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Genetic Factors inAcute Pancreatitis

Mitchell L. Ramsey and Georgios I. Papachristou

The Ohio State University Wexner Medical Center, Columbus, OH, USA

Introduction

Approximately 70% of acute pancreatitis (AP) in adults is attributable to alcohol use or pancreatic duct obstruction from choledocholithiasis[1]. However, it is increasingly recognized that these stimuli are modulated by other susceptibility factors such as trypsinogen activity, pancreatic ductal clearance, and endoplasmic reticulum (ER) stress. This observation is supported by the large number of patients with environmental exposures such as heavy alcohol use who never develop clinical AP[2]. Some predisposing factors are anatomic, such as pancreas divisum, while others are related to germline pathogenic variants leading to alterations in the structure or function of proteins integral to normal pancreas functions. Following alcohol and gallstones, the next most common AP etiologic group is unexplained or idiopathic [1]. With the increasing availability of germline genetic test panels, several studies have reported high rates of germline pathogenic variants among patients with idiopathic recurrent AP (IRAP) [3–5]. Pathogenic variants in pancreatitis- related genes are hypothesized to decrease the threshold to develop AP following exposure to an inciting event. In this chapter, germline pathogenic variants that are associated with increased susceptibility or increased severity of AP will be discussed. The pancreas is divided into different anatomic and functional compartments that are predisposed to distinct mechanisms of injury[6]. Certain genetic factors are directly linked to the proper function of either the acinar cell or duct cell compartments, and it is useful to consider them in context of these compartments (Table13.1).

The clinical syndrome of pancreatic autodigestive injury, an acute inflammatory response, and a range of local and systemic complications defines AP [6]. Autodigestive

injury is promoted by premature activation of pancreatic proenzymes within the acinar cells or within the pancreatic duct. This premature activation is mediated by trypsin and can be influenced by genetic variations. Indeed, the 1996 discovery of the gain-

of- function mutations in the cationic trypsinogen gene (PRSS1) serves as the prototypical example[7]. Since that discovery, a variety of other susceptibility genes have been described that influence trypsin activity and ductal cell function thereby increasing the risk of AP. The most prevalent genes associated with AP are PRSS1, cystic fibrosis transmembrane conductance regulator (CFTR), pancreatic serine protease inhibitor Kazaltype 1 gene (SPINK1), and claudin 2 (CLDN2) [8,9]. Multiple genes have been associated with progression to chronic pancreatitis (CP), including variants in chymotrypsin C (CTRC) and calcium- sensing receptor (CASR), which are introduced here but are more completely discussed in Chapter45. Lastly, severity modifying genes have been described, including monocyte chemotactic protein 1 (MCP- 1), which increase the severity of AP[10].

Acinar Cell- Associated Susceptibility Factors

Calcium dysregulation appears to be the primary pathway for triggering AP within acinar cells [11,12]. In health, multiple protective mechanisms limit trypsinogen exposure to calcium, including trypsinogen packaging in zymogen granules, calcium sequestration in the ER, and numerous cytosolic calcium homeostasis processes[13]. When calcium occupies the calcium- binding domains of the trypsinogen molecule it results in both trypsinogen activation and prevention of its degradation[11]. Therefore, alterations in cellular calcium concentration, zymogen granule formation, or alteration to the calcium- dependent regulatory domains of the trypsinogen molecule can potentially increase the risk of

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Introduction 129

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Table13.1 Genes andspecific pathogenic variants implicated

inthe pathogenesis ofacute pancreatitis.

Susceptibility factors

Acinar cell-

ER stress-

Duct-

Severity modifying factors

Proinflammatory cytokines

CFTR variable pathogenic variants in CFTR.

associated PRSS1: R122H, R122C, N29I, A16V

SPINK1: N34S, R67H, c.194+2T>C

CTRC: G60G, R254W, P249L,

K247_R254del

CLDN2: rs7057398, rs12688220

associated CPA1: A208T, T124I, Y318fs

associated CFTR

sev

: severe pathogenic variants in CFTR; CFTR

sev

: F508del, G551D

m- v

CFTR

R1162X, c.2789+5G>A

CASR: A986S, R69H, c.60T>A

MCP-

TNF- α: c.−1031C, c.−863A

IL-

: R117H, R334W, G85E,

1: c.−2518G

8: c.−251A

m- v

: mild or

pancreatic autodigestion. Several pathogenic variants have been identified among subjects with AP that alter calcium and trypsinogen homeostasis, including variants in PRSS1, SPINK1, and CLDN2.

