Genetic variants associated with PDAC also contribute to chronic pancreatitis susceptibility

Abstract

s / Pancreatology 15 (2015) S1eS141 S16 Materials & methods: SPINK1 promoter variants were constructed by site-directed mutagenesis and cloned into a luciferase reporter vector. Cells were transfected with the reporter plasmids and luciferase expression was then measured from the cell lysates. Results: We found that most variants caused relatively small changes in promoteractivity. Surprisingly, however,weobserved significantvariations in theeffectsof thepromotervariants inthedifferentcell lines.Only fourvariants exhibited consistently reduced promoter activity in all acinar cell lines, confirming previous reports that variants c.-108G>T, c.-142T>C, and c.-147A>G are risk factors for chronicpancreatitis and identifying c.-52G>Tas anovel risk variant. In contrast, variant c.-215G>A, which is linked with the diseaseassociated splice-site mutation c.194þ2T>C, caused increased promoter activity, which may mitigate the overall effect of the pathogenic haplotype. Conclusion: Our study lends further support to the notion that sequence evaluation of the SPINK1 promoter region in patients with chronic pancreatitis is justified as part of the etiological investigation.