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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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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Decreased risk of colorectal cancer with the high natural killer cell activity NKG2D genotype in Japanese

Hiroki Furue1,5, Keitaro Matsuo2,6,*, Hiroshi Kumimoto1, Akio Hiraki2, Takeshi Suzuki2, Yasushi Yatabe3, Koji Komori4, Yukihide Kanemitsu4, Takashi Hirai4, Tomoyuki Kato4, Minoru Ueda5, Kanji Ishizaki1 and Kazuo Tajima2,6

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


   Abstract
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 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 
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


   Introduction
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 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 References
 
Colorectal cancer (CRC) is one of the major types of cancer worldwide (1). Many epidemiological as well as biological studies have revealed risk/protective factors but our level of knowledge is still not satisfactory if we are to conquer the disease, and researchers continue struggling to elucidate potential mechanisms.

It is generally accepted that the cells of the immune system are responsible for the recognition and elimination of nascent transformed host cells within the ‘immune surveillance system’ (2–4). Thus, many studies of immune cells have been conducted with reference to their influence on carcinogenesis and metastasis (5–8). In all immune networks, the receptors of immune cells play primary roles (9,10). NKG2D, which is expressed not only on natural killer (NK) cells but also on {gamma}{sigma} T cells and CD8+ T cells, has been studied most intensively (11) since it makes a critical contribution to immune surveillance.

NKG2D is located in the NK complex region composed of NK cell receptors that have activating or inhibitory functions (12). Recently, a haplotype block in the NK complex region, NK hb-1, was identified (Figure 1) (13). One haplotype of NK hb-1, HNK1, significantly correlates with high cytotoxic activity and has demonstrated a strong association with reduced overall cancer risk in the Japanese population (13). Moreover, several studies have been conducted to evaluate association between NK activity and lifestyle factors. Nakachi et al. (14) reported physical activity and several lifestyle factors were strongly correlated with NK activity in the cross-sectional study in the general population. Thus, the interaction between lifestyle factors and NKG2D haplotype can be the subject of interest.


Figure 1
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  		Fig. 1. Schematic overview of the haplotype in the NK complex gene region and linkage disequilibrium (LD) analysis for selected subjects. (a) Natural cytotoxic activity-related haplotype alleles (LNK1 and HNK1) in the NK-hb1. (b) Examination of 45 randomly selected controls confirmed complete LD across the five loci (D' = 1.0 and R2 = 1.0); therefore, rs1049174 was selected as the candidate out of five loci.

 
The aim of the present case–control study was to clarify the impact of a NKG2D polymorphism on CRC risk. In addition, we explored the gene–environmental interaction between potential confounders and NKG2D genotype for CRC risk in Japanese.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 References
 
Subjects
Cases were 379 patients who were histologically diagnosed as having CRC (180 with colon cancer, 196 with rectum cancer and 3 with both cancers) between January 2001 and May 2005 at Aichi Cancer Center Hospital (ACCH) and did not have any prior history of cancer. Controls were first-visit outpatients at ACCH during the same period and were confirmed to have neither cancer nor a prior history of neoplasia. Controls were randomly selected and matched for sex and age (±5 years) to cases with a 1:3 case–control ratio (n = 1137) to achieve >80% power to detect an odds ratio (OR) of 0.5 with the proportion of the risk genotype among controls being 60%. The subjects were selected from the database of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). The framework of HERPACC has been described elsewhere (15,16). Briefly, all outpatients, aged 20–79 years, were asked at their first visit to fill out a questionnaire regarding their lifestyle as well as to provide 7 ml of blood. A trained interviewer checked the completion of each questionnaire. Approximately 95% of eligible subjects completed the questionnaire and 55% provided blood samples. Some 30% of first-visit outpatients were diagnosed at ACCH as having cancer. Under the assumption that the non-cancer population within HERPACC will visit ACCH when they suffer from cancer in the future, we define non-cancer first-visit outpatients as those from among whom such cases may arise. Our previous study showed lifestyle patterns of first-visit outpatients to match the profile of those in the general population randomly selected from Nagoya city, conferring external validity on the study (17). Written informed consent was obtained from all the subjects and the ethical committee of Aichi Cancer Center approved this investigation.

Determination of the NKG2D genotype
The NKG2D hb-1 haplotype block consists of two haplotypes, one with high NK activity (HNK1) and the other low NK activity (LNK1), and can be assessed with regard to five tightly linked single nucleotide polymorphisms (SNPs), rs1049174, rs2617160, rs2617170, rs2617171 and rs1982526 as shown in Figure 1 (13). In our examination of the five loci in randomly selected 45 subjects by direct sequencing or TaqMan method, complete linkage was observed across the five loci. Linkage disequilibrium was assessed by D' and R2 were presented in Figure 1. All the pairwise D' were 1; therefore, we decided to use a single locus, rs1049174, featuring a G–C substitution, as the candidate SNP. Genotypes defined by this locus are presented as LNK1/LNK1:CC; LNK1/HNK1:CGand HNK1/HNK1:GG.

