ABO Blood Group and Risk of Colorectal Cancer

Studies have suggested a link between inherited human blood group antigens and the risk of various cancers (1, 2). Recently, we have shown an association between non-O blood group serotype and risk of pancreatic cancer that has been confirmed in other studies (3–7). Whether this association is also observed with other gastrointestinal malignancies, including colorectal cancer, is unclear. We therefore sought to examine the relationship between ABO blood group and colorectal cancer risk in two large prospective cohort studies.

Our methods have been previously described in detail (3). Briefly, we examined male and female health professionals enrolled in the Nurses' Health Study (NHS) and Health Professional Follow Up Study (HPFS) who returned the 1996 biennial questionnaire in which they were specifically queried about their blood group (A, B, AB, O, or unknown). In a subsample of 98 participants, this self-reported blood group was 91% concordant with the results of serological testing in the medical record (3). Among 187 participants, self-reported blood group was 92% concordant with the results of genotype-derived blood typing (4). As previously reported, the distributions of ABO blood groups in these cohorts are similar to those for other US white populations³. We excluded participants with ulcerative colitis or history of cancer (except nonmelanoma skin). In both cohorts, when a participant (or next-of-kin for decedents) reported a diagnosis of colorectal cancer we obtained their hospital records and pathology reports. We identified deaths through the National Death Index and next-of-kin. A study physician reviewed records to confirm cancer diagnoses.

Follow-up time was calculated from the date of return of the 1996 questionnaire to the date of colorectal cancer diagnosis, death, or June 30, 2006, whichever came first. We used Cox proportional hazards models to calculate adjusted HR and 95% CIs. We evaluated effect modification by diabetes mellitus, based on prior report suggesting potential interactions between diabetes and blood group type using cross-classified categories (8); significance of the interaction was assessed using the log–likelihood ratio test. Based on the number of cases of colorectal cancer and prevalence of each blood group, our study had greater than 80% power at a significance level of 0.05 to detect a HR of 1.2 when comparing non-O blood groups with blood group O.

Among 104,885 participants (76,408 females and 28,477 males), we documented 1,025 colorectal cancer cases after a mean follow up of 9.8 years. Baseline characteristics of the participants were similar with regards to regular aspirin use, family history of colorectal cancer, and history of polyps (Table 1). The risk of developing colorectal cancer did not significantly differ by ABO blood group (Table 2). Compared with blood group O, we did observe a modest association of blood group B with colon cancer, but not rectal cancer that was statistically significant only in the multivariate analysis. However, there did not appear to be statistically significant risk associated with blood group AB.

Among subgroups defined by the presence or absence of diabetes mellitus, there was no statistically significant association between any blood group and colorectal cancer (P_interaction = 0.91).

Several lines of evidence had suggested a potential association between ABO blood group and risk of colorectal cancer (1, 2). Human blood group antigens are expressed on the surface of red blood cells and other tissues, including cells of the gastrointestinal tract. These glycoconjugates may participate in modifying intercellular adhesion, membrane signaling, and immune surveillance, which could in turn influence tumorigenesis (9). In addition, recent genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at the ABO blood locus with serum levels of circulating TNF-α and diabetes mellitus (8, 10). TNF-α is an inflammatory marker that has been associated with colorectal neoplasia (11). Diabetes and colorectal cancer share risk factors and potentially have common pathogenic mechanisms (e.g., insulin-related pathways; ref. 12).

Despite this rationale, in two large prospective cohorts, we did not find a consistent association between blood group serotypes and overall risk of colorectal cancer. We did observe a borderline significant association between blood group B and overall risk of colon cancer. However, there is no clear biological mechanism that would explain the differential association of group B compared with group A antigen with cancer. Taken together with the lack of similar associations observed with blood group AB and overall risk of colon cancer, these findings for blood group B are likely due to chance. Finally, we did not observe a differential effect between blood group and risk of colorectal cancer according to presence or absence of diabetes.

These findings contrast with our previous analysis of ABO blood group and risk of pancreatic cancer using these same population cohorts in which, compared with blood group O, the multivariate adjusted HRs were 1.32 (95% CI, 1.02–1.72) for blood group A, 1.51 (95% CI, 1.02–2.23) for blood group AB, and 1.72 (95% CI, 1.25–2.38) for blood group B (3). These results have been subsequently supported by findings from other pancreatic cancer cohorts (5, 6). The lack of similar associations of blood group type with colorectal cancer suggest that ABO blood group-related mechanisms of tumorigenesis may uniquely influence specific types of cancers including pancreatic cancer (7). Nonetheless, further research into a potential, more modest effect of ABO blood group type on colorectal cancer, is needed.

No potential conflicts of interest were disclosed.

Funded by R01 CA137178, P01 CA55075, P01 CA87969. Dr. Chan is a Damon Runyon Cancer Research Foundation Clinical Investigator. Dr. Khalili is supported by a career development award from the IBD Working Group.