The authors conclude that anti-TNF modulation might have a potential role in AD treatment. This was an excellent multi-center study published in the Archives of Neurology which suggests a higher risk of late-onset AD in patients with a polymorphism in the promoter region of the TNF-alpha 308 gene.
Press release:
Reuters Health Information
TNF-alpha Polymorphisms Tied to Alzheimer's Risk
NEW YORK (Reuters Health) Aug 25 - Variations in the tumor necrosis factor (TNF) alpha promoter region appear to be associated with the risk of late-onset Alzheimer's disease, researchers report in the August issue of the Archives of Neurology.
"We studied the genetic variations of subjects from a community-based population; and our data suggest that the genetic modulation of a prominent inflammation mediator, TNF-alpha," is related to Alzheimer's disease risk, senior investigator Dr. Lee-Way Jin, University of California-Davis, told Reuters Health."
Dr. Jin and associates conducted a case-control study involving 265 elderly white subjects who met criteria for probable or definite Alzheimer's disease. They were compared with 347 controls.
Genotyping results indicated that the TNF-alpha-863 A allele was associated with reduced odds of developing Alzheimer's disease. This allele was seen in 16.9% of controls and 12.6% of cases.
The researchers note that the TNF-alpha-863 A allele is associated with 31% lower transcriptional activity and significantly lower serum TNF-alpha levels than normal.
The team looked at haplotypes based on transcriptional activity, and after adjusting for factors including age and the presence of the APOE epsilon 4 genotype, they found increasing odds of Alzheimer's disease with increasing transcriptional activity.
These results suggest that strategies designed to reduce TNF-alpha protein production or activity might offer a treatment for Alzheimer's disease, Dr. Jin concludes.
Arch Neurol 2006;63:1165-1169.
Abstract:
Title Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease.
Author(s) Ramos EM, Lin MT, Larson EB, Maezawa I, Tseng LH, Edwards KL, Schellenberg GD, Hansen JA, Kukull WA, Jin LW
Institution Institute for Public Health Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Source Arch Neurol 2006 Aug; 63(8) :1165-9.
MeSH Age of Onset
Aged
Aged, 80 and over
Alzheimer Disease
Case-Control Studies
Comparative Study
Female
Gene Frequency
Haplotypes
Humans
Interleukin-10
Male
Polymorphism, Genetic
Promoter Regions (Genetics)
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Risk Factors
Tumor Necrosis Factor-alpha
Abstract BACKGROUND: Functional polymorphisms in tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) can affect immune response, inflammation, tissue injury, and possibly the susceptibility to Alzheimer disease (AD).
OBJECTIVE: To evaluate the association between promoter region polymorphisms in the TNF-alpha and IL-10 genes and risk of late-onset AD in older white subjects.
DESIGN: Community-based case-control study.
SETTING: Group Health Cooperative of Puget Sound.
PARTICIPANTS: White subjects (n = 265) meeting criteria for probable or definite AD (cases) and white control subjects (n = 347) (controls).
MAIN OUTCOME MEASURES: Genotyping results for TNF-alpha, IL-10, and apolipoprotein E (APOE) genotyping.
RESULTS: The TNF-alpha -863 A allele was associated with reduced odds of developing AD, and the test for trend suggested that having 2 copies of the A allele further reduces the risk (odds ratios [C/C, reference], 0.66 for C/A and 0.58 for A/A; P = .04). Because of linkage disequilibrium in the TNF-alpha region, we constructed promoter region haplotypes as defined by single nucleotide polymorphisms at positions -863 and -308. Based on knowledge of TNF-alpha protein production, we ordered the haplotypes based on apparent increasing transcriptional activity. After adjusting for age, education, and the presence of the APOE epsilon4 genotype, the test for trend showed increasing odds of AD with increasing transcriptional activity (P = .02). The IL-10 -1082 and IL-10 -592 allele and genotype frequencies were not significantly different between cases and controls.
CONCLUSION: Variation in the TNF-alpha promoter region, or possibly polymorphisms in nearby genes, could affect cerebral inflammatory response and the risk of late-onset AD.
Language eng
Pub Type(s) Journal Article
PubMed ID 16908746
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