Human Molecular Genetics Advance Access originally published online on January 9, 2007
Human Molecular Genetics 2007 16(6):592-599; doi:10.1093/hmg/ddl483
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Polymorphisms in pro- and anti-inflammatory cytokine genes and susceptibility to atherosclerosis: a pathological study of 1503 consecutive autopsy cases
1 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan, 2 Department of Clinical Bioinformatics, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan, 3 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan, 4 Department of Advanced Medicine, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan and 5 Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
* To whom correspondence should be addressed. Tel: +81 03 5280 8060; Fax: +81 03 5280 8061; Email: muramatsu.epi{at}mri.tmd.ac.jp
Received October 28, 2006; Revised December 22, 2006; Accepted December 28, 2006
Atherosclerosis is a chronic inflammatory disease in the intima of the arterial wall, where cytokines play a crucial role in the pathogenesis of this disease. However, the question of whether or not genetic variations in the cytokine genes could influence the development of atherosclerosis has been poorly investigated. We investigated the relationship of nine common single-nucleotide polymorphisms (SNPs) in tumor necrosis factor-
(TNF-), interleukin (IL)-1ß, IL-10, IL-4 and transforming growth factor (TGF)-ß1 with the atherosclerotic severity in 10 different arteries based on 1503 consecutive autopsies of elderly Japanese subjects registered in the Japanese SNPs for geriatric research (JG-SNP) study. The –1031C allele of TNF- was a significant protective factor for atherogenesis in the carotid, femoral and intracranial arteries [odds ratio (OR): 0.72, 0.73 and 0.70, respectively]. The –511T of IL-1ß and the +29T of TGF-ß1 were significant risk factors for atherogenesis in the subclavian and intracranial arteries (OR: 1.35 and 1.48, respectively). In contrast, conventional risk factors for atherogenesis, such as hypertension and diabetes mellitus, conferred independent risks for almost all arteries. Functional SNPs in TNF-, IL-1ß and TGF-ß1 genes play a role in atherogenesis, although their influences are less pronounced than those of conventional risk factors and appear to be limited to specific arteries in the Japanese elderly.