Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms

Genetic determinants of pancreatitis: relevance in severe hypertriglyceridemia

“…In 2022, Schmidt et al [ 28 ▪ ] reported a GWAS in 584 mainly European patients with nonalcoholic chronic pancreatitis and 6040 controls coupled with analysis of RNA transcripts in alcohol-exposed pancreatic tissue. They found that common variants at CTRC and SPINK1 reached genome-wide significance in nonalcoholic chronic pancreatitis, while CTRC and CLDN2-MORC4 risk variants colocalized with altered mRNA expression in pancreatic tissue [ 28 ▪ ].…”

“…In 2022, Schmidt et al [ 28 ▪ ] reported a GWAS in 584 mainly European patients with nonalcoholic chronic pancreatitis and 6040 controls coupled with analysis of RNA transcripts in alcohol-exposed pancreatic tissue. They found that common variants at CTRC and SPINK1 reached genome-wide significance in nonalcoholic chronic pancreatitis, while CTRC and CLDN2-MORC4 risk variants colocalized with altered mRNA expression in pancreatic tissue [ 28 ▪ ]. The concordance of findings between the independent GWAS of Rosendahl et al [ 27 ] and Schmidt et al [ 28 ▪ ] was notable, since the top loci in both studies were identical to known loci described above, that is, CTRC , SPINK1 and PRSS1 .…”

“…They found that common variants at CTRC and SPINK1 reached genome-wide significance in nonalcoholic chronic pancreatitis, while CTRC and CLDN2-MORC4 risk variants colocalized with altered mRNA expression in pancreatic tissue [ 28 ▪ ]. The concordance of findings between the independent GWAS of Rosendahl et al [ 27 ] and Schmidt et al [ 28 ▪ ] was notable, since the top loci in both studies were identical to known loci described above, that is, CTRC , SPINK1 and PRSS1 . In addition, the novel strong signals for CLDN2-MORC4 and the CTRB1-CTRB2 inversion deserve further comment.…”

“…A comprehensive meta-analysis by Van den Berg et al [ 40 ▪▪ ] found that most studies were negative, with some borderline evidence in favor of associations with acute pancreatitis for variants at IL1B and IL6 genes, encoding interleukins 1B and 6, respectively. However, neither locus has been prominent in GWAS of pancreatitis [ 27 , 28 ▪ ]. Similarly, findings for common variants in candidate genes involved in oxidative stress and apoptosis, such as several encoding members of the glutathione S-transferase, caspase, tumor necrosis factor and tumor associated protein gene families were negative [ 41 ], and need not be considered further unless new data emerge.…”