Variant ABO blood group alleles, secretor status, and risk of pancreatic cancer: results from the pancreatic cancer cohort consortium.
Wolpin BM., Kraft P., Xu M., Steplowski E., Olsson ML., Arslan AA., Bueno-de-Mesquita HB., Gross M., Helzlsouer K., Jacobs EJ., LaCroix A., Petersen G., Stolzenberg-Solomon RZ., Zheng W., Albanes D., Allen NE., Amundadottir L., Austin MA., Boutron-Ruault M-C., Buring JE., Canzian F., Chanock SJ., Gaziano JM., Giovannucci EL., Hallmans G., Hankinson SE., Hoover RN., Hunter DJ., Hutchinson A., Jacobs KB., Kooperberg C., Mendelsohn JB., Michaud DS., Overvad K., Patel AV., Sanchéz M-J., Sansbury L., Shu X-O., Slimani N., Tobias GS., Trichopoulos D., Vineis P., Visvanathan K., Virtamo J., Wactawski-Wende J., Watters J., Yu K., Zeleniuch-Jacquotte A., Hartge P., Fuchs CS.
BACKGROUND: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A(1) versus A(2) variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A(1) allele would confer greater risk than A(2) allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk. METHODS: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression. RESULTS: An increased risk was observed in participants with A(1) but not A(2) alleles. Compared with subjects with genotype O/O, genotypes A(2)/O, A(2)/A(1), A(1)/O, and A(1)/A(1) had ORs of 0.96 (95% CI, 0.72-1.26), 1.46 (95% CI, 0.98-2.17), 1.48 (95% CI, 1.23-1.78), and 1.71 (95% CI, 1.18-2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A(1), and A(2) were 1.00 (95% CI, 0.87-1.14), 1.38 (95% CI, 1.20-1.58), and 0.96 (95% CI, 0.77-1.20); P, O01 versus O02 = 0.94, A(1) versus A(2) = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63). CONCLUSIONS: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk. IMPACT: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34.