencies between the Alzheimer disease patients and healthy subjects. Contrary to that, no significant difference was observed in TNF-α-863 C/A genotype and allele frequencies between these two groups.

Conclusions: TNF-α-308 G/A gene polymorphism could affect cerebral inflammatory response and the risk of late-onset Alzheimer disease but -863 C/A polymorphism does not influence the risk of this disease and this possible association between TNF-α -308G/A and -863C/A gene polymorphisms have to be further elucidated in larger case control studies.

Keywords: -308G/A; -863C/A; Alzheimer; PCR-RFLP; Polymorphism; TNF- α; β-Amyloid.

Figure 1

The PCR yields a 107-base-pair (bp) product; the NcoI restriction enzyme cleaves the wild-type (TNF1) allele (restriction sequence: C’CATGG), giving rise to two different fragments of 87 and 20 bp. Thus, in subjects homozygous for the wild-type (TNF1) allele, a single band of 87 bp is observed (lane 2,3); in heterozygous subjects (TNF1/TNF2), two bands of 107 and 87 bp (lane 1,3,6,7); and in subjects homozygous for the mutated (TNF2) allele, a band of 107 bp (lane 4,8).

Figure 2

The PCR yields a 125-base-pair product; the TaiI restriction enzyme cleaves the mutated (-863A) allele (restriction sequence: ACGT), giving rise to two different fragments of 104 and 21 bp. Thus, in subjects homozygous for the wild-type (-863C) allele, a single band of 125 bp is observed (lane 2); in heterozygous subjects (-863C/A), two bands of 104 and 125 bp (lane 1,3); and in subjects homozygous for the mutated (-863A) allele, a band of 104 bp (lane 4).