Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population

Abstract

Background and aim: Colorectal cancer (CRC) is a multifactorial disease with both environmental and genetic factors contributing to its development. The incidence of CRC is increasing year by year in Japan. Patients with CRC in advanced stages have a poor prognosis, but detection of CRC at earlier stages can improve clinical outcome. Therefore, identification of epidemiologial factors that influence development of CRC would facilitate the prevention or early detection of disease.

Methods: To identify loci associated with CRC risk, we performed a genome-wide association study (GWAS) for CRC and sub-analyses by tumour location using 1583 Japanese CRC cases and 1898 controls. Subsequently, we conducted replication analyses using a total of 4809 CRC cases and 2973 controls including 225 Korean subjects with distal colon cancer and 377 controls.

Results: We identified a novel locus on 6q26-q27 region (rs7758229 in SLC22A3, p = 7.92 × 10⁻⁹, OR of 1.28) that was significantly associated with distal colon cancer. We also replicated the association between CRC and SNPs on 8q24 (rs6983267 and rs7837328, p = 1.51 × 10⁻⁸ and 7.44 × 10⁻⁸, ORs of 1.18 and 1.17, respectively). Moreover, we found cumulative effects of three genetic factors (rs7758229, rs6983267, and rs4939827 in SMAD7) and one environmental factor (alcohol drinking) which appear to increase CRC risk approximately twofold.

Conclusions: We found a novel susceptible locus in SLC22A3 that contributes to the risk of distal colon cancer in an Asian population. These findings would further extend our understanding of the role of common genetic variants in the aetiology of CRC.

Figure 1

Case–control association results, genomic structure, and linkage disequilibrium map of chromosomal region of 6q26-q27. The top panel shows single-marker association results calculated by Cochran–Armitage trend tests. Results from the screening stage and combined analysis (screening stage, first and second replication studies) are indicated by black and red dots, respectively. The bottom panel shows the pairwise linkage disequilibrium for SNPs in HapMap JPT. The red line indicates the significance threshold after Bonferroni's correction for multiple testing (p=1.27×10⁻⁷).

Figure 2

Impact of genetic and environmental factors on CRC susceptibility. Three genetic factors (rs6983267, rs4939827, and rs7758229) and alcohol consumption were used in the scoring system. We assigned a score of 0, 1, or 2 for non-, light, and heavy drinker, as well as a score of 1 for each risk allele. (A) Distribution of scores in CRC cases (white bars) and controls (black bars). (B) The OR and 95% CIs were indicated relative to the subjects with a score of 2. Horizontal line marks the null value (OR=1). The distribution of scores follows a normal distribution in both cases and controls, with a shift towards higher scores in cases.