Risk of carotid atherosclerosis associated with genetic polymorphisms of apolipoprotein E and inflammatory genes among arsenic exposed residents in Taiwan Yi-Chen Hsieh a , Fang-I Hsieh a , Li-Ming Lien b , Yi-Li Chou a , Hung-Yi Chiou a,c, ⁎ , Chien-Jen Chen d a School of Public Health, Taipei Medical University, Taipei, Taiwan b Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan c Topnotch Stroke Center, Taipei Medical University, Taipei, Taiwan d Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan Received 16 July 2007; revised 6 October 2007; accepted 16 October 2007 Available online 22 October 2007 Abstract Arsenic had been reported to be associated with carotid atherosclerosis. However, there were few studies to evaluate the association between the susceptible gene of lipid metabolism and inflammation and carotid atherosclerosis among arsenic exposure residents. The aim of the study was to investigate the associations between the genetic polymorphisms of APOE and MCP-1 and the risk of carotid atherosclerosis among residents of Lanyang Basin in Taiwan which was a newly confirmed arsenic-endemic area. In total, 479 residents who had been genotyped of these two genes and examined the severity of carotid atherosclerosis were included in this study. The study subjects with carotid intima media thickness (IMT) ≥ 1.0 mm or with the observable plaque in the extracranial carotid artery were diagnosed as carotid atherosclerosis. A significantly age- and gender-adjusted odds ratio of 2.0 for the development of carotid atherosclerosis was observed in study subjects with ε4 allele of APOE than those without ε4 allele. Compared with study subjects who carried wild genotypes of APOE and MCP-1, those with both risk genotypes of APOE and MCP-1 had 2.5-fold risk of carotid atherosclerosis after adjustment for age and gender, revealing a significant dose–response relationship between number of risk genotypes of these genes and risk of carotid atherosclerosis. Additionally, study subjects with two risk genotypes of APOE and MCP-1 and either had ingested well water contained arsenic level N 10 μg/L or had arsenic exposure N 0.22 mg/L-year would have strikingly highest risk of 10.3-fold and 15.7-fold, respectively, for the development carotid atherosclerosis, showing significant joint effect of arsenic exposure and risk genotypes of APOE and MCP-1. © 2007 Elsevier Inc. All rights reserved. Keywords: Atherosclerosis; Arsenic; APOE; MCP-1; Polymorphism Introduction Arsenic is a metalloid element and widely distributed in the environment. Drinking arsenic-contaminated groundwater is the main way of human exposure to arsenic (Sheehy and Jones, 1993). Epidemiological evidence has shown that long-term chronic arsenic exposure in drinking water is associated with an increased risk of peripheral arterial disease (Tseng et al., 1996), ischemic heart disease (Chen et al., 1996) and cerebral in- farction (Chiou et al., 1997a). A recent report also indicated a dose–response relationship between long-term exposure to inorganic arsenic from groundwater and carotid atherosclerosis in Taiwan (Wang et al., 2002). Accumulating researches demonstrated that arsenic induces pathophysiological events relevant with atherogenic potential including increased oxida- tive stress (Barchowsky et al., 1996, 1999; Del Razo et al., 2001; Kitchin and Ahmad, 2003). The generation of reactive oxidants is a general manifestation of an inflammatory reaction, an important modifying factor of atherosclerosis progression, which involved low-density lipoprotein (LDL) deposition and oxidation, the interactions of migratory leukocytes with resident vascular endothelial cells, smooth muscle cells and fibroblasts (Ross, 1999). Available online at www.sciencedirect.com Toxicology and Applied Pharmacology 227 (2008) 1 – 7 www.elsevier.com/locate/ytaap ⁎ Corresponding author. School of Public Health, Taipei Medical University, 250 Wusing St., Taipei 110, Taiwan. Fax: +886 2 23779188. E-mail address: hychiou@tmu.edu.tw (H.-Y. Chiou). 0041-008X/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.taap.2007.10.013