Cationic Trypsinogen: PRSS1

Hereditary pancreatitis is characterized by recurrent AP leading to CP, and is attributed to autosomal dominant inheritance of pathogenic variants in PRSS1 (located on chromosome 7q35), the gene coding for cationic trypsinogen [7]. Cationic trypsinogen is the predominant trypsinogen found in human pancreatic secretions, followed by anionic trypsinogen (PRSS2 on 7q35) and meso trypsinogen (PRSS3 on 9p13) [14]. Trypsinogens are serine proteases synthesized in pancreatic acinar cells and are activated on cleavage of a short exposed peptide chain called trypsinogen activation peptide (TAP). Enterokinase or a second trypsin molecule can cleave TAP, allowing for the transformation of trypsinogen to active trypsin[15]. Once activated, trypsin activates other pancreatic proenzymes to initiate digestion of chyme. Trypsin can also inactivate trypsin at the arginine residue (codon 122) in the side- chain. Trypsin has two calcium- binding domains, one at the activation site and one at the autolysis site, and nearly all of the described variants identified among subjects with hereditary pancreatitis involve one of these two calciumregulated sites[16].

The first PRSS1 mutation to be identified was the c.365G>A substitution, replacing arginine with histidine at codon 122 (R122H)[7]. Arginine 122 is the initial site of hydrolysis of trypsin by other trypsin molecules. In the case of the PRSS1 mutation, the arginine to histidine substitution renders trypsin resistant to fail- safe autolysis leading to prolonged activity of trypsin and pancreatic autodigestion. Over 50 variants of PRSS1 have been reported, including gain- of- function variants with deleterious effects (R122H, N29I, A16V) and lossof- function variants with beneficial effects (Y37X)[16]. Among kindreds, a wide variation in phenotype suggests that additional modifying environmental and/or genetic factors are involved in the pathogenesis of hereditary pancreatitis[17,18].

Hereditary pancreatitis due to variants in PRSS1 has a high but variable disease penetrance (80% by age 20 years, 96% by age 50 years) and typically presents in childhood with recurrent AP[19–22]. After repeated episodes of AP, approximately half of patients with pathogenic variants in PRSS1 progress to CP[20,23]. Additionally, the cumulative risk of pancreatic cancer approaches 40% of affected patients by age 70[20,22]. There are no specific therapies directed at PRSS1, so the mainstay of treatment is avoidance of toxic exposures (smoking, alcohol), monitoring for pancreatic endocrine and exocrine insufficiencies, and screening for pancreatic cancer beginning at age 40[24]. A pilot clinical trial investigated the use of amlodipine (dihydropyridine calcium channel blocker) in four subjects and showed a modest reduction in symptoms and analgesic use, but this has not been replicated [25]. Total pancreatectomy with islet autotransplant (TPIAT) is often considered for intractable CP- related pain in hereditary pancreatitis[26]. The indications and outcomes of TPIAT are discussed in Chapter66.

Serine Protease Inhibitor Kazal Type 1: SPINK1

Serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor (PSTI), is encoded by SPINK1 on chromosome 5q32 and is packaged in exocrine granules along with trypsinogen. SPINK1 is a 56- amino- acid acute- phase protein that directly blocks the active catalytic site of trypsin, thus preventing trypsin from activating trypsinogen. The proportion of SPINK1 protein to its RNA has been shown to range from less than 1 : 1000in the normal pancreas to at least 6 : 1in the inflamed pancreas[18]. This indicates that SPINK1 translation is rapidly increased after pancreatic injury, and therefore likely plays a role in limiting the extent and duration of an attack by inhibiting trypsin[27]. These findings also fit with the observation that SPINK1 is an acute- phase reactant[28].

