The Panscan consortium (which consists of the Pancreatic Cancer Cohort Consortia and the Pancreatic Cancer Case-Control Consortia (Panc4)) performed a genome-wide association study (GWAS) with approximately 550,000 single nucleotide polymorphisms (SNPs) comparing 1,896 individuals with pancreatic cancer and 1,939 controls ascertained from 12 cohort studies and the Mayo clinic case-control study (PanScanI) [14
]. The SNP variants that provided the strongest evidence of association were then validated in an independent set of 2,457 cases and 2,654 controls from eight case-control studies. In this work, several common variants at the ABO
blood group locus showed significant evidence of association with pancreatic cancer in the combined data [14
]. Among individuals of European ancestry, the SNP rs505992, located within the first intron of the ABO
gene, was strongly associated with pancreatic cancer (multiplicative per-allele odds ratio (OR) 1.20, 95% confidence interval (CI) 1.12 to 1.28, P
= 5.37 × 10-8
). This SNP is in complete linkage disequilibrium with, and is thereby perfectly correlated with, the O/non-O blood group variant.
The ABO system was first described by Karl Landsteiner in 1900, and the ABO
gene was cloned in 1990 [16
]. The ABO
gene encodes glycosyltransferase enzymes that transfer specific sugar residues to the H antigen. There are three variant alleles (A, B and O), which encode three different glycosyltransferases. The A allele encodes the enzyme α1R3 N
-acetylgalactosaminyltransferase, which attaches N
-acetylgalactosamine to the H antigen to form the A antigen. The B allele encodes α1R3 galactosyltransferase, which attaches D
-galactose, and the O allele encodes a non-functional glycosyltransferase and thus the H antigen remains unmodified.
The association between ABO genotypes and pancreatic cancer reported by PanScan [14
] was supported by Wolpin et al.
], who identified an association between ABO serotypes and pancreatic cancer risk. They used two large prospective cohort studies (the Nurses' Health Study and Health Professionals Follow-up Study) with 107,503 participants [12
]. Cox proportional hazards model, adjusted for age, tobacco use, body mass index, physical activity and history of diabetes mellitus, was used to calculate hazard ratios for pancreatic cancer by ABO blood type. Compared with individuals of O serotype, individuals with blood group A, AB or B had a significantly increased rate of pancreatic cancer (Table ).
Hazard ratios for risk of pancreatic cancer by blood group
To examine this association further, Wolpin et al.
] then used the SNP data generated from the 12 cohort studies included in full PanScan GWAS to derive ABO genotypes (OO, AO, AA, AB, BO and BB) and ABO serotypes (A, B, AB and O) and then examined the association of these two measures with pancreatic cancer risk [13
]. Patients with pancreatic cancer were compared with controls without pancreatic cancer and matched for year of birth, gender, race/ethnicity and source of DNA, and four of the cohorts were matched for smoking status and baseline age. This analysis further supported their earlier findings: compared with individuals of blood group O, the odds of developing pancreatic cancer were significantly higher for individuals with blood group A, AB or B. The analyses also provided important information on the influence of genotype: individuals with AA, BB or AB genotype were at higher risk of pancreatic cancer than individuals with AO or BO genotype (Table ). The authors estimated that inheritance of non-O blood group accounted for 19.5% of all pancreatic cancer in individuals of European ancestry.
Odds ratios for risk of pancreatic cancer by blood group and ABO genotype
The mechanism(s) by which ABO status influences pancreatic cancer risk remains unclear. ABO antigens are found not only on the surface of red blood cells but also on the surface of epithelial cells of the gastrointestinal, bronchopulmonary and urogenital tracts [17
]. ABO blood group is associated with differences in several circulating inflammatory, infectious and vascular mediators, and therefore chronic inflammation has been suggested as a potential mechanism for the association between ABO blood group and cancer risk. On the other hand, loss of expression of ABO blood group has been described in some pancreatic cancers and a systemic mechanism by which ABO blood groups predispose to pancreatic cancer would not be expected to require loss of expression of ABO in pancreatic cancers [9
]. Also, if an inflammatory modifier role of ABO is causal in cancer development, then ABO should be important in the development of numerous inflammation-mediated cancers, such as esophageal or gall-bladder cancer or colitis-associated colorectal cancer, but no such association has been found yet [19
]. The association between ABO and a limited number of cancers and evidence for loss of expression during tumor development implicate a tumor suppressor role for blood groups A and B in cancer development. Further studies to better elucidate the mechanism by which ABO mediates cancer susceptibility are needed to fully understand this association.