Title: Analysis of 5 TNF-α Promoter Polymorphisms in Acute Pancreatitis (AP) in Pittsburgh: No Replication Evidence of Increased Susceptibility to AP but New Evidence for -1031c and -863a as Risk Alleles for Multi-Organ Failure (Mof)
Abstract: Background: Chronic pancreatitis (CP) describes ongoing pancreatic inflammation from multiple etiologies.CFTR gene sequencing in small case series of CP identify an excess of atypical variants that do not cause cystic fibrosis (CF), possibly due to disruption of bicarbonate conductance.Methods: Targeted genotyping was performed in 956 pancreatitis cases (CP and recurrent acute pancreatitis, RAP) and 467 unrelated controls for 44 CFTR variants in the NAPS2 cohort.Association within individual and compound genotypes in cases classified by etiology and the presence or absence of PRSS1/SPINK1 co-variants was also analyzed.Results: Mutations in CFTR or PRSS1 were not significantly overrepresented among patients with an alcoholic etiology, but 7 CFTR variants not clearly associated with CF (R75Q, S1235R, L997F, L967S, R1162L, D1152H and R117H*T7or9) were overrepresented in cases with non-alcoholic pancreatitis and the effect was amplified by transheterozygous mutations in SPINK1 (OR 1.6 p=0.014; w/ SPINK1 OR 10.1 p=0.0001).These non-CF CFTR variants comprised 60% of CFTR variants among all cases.Of the 190 carriers of CFTR variants, 54 had multiple mutations in CFTR, SPINK1 or PRSS1; 262 cases carried at least one genetic variant and 86 carried a high-risk combination of mutations in CFTR, SPINK1 or PRSS1.Conclusions: A new class of non-CF associated CFTR variants may play a major role in the etiopathology of CP.Complex genotypes with CF-associated and non-CF-associated CFTR, and SPINK1 variants were common.This defines a subtype of CP patients that is distinct from CF, hereditary pancreatitis and alcoholic pancreatitis, and has implications for the genetic panel used for testing pancreatitis patients, and in guiding treatment strategies.