Several loss- of- function pathogenic variants have been identified in SPINK1 and the N34S haplotype is the most

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130

prevalent throughout the world, found in 1–3% of the general population[29]. Pathogenic variants in SPINK1 are identified in 7–10% of subjects with AP and in 25–50% of cases of early- onset idiopathic CP, including tropical fibrocalculous pancreatitis [30–34]. The N34S variant is more prevalent among alcoholics with CP than among alcoholics without CP, suggesting that loss- offunction of SPINK1 increases susceptibility to alcoholrelated CP [35]. The risk and severity of pancreatitis appears to be similar between subjects with homozygous, heterozygous, or compound heterozygous genotypes, suggesting that the genetics underlying the disease state is complex and involves other susceptibility factors[31,32].

Among those who develop pancreatic disease associated with pathogenic variants in SPINK1, the phenotype is variable but generally presents in young adulthood [36,37]. Pathogenic variants in SPINK1 increase susceptibility to recurrent AP and CP, but do not appear to be a major risk factor for sentinel AP[5,11,38]. These observations indicate that SPINK1 acts as a disease modifier, so the clinical phenotype of those with pathogenic variants reflects the etiologic agent of AP [27,35]. No specific therapy exists for patients with AP who have pathogenic variants in SPINK1, although a case report of a patient with familial hypocalciuric hypercalcemia and R67H variant in SPINK1 describes abrogation of recurrent AP when treated with cinacalcet (a calcimimetic agent)[39]. This report demonstrates the disease modifier effect of SPINK1: when the underlying cause of AP (hypercalcemia) resolved, no further AP recurrences occurred. Pancreatic cancer screening is not currently recommended in this group[24].

AP and controls[43,44]. Lastly, an additional case series identified similar detection rates for pathogenic variants (V235I, I259V, K247_R254del) in CTRC among AP cases (1.8%) and controls (1.2%)[45]. Thus, similar to SPINK1, pathogenic variants in CTRC are associated with recurrent AP and CP, but do not appear to be risk factors for sentinel AP. Unlike pathogenic variants in PRSS1 and SPINK1, the natural history and management of subjects carrying variants in CTRC has not been well described.

Claudin 2: CLDN2

Claudins are a family of transmembrane proteins that regulate paracellular permeability of ions and water[46]. Claudin 2 is encoded by CLDN2 (Xq22.3), and, in health, localizes to the plasma membrane between pancreatic islet and duct cells[47]. Under stress, pancreatic acinar cells can express claudin 2, which may contribute to the development of pancreatic edema that is characteristic of interstitial AP [48]. Germline polymorphisms in the CLDN2- MORC4 locus, including rs7057398 and rs12688220, have been associated with increased susceptibility to AP[49,50], IRAP (in homozygous females)[51], and CP[47,52]. In particular, homozygous females and hemizygous males are most susceptible to alcoholrelated pancreatic injury, suggesting that variants in CLDN2 act as a disease modifier in the setting of environmental exposure [47,52]. In contrast to PRSS1, SPINK1, and CTRC, claudin 2 does not appear to interact with the trypsin- dependent pathway of AP [47]. There is no specific therapy for subjects with AP and pathogenic variants in CLDN2, although strict abstinence from alcohol should be emphasized.

Chymotrypsin C: CTRC

Another pancreatic secretory enzyme involved in trypsin regulation is chymotrypsin C, which is able to rapidly degrade trypsin in the absence of calcium through cleavage of the calcium binding loop[15]. Chymotrypsin C is encoded by CTRC (1p36.21) and is stored within zymogen granules until it is released into the pancreatic duct. The function of chymotrypsin C was initially described by Rinderknecht et al. in 1988 as the second line of defense against prematurely activated trypsin, following PSTI/SPINK1[40]. Thus, it follows that loss- of- function variants in CTRC may produce a similar clinical phenotype as loss- of- function variants in SPINK1.

Several pathogenic variants have been described in CTRC, including the association of R254W and K247_ R254del with idiopathic CP[41,42]. One group identified the G60G variant at higher rates among patients with AP than among healthy controls, but subsequent study in the North American Pancreatitis Study II cohort identified similar rates of G60G among subjects with recurrent

Endoplasmic Reticulum (ER) Stress- Associated Susceptibility Factors

An additional mechanism leading to AP is ER stress. Although this more commonly predisposes to CP, a brief discussion is included here due to the involvement of similar genes discussed above. For example, the PRSS1 G208A variant leads to misfolding and accumulation within the cell rather than premature activation within the pancreatic duct[53]. Similarly, misfolded CTRC caused by the A73T and G61R variants precipitates within the cell, causing ER stress and altering microtubule function that ultimately leads to the development of CP[54]. In addition to these variants in PRSS1 and CTRC, variants in carboxypeptidase A1 (CPA- 1) also cause ER stress and contribute to the development of CP, but have not been associated with AP.

