Tumor necrosis factor α and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease

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 epsilon 4 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.