Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Abstract

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.

Trypsin-antitrypsin Imbalance in Immune Escape and Clonal Proliferation of Pancreatic Cancer

“…Trypsinogen gene (PRSS1) located in the 7q35 has been proven to be a pathogenic gene of hereditary pancreatitis for nearly 20 years [4][5][6]. For a long time trypsin has been only used as a tool of biomedical research, while how the balance between trypsin and AAT will influence the cellular microenvironment has rarely been studied.…”

“…What is more, the mutations of PRSS1 gene can be found in the exfoliated cells. it is servers as a noninvasive method and offers the more humanistic care to the potential of pancreatic cancer patients [4][5][6][7][8][9].…”

Genetics of endocrine and exocrine diseases of the pancreas

“…In our investigations we found smaller values (41%), however, these difference seem to fall within experimental error and may represent strain-specificity. In our experiments we used unstimulated mouse pancreas and it is possible, even likely, that upon hormonal stimulation, the trypsinogen expression pattern may change, as shown previously for rat p23, the ortholog of mouse T4 and T5, which becomes drastically upregulated upon cerulein stimulation [64]. Marked upregulation of T5 was observed in a knock-out mouse strain deficient in interferon regulatory factor 2 [44].…”

Genetics of acute pancreatitis

“…These techniques are rather expensive and require large cohorts of clinically well-defined individuals but they are ideally suited to identify new risk factors outside the already known or suspected signaling pathways or regulatory mechanisms involved in the pancreas physiology. To date few GWA studies have been performed, mainly in CP and RAP patients, and the study by Whitcomb et al was able to identify one new susceptibility locus in the Claudin-2 gene (CLDN2) (76). A second SNP found in the PRSS1-PRSS2 locus seems to further confirm the importance of this established risk locus for the development of pancreatitis.…”