Carboxypeptidase A1: CPA- 1

Carboxypeptidases are metalloproteases that cleave C- terminal peptide bonds from dietary polypeptides [55]. Among these carboxypeptidases is CPA- 1,

Introduction 131

Degree of pancreatic ductal obstruction (dotted

)

Pl = Pancreatic insufficiency

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which is secreted as a zymogen, procarboxypeptidase A1, and is activated by trypsin and chymotrypsin C in the duodenum[56]. Procarboxypeptidase A1 is a highly prevalent protein in pancreatic juice, and loss- offunction variants in CPA- 1 (located at 7q32.2) (N256K, R382W, and c.1073- 2A>G) have been associated with early onset CP, but not with AP[56]. The mechanism of injury leading to CP is thought to involve ER stress, as reduced CPA- 1 does not affect trypsin activity.

Duct- Associated Susceptibility Factors

Pancreatic ductal blockage is another factor that may contribute to premature zymogen activation within the pancreatic parenchyma. This is most clearly illustrated by gallstone pancreatitis; however, there are additional important duct- associated factors and susceptibility genes that can contribute to the development of AP.

The pancreatic duct cell differs from many other types of epithelial cells in its expression of a combination of ion channels and transporters. The primary apical (luminal) ion channel of the duct cell is CFTR[57], which is permeable to chloride and, to a lesser degree, bicarbonate[58,59]. The continuous entry of bicarbonate into the duct cell is facilitated by a sodium–bicarbonate cotransporter on its basolateral surface[60]. Simultaneously, minimal chloride permeability on the basolateral surface results in bicarbonate being the dominant diffusible anion within the duct cell. In this setting, a concentration gradient across the apical membrane favors bicarbonate secretion[61]. This ion secretion is dependent on CFTR, so any alterations in CFTR function can potentially limit fluid secretion into the pancreatic duct which increases the transit time of protein- rich acinar secretions to the duodenum. Maintenance of a high pancreatic duct pH and presence of trypsin inhibitors reduce the potential for activation of

trypsinogen within the pancreatic duct. Failure to flush the pancreatic duct is a susceptibility factor for AP, and CFTR loss- of- function mutations represent the prototype genetic defect.

Cystic Fibrosis Transmembrane Conductance Regulator: CFTR

The epithelial cells of multiple organs (i.e., lungs, pancreas, intestine, bile ducts) contain the CFTR ion channel, and severe pathogenic variants in CFTR (located on 7q31.2) may lead to multiple organ dysfunction resulting in the clinical phenotype of cystic fibrosis (CF) [62]. In health, CFTR- mediated secretion of bicarbonate and chloride into the pancreatic duct dilutes the protein- rich fluid from the acinar cells and maintains a basic pH to prevent premature zymogen activation. Active transport of anions creates a gradient for osmosis, such that CFTR is primarily responsible for creating a fluid current thatcarries zymogens expediently to the duodenum[63]. The risk of AP among subjects with pathogenic variants in CFTR is dependent on the balance of ductal clearance and zymogen production (Fig. 13.1) [64]. Ductal clearance correlates with the activity of mutant CFTR in ductal cells, and zymogen production correlates with acinar cell function, which may be reduced by damage from recurrent AP[65].

The first pathogenic variant in CFTR was identified in 1989, and now more than 2000 variants in CFTR have been identified [62]. Although the functional role of many of these variants remains unknown, the more commonly identified variants have been categorized according to their effect on the CFTR protein, where classes IV and V are milder mutations (CFTR VI are more severe (CFTR

sev

m- v

) and I, II, III, and

)[62]. A number of online databases have been created to assist clinicians in interpreting identified variants, including CFTR2.org and

Figure13.1 Relationship between percent of cystic

fibrosis transmembrane conductance regulator (CFTR) function and risk of acute pancreatitis among subjects with cystic fibrosis. Source:[104] / With permission of Elsevier.

