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Tumor Necrosis Factor and Interleukin 10 Promoter Region Polymorphisms and Risk of Late-Onset Alzheimer Disease
Erin M. Ramos, MPH;
Ming-Tesh Lin, MD, PhD;
Eric B. Larson, MD;
Izumi Maezawa, PhD;
Li-Hui Tseng, MD, PhD;
Karen L. Edwards, PhD;
Gerard D. Schellenberg, PhD;
John A. Hansen, MD;
Walter A. Kukull, PhD;
Lee-Way Jin, MD, PhD
Arch Neurol. 2006;63:1165-1169.
Background Functional polymorphisms in tumor necrosis factor (TNF- ) 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- 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- , IL-10, and apolipoprotein E (APOE) genotyping.
Results The TNF- 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- region, we constructed promoter region haplotypes as defined by single nucleotide polymorphisms at positions 863 and 308. Based on knowledge of TNF- protein production, we ordered the haplotypes based on apparent increasing transcriptional activity. After adjusting for age, education, and the presence of the APOE 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- promoter region, or possibly polymorphisms in nearby genes, could affect cerebral inflammatory response and the risk of late-onset AD.
Author Affiliations: Institute for Public Health Genetics (Ms Ramos and Dr Edwards), Departments of Medicine (Dr Schellenberg), Neurology (Dr Schellenberg), Pharmacology (Dr Schellenberg), and Epidemiology (Drs Edwards and Kukull), University of Washington; Division of Clinical Research, Fred Hutchinson Cancer Research Center (Drs Lin and Hansen); Center for Health Studies, Group Health Cooperative of Puget Sound (Dr Larson); and Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle Division (Dr Schellenberg); Seattle, Wash; Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute and Department of Pathology, University of CaliforniaDavis, Sacramento (Drs Maezawa and Jin); and Department of Medical Genetics, National Taiwan University Hospital, Taipei (Dr Tseng).
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