DNA of each subject was extracted from the buffy coat fraction with a Blood Mini Kit (Qiagen K.K., Tokyo, Japan) and was assessed using the polymerase chain reaction TaqMan method (18) with the 7500 Fast Real-time PCR System (Applied Biosystems, Foster City, CA). The probe used here was specifically designed for rs1049174 (product No:C__9345347_10). Quality of genotyping was routinely assessed statistically using the Hardy–Weinberg test in our laboratory. Reliability of genotyping was also confirmed with duplicate examination in randomly selected 100 controls.

Exposure data
Cumulative smoking dose was evaluated as pack-years, the product of the number of packs consumed per day and years of smoking. The smoking habit was classified into the four categories of never, former, current smokers of <40 (moderate) and ≥40 pack-years (heavy). Former smokers were defined as those who quit smoking at least 1 year before the survey. Consumption of each type of alcoholic beverage (Japanese sake, beer, shochu, whiskey and wine) was determined with reference to the average number of drinks per day, which was then converted into a Japanese sake (rice wine) equivalent (19). The drinking habit was also classified into the four categories of never, former, moderate and heavy. Heavy drinkers were those currently drinking alcoholic beverages 5 days or more per week at a daily amount of 46 g (two ‘go’) or more, whereas moderate drinkers were defined as those currently consuming less frequently than 5 days per week, lower amounts or both. Former drinkers were defined as those who quit drinking at least 1 year before the survey. The consumption of folate was determined using a semi-quantitative food frequency questionnaire (SQFFQ) as described in detail elsewhere (20). Briefly, the SQFFQ consisted of 47 single food items with frequencies in the eight categories of never or seldom, 1–3 times/month, 1–2 times/week, 3–4 times/week, 5–6 times/week, once/day, twice/day and 3+ times/day. We estimated the average daily intake of nutrients by multiplying the food intake (in grams) or serving size by the nutrient content per 100 grams of food as listed in standard tables of food composition. Consumption of supplemental folate was not considered in the total consumption because the questionnaire for multivitamins was not quantitative. Energy-adjusted intake of nutrients was calculated by the residual method (21). The SQFFQ was validated by referring to a 3-day weighed dietary record as a standard, which showed reproducibility and validity to be acceptable (22,23). The deattenuated correlation coefficients for energy-adjusted intakes of folate were 0.36 in men and 0.38 in women. Body mass index (BMI) was calculated as self-reported weight (kilograms) divided by square of self-reported height (meters). A family history of CRC in first-degree relatives was based upon self-reporting as described elsewhere (24). Regular physical exercise was also covered in the questionnaire. Subjects were asked to report frequency and intensity of recreational exercise. In this analysis, exercise at least once a month was defined as regular.

Statistical analysis
Multivariable logistic regression models were employed to calculate the ORs and 95% confidence intervals (CIs) for assessment of the impact of the NKG2D genotypes, included in the model as an ordinal score (1, 2 and 3). Confounders considered in the analysis were age (as a continuous variable), sex (male versus female), smoking status (never, former, current moderate and heavy with scores (1, 2, 3 and 4)], drinking status [never, former, current moderate and heavy with scores (1, 2, 3 and 4)], folate consumption in quartile (Q1–4 in scores 1–4), BMI (<25 versus ≥25 kg/m2), family history of CRC (yes versus no) and regular exercise (yes versus no). Trends were assessed with a score test. Interactions between NKG2D genotypes and lifestyle factors such as smoking, drinking and other lifestyle factors were also assessed in multivariable logistic regression models. We assessed accordance with the Hardy–Weinberg equilibrium among control by the {chi}2 test. Statistical analyses were performed using Stata version 8 (Stata, College Station, TX) and P values <0.05 were considered statistically significant.


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 References
 
Table I shows baseline characteristics of the 379 CRC cases, with an average age of 58.8 years, and the 1137 controls matched for sex and age. Males accounted for 63.9% of the studied subjects. Cases consisted of 180 colon cancer patients (47.5%) and 196 rectum cancer patients (51.7%) and 3 with both cancers (0.8%). Smoking and drinking status did not show clear differences between cases and controls. Although not significant, those with lower folate consumption were more prevalent in cases compared with controls. Family history showed a significant positive association with CRC. BMI and regular exercise did not show marked differences between cases and controls.


