Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(2):316-320; doi:10.1093/carcin/bgm260
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Decreased risk of colorectal cancer with the high natural killer cell activity NKG2D genotype in Japanese
1 Central Laboratory and Radiation Biology and
2 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya
3 Department of Pathology and Molecular Diagnosis and
4 Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
5 Department of Oral and Maxillofacial Surgery
6 Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
* To whom correspondence should be addressed at Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Tel: +81 52 762 6111; Fax: +81 52 763 5233; Email: kmatsuo{at}aichi-cc.jp
Background: NKG2D is an immune receptor on natural killer (NK) and other cells active in the immune system. It recognizes ligands expressed on mainly transformed cells and plays a role in their elimination through the so-called ‘cancer immune surveillance’. It was reported that there are two haplotypes of NKG2D, HNK1 (high NK activity) and LNK1 (low NK activity). Harboring the HNK1 is reported to reduce the overall cancer risk. To elucidate its impact on colorectal cancer (CRC), we conducted the present case–control study. Method: The subjects were 379 CRC patients and 1137 sex–age-matched non-cancer controls. Data on lifestyle factors including diet were obtained by self-administered questionnaire. The NKG2D genotypes (rs1049174: G–C, LNK1/LNK1:CC; LNK1/HNK1:CG and HNK1/HNK1:GG) were assessed by the TaqMan method. Associations were then assessed by multivariate logistic regression models, considering potential confounders. The measure of association was the odds ratio (OR) and its confidence intervals (CIs). Results: We found a reduced risk of CRC with the NKG2D HNK1. Adjusted ORs were 0.77 for LNK1/HNK1 (95% CI: 0.60–0.99) and 0.48 for HNK1/HNK1 (0.32–0.72) relative to LNK1/LNK1. The same association was consistently observed with stratified analyses across all confounders except regular exercise and body mass index (BMI). Thus, the impact of harboring HNK1 was more evident among those with BMI 
25 and those exercising regularly, suggesting possible interactions between NKG2D genotype and these factors. Conclusion: We found that the HNK1 genotype, associated with high NK cell activity, might be an independent protective factor for CRC among the Japanese population. This possibility warrants further analysis.
Abbreviations: ACCH, Aichi Cancer Center Hospital; BMI, body mass index; CI, confidence interval; CRC, colorectal cancer; HERPACC, Hospital-based Epidemiologic Research Program at Aichi Cancer Center; NK, natural killer; OR, odds ratio; SNP, single nucleotide polymorphism; SQFFQ, semi-quantitative food frequency questionnaire
Received August 21, 2007; revised October 22, 2007; accepted November 7, 2007.