BMC Cancer 2006, 6:175 http://www.biomedcentral.com/1471-2407/6/175 With 156 CRC cases and 399 controls we have a 74 % chance (at the 5 % level) to detect an OR of 2 for the ERCC1 polymorphism (allele frequency 0.41) and a 92 % chance for the ASE-1 polymorphism (allele frequency 0.18) and the RAI polymorphism (allele frequency 0.20). Results The genotypic distribution of the three polymorphisms in the RAI, ASE-1 and ERCC1 genes for both cases and con- trols are shown in Table 2 [see Additional file 1]. The gen- otype distributions for the studied polymorphisms were all in Hardy-Weinberg equilibrium (ERCC1 Asn118Asn p = 0.945, ASE-1 G-21A p = 0.757 and RAI IVS1 A4364G p = 0.673), and the distributions of the alleles are in agree- ment with those found in other Scandinavian populations [7,8]. Table 2 [see Additional file 1] also presents the esti- mates of relative risk associated with the three polymor- phisms as well as the predefined haplotype. The RAI polymorphism showed a trend towards risk reduction for both adenomas and carcinomas in women. The risk estimate was lowest but not statistically signifi- cant for carcinoma. For adenomas the result was border- line statistically significant, OR of 0.70 (95% CI 0.49– 1.01). The ASE-1 polymorphism was associated with an increased risk of adenomas, OR of 1.39 (95% CI 1.06– 1.81), which upon stratification was apparent among women only, OR of 1.66 (95% CI 1.15–2.39). No associ- ation was found for carcinoma cases. There was no significant association between the ERCC1 polymorphism and risk of colorectal adenomas and carci- nomas. Women who were homozygous carriers of the high risk haplotype had an increased risk of colorectal cancer, OR of 2.19 (95% CI 0.95–5.04) compared to all non-carriers although the estimate was not statistically significant. Among men an inverse association between the high-risk haplotype and colorectal cancer was found, although the association was not statistically significant. No associa- tion was found with adenoma cases. We have also tested the gene-environment interaction between the haplotype and the three polymorphisms, and cigarette smoking and alcohol intake, but they showed no significant association with colorectal adenoma or carci- noma (results not shown). Discussion In this case-control study we investigated whether carriers of a specific haplotype, encompassing genes of DNA repair and apoptosis located on chromosome 19q13.2-3, were at increased risk of colorectal adenomas and carcino- mas. In addition we investigated whether polymorphisms in these genes alone contributed to colorectal adenoma and carcinoma risk. The high-risk haplotype has previously been shown to be associated with increased risk in young or middle-aged persons. For basal cell carcinoma, effects were only seen for the age group below 50 years [5,18,19]. For lung can- cer and breast cancer, an effect was observed for women in the age interval 50–55 years [6,7]. We detected no associ- ation (prior to gender stratification) among patients with colorectal adenomas or carcinomas for the high-risk hap- lotype. It is possible that at least the colorectal cancer patients in this material are too old to allow a detection of an effect. In accordance with this, no effect of the high risk haplotype was observed for basal cell carcinoma patients who were older than 50 years of age [20]. However, we did detect an effect in women and an inversely effect in men after stratifying for gender, in relation to CRC cases, although not significant. There are indications that effect of the haplotype may vary between the sexes because the haplotype was associated with increased risk of breast can- cer [6] and not with risk of testis cancer [8]. In lung cancer Vogel et al. [21] have found statistically significant differ- ences between sexes. Women who are homozygous carri- ers of the haplotype are at increased risk of lung cancer compared to men. The polymorphism in RAI is shown to be the strongest determinant of the haplotype [6,21]. RAI was discovered as an inhibitor of RelA (a subunit of NF-κB) and is thus presumably involved in the control of transcription [13], but its function is poorly understood. RAI is involved in control of apoptosis, and over-expression of RAI has been shown to suppress apoptosis induced by cisplatin or UV light [22]. Up regulation of RAI expression has been observed in cancer cells [22,23]. Previous data suggest that the predefined haplotype is associated with defective apoptosis [21]. It is therefore likely that the haplotype is linked to a functional polymorphism in RAI which increases the protein level of RAI, resulting in a defective apoptosis trigger. It has previously been observed that the polymorphism in RAI and the high risk haplotype may be associated with cancer risk in women only [6-8]. For the polymorphism in RAI, we have consistently found protec- tive effect of the variant allele. For lung cancer, however, it was found that the variant allele was protective among women (AG: RR= 0.58, CI 0.33–1.03, GG: RR = 0.12, CI 0.01–1.04, p trend 0.007), while no protective effect was observed for men (AG: 1.79, CI 1.12–2.87, GG: RR = 0.51, CI 0.13–2.05, Ole Raaschou-Nielsen and Ulla Vogel, unpublished results). Here, we see the same pattern. Among women, carriers of the variant allele of RAI IVS1 A4364G were at reduced risk of both colorectal cancer Page 4 of 6 (page number not for citation purposes)