Chronic pancreatitis: the true pathogenic culprit within the SPINK1 N34S-containing haplotype is no longer at large

Pu, Na, Masson, Emmanuelle, Cooper, David N. ORCID: https://orcid.org/0000-0002-8943-8484, Génin, Emmanuelle, Férec, Claude and Chen, Jian-Min 2021. Chronic pancreatitis: the true pathogenic culprit within the SPINK1 N34S-containing haplotype is no longer at large. Genes 12 (11) , 1683. 10.3390/genes12111683

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Abstract

A diverse range of loss-of-function variants in the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) has been identified in patients with chronic pancreatitis (CP). The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser or N34S) variant (rs17107315:T>C) is one of the most important heritable risk factors for CP as a consequence of its relatively high prevalence worldwide (population allele frequency ≈ 1%) and its considerable effect size (odds ratio ≈ 11). The causal variant responsible for this haplotype has been intensively investigated over the past two decades. The different hypotheses tested addressed whether the N34S missense variant has a direct impact on enzyme structure and function, whether c.101A>G could affect pre-mRNA splicing or mRNA stability, and whether another variant in linkage disequilibrium with c.101A>G might be responsible for the observed association with CP. Having reviewed the currently available genetic and experimental data, we conclude that c.-4141G>T (rs142703147:C>A), which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module located ∼4 kb upstream of the SPINK1 promoter, can be designated as the causal variant beyond reasonable doubt. This case illustrates the difficulties inherent in determining the identity of the causal variant underlying an initially identified disease association.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article distributed under the Creative Commons Attribution License (https:// creativecommons.org/licenses/by/ 4.0/
Publisher:	MDPI
ISSN:	2073-4425
Date of First Compliant Deposit:	22 December 2021
Date of Acceptance:	23 October 2021
Last Modified:	12 May 2023 00:36
URI:	https://orca.cardiff.ac.uk/id/eprint/146277

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