100

line) and pancreatic acinar reserve (solid line) (%

Ductal obstruction

Pancreatic acinar reserve

Pancreatitis

CFTR function (%)

High

Risk of

pancreatitis

(shaded area)

None

100

Genetic Factors inAcute Pancreatitis

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132

umd.be/CFTR, that include genotype and clinical details (i.e., sweat chloride, lung function, and pancreatic sufficiency)[66,67]. The prevalence of the CFTR pathogenic variant carrier state is 3–4% in Caucasians [68,69] and 1–2% among those of African descent[68,69]. CF has a prevalence of between 1/2500 to 1/6000live births[62,70].

Severe pathogenic variants that are found among subjects with pancreas insufficient CF include F508del, the most prevalent variant in Caucasians, I507del, R33X, and G542X[64]. Patients who are homozygous for severe pathogenic variants (i.e., F508del/F508del) or have complex heterozygosity involving severe variants (i.e., F508del/G551D) present with typical CF at a young age, with impaired pulmonary function, exocrine insufficiency, and a low incidence of AP[62]. In contrast, class IV and V mutations reduce CFTR function to 10–49% of normal function and are identified among subjects with pancreas sufficient CF [71]. These pathogenic variants include R117H, R1162X, and c.2789+5G>A, among others[64]. Patients with homozygosity or complex heterozygosity for these milder mutations present with atypical CF, with milder pulmonary symptoms and pancreas sufficiency, and may experience recurrent AP[72,73]. It is increasingly recognized that carriers of CFTR mutations are also at heightened risk for CFrelated conditions, including AP[74]. This is referred to as CFTR- related disorder (CFTR- RD), and includes subjects who have at least one pathogenic variant in CFTR but do not meet diagnostic criteria for typical or atypical CF[75]. In this category are a number of variants including R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N that have been associated with recurrent AP and CP without lung disease[76]. In summary, subjects with two milder mutations or a single severe mutation are at increased risk of AP while those with <2% of normal CFTR function have a very low risk of AP [75,77]. Furthermore, it is suggested that some variants of CFTR may augment the inflammatory response, predisposing to severe disease[78].

It has been estimated that approximately 20–30% of patients with IRAP or idiopathic CP carry a pathogenic variant of CFTR, and only a minority of these will meet criteria for a diagnosis of CF [75]. One of the earliest studies on this topic observed pathogenic CFTR variants in 10% of German subjects with alcohol- related CP and 21% of subjects with early- onset, idiopathic CP, but no pathogenic variants were identified in subjects with recurrent AP[79]. Similarly, an Italian cohort identified pathogenic CFTR variants in 20% of CP (majority of cases were alcohol- related) but only 6% of AP subjects [80]. These findings have been replicated in a Spanish cohort[81], an Austrian cohort[82], and pediatric and adult American cohorts[3,5,83]. A single cohort in Indian patients found a prevalence of pathogenic

variants in CFTR of only 2.3% among children with IRAP, but the only CFTR variants used in their study were F508del, G551D, G542X, and A117H, while these other studies generally used CFTR panels assessing for over 20 different variants[4]. More recent studies include expanded gene panels and are able to identify CFTR pathogenic variants in 10–20% of subjects with alcoholrelated recurrent AP and CP, and in nearly half of adult subjects with IRAP or idiopathic CP [84]. Thus, CFTR dysfunction appears to be a major susceptibility factor for alcohol- related or IRAP and idiopathic CP.

The majority of CFTR mutations identified among American patients with CF are now targetable by CFTR modulator therapy, including the CFTR potentiator ivacaftor and CFTR correctors elexacaftor, lumacaftor, and tezacaftor. Several observational studies have demonstrated a reduction in AP episodes among patients with CF during treatment with CFTR modulators. In particular, subjects with pancreas sufficient CF appear to have the greatest reduction in AP episodes during treatment[85,86]. The effect of CFTR modulators on AP risk among patients with pancreas insufficient CF is uncertain at this time[86,87]. Subjects with pathogenic variants in CFTR are not currently recommended to undergo pancreatic cancer surveillance[24]. Smoking and alcohol use may induce CFTR dysfunction, so abstinence should be emphasized for all subjects with a pathogenic variant in CFTR[88].

