Table 1.

Recurrent Acute Pancreatitis / Chronic Pancreatitis Genetic Risk Factors

% of Persons w/CP w/a Pathogenic Variant in GeneGeneMOIDistinguishing Clinical FeaturesOther / Risk for PancreatitisReferences /
Selected
OMIM Links
44% of children; 2% of adults PRSS1 ADOnset age is ~10 yrs earlier.Exon &/or multiexon deletions/duplications reported 1Schwarzenberg et al [2019], PRSS1-Related Hereditary Pancreatitis
~37% 2 CLDN2 XL 3Assoc w/progression from RAP to CP
  • Common variants assoc w/mild-to-moderate risk
  • ↑ risk w/alcohol abuse, esp in hemizygous males & homozygous females
 Whitcomb et al [2012]
28% of children; 15% of adults CFTR AD
AR 3		May have sinusitis, respiratory symptoms, male infertility, constipation, indeterminate sweat chloride
  • Heterozygotes are at ↑ risk.
  • Several pathogenic variants assoc w/pancreatitis do not cause lung disease of cystic fibrosis. 4
  • See footnote 5 for modifiers.
Miller et al [2020], Schwarzenberg et al [2019], Cystic Fibrosis
23% of children; 7% of adults SPINK1 AD
AR 3
  • ↑ risk for CP following AP
  • Early-onset aggressive pancreatitis assoc w/biallelic p.Asn34Ser
  • Heterozygous & biallelic pathogenic variants reported w/↓ penetrance
  • Several common variants assoc w/mild-to-moderate risk
  • Founder variants reported in US, Europe, India, China, Japan, & Korea 6
Schwarzenberg et al [2019], OMIM 608189
9.7% of children age ≤10 yrs; <1% of adults CPA1 AD 3Early onset, nonalcoholic CP
  • More common in Europe
  • Misfolding variants may cause AD CP.
Witt et al [2013], OMIM 114850
8% of children; 1% of adults CTRC AD 3Early-onset CP
  • Loss-of-function variants assoc w/moderately ↑ risk
  • Common risk variant c.180C>T may ↑ risk for CP in persons w/variants in CFTR or SPINK1.
Schwarzenberg et al [2019], OMIM 601405
<1% 7 CASR AD 3
  • Loss-of-function variants may ↑ risk in persons w/variants in PRSS1, SPINK1, or CFTR.
  • Common gain-of-function variant assoc w/moderate ↑ risk, particularly w/alcohol use.
Muddana et al [2008], OMIM 601199
<1% CEL AD 3
  • Diabetes mellitus
  • Pancreatic lipomatosis
  • Pancreatic exocrine, endocrine dysfunction
  • CP w/o severe malnutrition
  • Exon &/or multiexon deletions/ duplications reported 1
  • Nonallelic homologous recombination between CEL & adjacent pseudogene CELP → CEL-HYB assoc w/↑ risk 8
See Maturity-Onset Diabetes of the Young Overview.
9.7% of early-onset CP; 2%-4.3% of adults TRPV6 AR 3Early-onset nonalcoholic CPLoss-of-function variants assoc w/↑ risk Masamune et al [2020]
<20%UnknownNA

AD = autosomal dominant; AP = acute pancreatitis; AR = autosomal recessive; CP = chronic pancreatitis; MOI = mode of inheritance; RAP = recurrent acute pancreatitis

1.
2.

Percentage of individuals with CP who have a common risk variant in CLDN2

3.

Variant(s) in this gene increase the risk for recurrent acute and/or chronic pancreatitis and can be contributors to complex (e.g., multifactorial, polygenic) inheritance pattern.

4.

CFTR pathogenic variants that affect bicarbonate conductance while maintaining chloride conductance (e.g., p.Arg75Gln [NM_000492​.3:c.224G>A]) have major effects on the pancreas but minimal effects on the lungs. The functional effect of CFTR genotypes is determined by the least severe pathogenic variant; thus, either two bicarbonate-defective (BD) variants (CFTRBD/CFTRBD) or one BD and one severe variant (CFTRBD/CFTRsev) can result in a monogenic pancreatitis-predominant disorder.

5.

SNPs in SLC26A9 have been reported to modify exocrine pancreatic damage in individuals with cystic fibrosis [Miller et al 2015]. SLC26A9 interacts with CFTR and may increase anion flow in the absence of CFTR [Bertrand et al 2009]. Additionally, a variant SLC26A9 modifies treatment response to ivacaftor [Strug et al 2016].

6.

SPINK1 founder variant p.Asn34Ser (NM_003122​.3:c.101A>G) is common in US, Europe, and India, with a minor allele frequency as high as 3%. Founder splice variant c.194+2T>C (NM_003122​.3), (also known as IVS3+2T>C) is common in individuals of Chinese, Japanese, and Korean ancestry.

7.

This percentage does not include the common gain-of-function variant associated with moderate increased risk for pancreatitis in those with alcohol use.

8.

From: Pancreatitis Overview

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