Genome-wide association analysis identifies fucosyltransferase 2 variants associated with pancreatic intraductal papillary mucinous neoplasms.

Abstract

Intraductal papillary mucinous neoplasms (IPMNs) are common pancreatic cystic neoplasms. Observation or surgical resection in patients with high-risk IPMNs is recommended because there is a risk of malignant transformation leading to pancreatic adenocarcinoma. Risk factors for the development of IPMNs are not well characterized. The authors hypothesized that common genetic variants are associated with development of IPMNs. Individuals were enrolled and genotyped as part of the Mass General Brigham Biobank, and individuals with IPMNs were identified retrospectively using electronic medical records. Single nucleotide variants (SNVs) with a minor allele frequency ≥5% were examined for an association with IPMNs. SNVs that surpassed the significance threshold (p < 5e-08) were further examined in a validation cohort. Of 68,931 individuals, 2525 (3.6%) had IPMNs. After genome-wide association analysis, a genetic locus at chromosome 19 was identified as associated with IPMNs. The lead SNVs were reference SNVs rs681343 (19:49206462; odds ratio, 1.01; p = 1.04e-8) and rs601338 (19:49206674; odds ratio, 1.01; p = 1.06e-8). This result was verified in an independent cohort of 5014 individuals. The rs601338 variant is in a noncoding exon of fucosyltransferase 2 (FUT2) and causes replacement of a normal codon with a stop codon and termination of protein translation. FUT2 codes the FUT2 enzyme, an important enzyme in the Lewis antigen system. FUT2 variants are associated with the development of pancreatic IPMNs. FUT2 and rs601338 have important functions in mucin synthesis, biliopancreatic duct homeostasis, carcinoembryonic antigen, and cancer antigen 19-9 regulation, which provide a biologically plausible role in IPMN pathogenesis.