Calcium- Sensing Receptor: CASR

Integral to proper functioning of CFTR is the calciumsensing receptor (CaSR), located in the apical membrane of ductal cells. CaSR monitors calcium concentration within the pancreatic duct, and may stimulate CFTR and other ion channels to maintain a low calcium concentration within the duct[89]. Gain- of- function and loss- offunction variants in CASR (located on 3q13.33) have been inconsistently identified in subjects with AP[5] and CP [90,91] but may contribute to pancreatitis when pathogenic variants in SPINK1, PRSS1, or CFTR are also present[92].

Multiple Genetic Defects and Susceptibility

It has been hypothesized that SPINK1 could, in fact, act as a disease- modifier gene[93,94]. This is supported by the observation that the SPINK1 N34S haplotype is relatively common, although there is no specific phenotype associated with this genotype. Furthermore, the severity of disease is similar between patients with homozygous and heterozygous genotypes. A small study of subjects with CFTR

sev

/CFTR

m- v

genotypes with SPINK1 mutations

References 133

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led to the hypothesis that defects in these gene products may act synergistically to increase the risk of pancreatitis[95]. The risk of AP is increased 10- fold in individuals with a SPINK1 mutation, 40- fold in individuals with CFTR compound heterozygosity, and 500- fold in individuals who have both[96]. Finally, pathogenic variants in CASR alter pancreatic calcium homeostasis but may require a second hit in pancreatitis- related genes in order to cause pancreatitis[92].

Severity Modifying Factors: Polymorphisms inCytokines

In addition to modifying the risk of developing AP, genetic factors may also modify the severity of AP by altering the production of proinflammatory cytokines. The interplay of cytokines in the inflammatory response to AP includes TNF-

α, IL- 1, IL- 8, and IL- 10, and may involve others as well[97]. Several pathogenic variants have been identified at higher frequency among subjects with severe AP, including variants in the genes coding for MCP- 1, IL- 1ß, and IL- 8.

The earliest pathogenic variant contributing to the development of severe AP was identified in MCP- 1[98]. MCP- 1 is a key chemokine in the regulation of inflammation, released by mononuclear cells to attract additional monocytes, lymphocytes, mast cells, and eosinophils. A single- nucleotide polymorphism (c.2518A>G) in the distal regulatory region of MCP- 1 results in a significantly greater MCP- 1 response to inflammatory stimuli than the wild- type sequence, which leads to greater severity of AP[10]. The presence of the G allele significantly increased the risk of severe AP from any cause about sevenfold (~40%), whereas subjects with an AA genotype had a low risk of severe AP (~5%)[10].

The acute inflammatory response is a highly regulated process, with proinflammatory and anti-

inflammatory

factors interacting in sequential and coordinated ways. TNF- α, the earliest cytokine to be released in inflamma- tion, is a principal mediator of immune responses to endotoxin. The c.−308G>A and c.−238G>A polymorphisms in TNF- α have not been consistently associated with the incidence or severity of AP[99]. In contrast, the c.−1031C and c.−863A polymorphisms significantly increase the risk of severe AP (odds ratio [OR] 2.7)[100]. IL- 8 is produced by macrophages and attracts neutrophils to the site of inflammation. The c.- 251T>A polymorphism in CXCL8 (the gene coding for IL- 8) is associated with an increased risk of developing AP (OR 1.4)[101,102]. A number of other candidate cytokines have been investigated, including IL- 1ß, IL- 6, and IL- 18, and pathogenic variants in these genes marginally increase the risk of severe AP (OR 1.23, 1.22, 1.25, respectively)[103].

Future Directions

Since the discovery of pathogenic variants in PRSS1 among subjects with hereditary pancreatitis, a number of genetic factors have been identified that modify the risk and severity of AP. These are most commonly encountered among subjects with recurrent AP and CP, but may be identified among subjects who have experienced a sentinel AP as well. Among subjects with recurrent AP and an identified genetic predisposition, integrating our understanding of the effect of the mutation with the therapeutic approach is necessary. This may take the form of environmental risk modification, such as cessation of smoking and alcohol use, but may also involve specific drug therapy, such as the case with CFTR modulator drugs in subjects with pancreas sufficient CF. Specific therapies for other predisposing variants are not yet available. Future studies to develop novel therapies to correct high prevalence pathogenic variants is necessary to halt the progression from recurrent AP to CP.

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