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  		Table I. Characteristics of cases and controls

 
The genotype distribution for the NKG2D polymorphism (rs1049174) and their ORs and 95% CI among cases and controls are shown in Table II. The allele frequency for LNK1 was 0.61 and the genotype distribution was 37.12% (LNK1/LNK1), 47.58% (LNK1/HNK1) and 15.30% (HNK1/HNK1) among controls and this was in concordance with the Hardy–Weinberg equilibrium (P = 0.98). We explored three models and found consistent results. The multivariate-adjusted ORs for CRC were significantly lower than unity with LNK1/HNK1 (OR: 0.77, 95% CI: 0.60–0.99) and HNK1/HNK1 (0.47, 0.32–0.72) compared with LNK1/LNK1 (trend P < 0.001). This trend was consistently observed in rectum, colon and subsite in colon.


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  		Table II. Distributions of NKG2D genotype and its impact for CRC risk

 
To explore possible interactions between lifestyle factors such as smoking and drinking, we conducted stratified analyses according to potential confounders (Table III). Regarding smoking, a trend for reduced CRC risk was consistently observed with LNK1/HNK1 and HNK1/HNK1 compared with LNK1/LNK1 except in heavy smokers. Similarly, consistently decreasing risk trends with the HNK1 for drinking and folate consumption was observed, indicating absence of effect modification by these factors. Stratified analyses according to family history of CRC showed different trends across two strata; however, this might have been due to the limited number of subjects with a positive family history of CRC.


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  		Table III. Adjusteda ORs and 95% CIs by smoking and drinking and other risk factors according to NKG2D genotypeb

 
BMI and regular exercise showed a non-significant but suggestive effect modification (Table III). Decreased risk with the HNK1 was evident in those with higher BMI. The OR for those harboring HNK1/HNK1 and having a BMI >25 was 0.17 (0.06–0.49) relative to those with LNK1/LNK1 in BMI <25. A significant reduction in the risk trend was also observed among those exercising regularly. We further focused on these interactions, and results of combination of BMI and regular exercise are presented in Table IV. A protective effect of HNK1 was observed only among those exercising regularly. Whether the impact of HNK1 differs with the BMI in regular exercisers was not clear from the results; however, point estimates did suggest this possibility (OR for BMI < 25: 0.47 and for BMI ≥ 25: 0.24).


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  		Table IV. Combined effect of BMI, regular exercise and NKG2D genotype on CRC riska

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 References
 
In this study, we found the allele in the SNP (rs1049174) associated with high NK activity (HNK1) to have a protective effect against CRC in a Japanese population regardless of other risk factors. This indicates that innate immunity might play a substantial role in CRC risk.

Recently, a clear correlation between NKG2D haplotype and NK cell activity in Japanese population was reported (13), the HNK1 being associated with a higher cytotoxic activity compared with homozyogous LNK1 and decreasing the overall cancer risk. However, its impact on specific types of cancer has hitherto remained unknown and this is the first indication of such an effect of the HNK1 on CRC.

Of note was that the possible interaction of NKG2D genotypes with BMI and regular exercise, two parameters intimately associated through the concept of energy balance. Obesity and physical exercise are well-established risk factors for CRC regardless of ethnicity (25). The interaction we observed might indicate a potential contribution of NK activity to the mechanisms behind obesity and regular exercise influence on CRC risk. There have been several studies suggesting possible association between NK activity and lifestyle factors (14,26–29). One population-based study demonstrated clear association between NK activity and physical activity and weight. In the study, those exercises daily showed higher NK activity than those less than once per week and those with relatively normal and lower showed higher NK activity than those with higher relative weight. This was quite concordant with our finding and warranting further studies to determine biological mechanisms behind interactions.

Several potential limitations of the present study require consideration. First, internal validity of this hospital-based study is a potential threat to causal inference. We used non-cancer patients at our hospital as controls, given the likelihood that our cases arose within this population base. Moreover, individuals selected randomly from our control population were earlier shown to be similar to the general population in terms of the exposure of interest (17), with external validity to the general population. The medical background of controls is another potential source of bias; however, our previous study, which focused on females, demonstrated only a limited impact of this factor (30) and little difference would be expected for men. Given this background and methodology, we conclude that the use of non-cancer outpatients as referents in HERPACC type epidemiological studies is reasonable. Second, as with other case–control studies, this study may have suffered from recall bias. Although the questionnaires were completed before the diagnosis in our hospital, in some cases patients referred from other institutions might have known the diagnosis. Third, we used a self-administered questionnaire to evaluate lifestyle, including nutrients intake such as folate. Regarding nutrients, the reproducibility and validity of the SQFFQ were earlier found to be acceptable (23). We could not consider the consumption of folate from supplements in total consumption, but the proportion of users of folate supplements is very low in Japan (0.1%) (31). Lastly, the limited number of cases and controls means that replication of our findings, especially about gene–environment interaction, in a larger study is required.

In conclusion, our present investigation showed an NKG2D SNP (rs1049174) to be an independent risk factor of CRC in a Japanese population. Further exploration of this possibility in other populations is warranted.


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
References
 
Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry of Health, Labour and Welfare, Japan.


   Acknowledgments
 
Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 

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Received August 21, 2007; revised October 22, 2007; accepted November 7, 2007.


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