Chronic Pancreatitis: The True Pathogenic Culprit within the SPINK1 N34S-Containing Haplotype Is No Longer at Large

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 (rs17107...

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Autores principales:	Na Pu, Emmanuelle Masson, David N. Cooper, Emmanuelle Génin, Claude Férec, Jian-Min Chen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chronic pancreatitis enhancer linkage disequilibrium regulatory variant <i>SPINK1</i> gene Genetics QH426-470
Acceso en línea:	https://doaj.org/article/deae52af45644327aa07400357a04fe0
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spelling	oai:doaj.org-article:deae52af45644327aa07400357a04fe02021-11-25T17:40:45ZChronic Pancreatitis: The True Pathogenic Culprit within the <i>SPINK1</i> N34S-Containing Haplotype Is No Longer at Large10.3390/genes121116832073-4425https://doaj.org/article/deae52af45644327aa07400357a04fe02021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1683https://doaj.org/toc/2073-4425A diverse range of loss-of-function variants in the <i>SPINK1</i> gene (encoding pancreatic secretory trypsin inhibitor) has been identified in patients with chronic pancreatitis (CP). The haplotype harboring the <i>SPINK1</i> 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 <i>cis</i>-regulatory module located ∼4 kb upstream of the <i>SPINK1</i> 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.Na PuEmmanuelle MassonDavid N. CooperEmmanuelle GéninClaude FérecJian-Min ChenMDPI AGarticlechronic pancreatitisenhancerlinkage disequilibriumregulatory variant<i>SPINK1</i> geneGeneticsQH426-470ENGenes, Vol 12, Iss 1683, p 1683 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chronic pancreatitis enhancer linkage disequilibrium regulatory variant <i>SPINK1</i> gene Genetics QH426-470
spellingShingle	chronic pancreatitis enhancer linkage disequilibrium regulatory variant <i>SPINK1</i> gene Genetics QH426-470 Na Pu Emmanuelle Masson David N. Cooper Emmanuelle Génin Claude Férec Jian-Min Chen Chronic Pancreatitis: The True Pathogenic Culprit within the <i>SPINK1</i> N34S-Containing Haplotype Is No Longer at Large
description	A diverse range of loss-of-function variants in the <i>SPINK1</i> gene (encoding pancreatic secretory trypsin inhibitor) has been identified in patients with chronic pancreatitis (CP). The haplotype harboring the <i>SPINK1</i> 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 <i>cis</i>-regulatory module located ∼4 kb upstream of the <i>SPINK1</i> 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.
format	article
author	Na Pu Emmanuelle Masson David N. Cooper Emmanuelle Génin Claude Férec Jian-Min Chen
author_facet	Na Pu Emmanuelle Masson David N. Cooper Emmanuelle Génin Claude Férec Jian-Min Chen
author_sort	Na Pu
title	Chronic Pancreatitis: The True Pathogenic Culprit within the <i>SPINK1</i> N34S-Containing Haplotype Is No Longer at Large
title_short	Chronic Pancreatitis: The True Pathogenic Culprit within the <i>SPINK1</i> N34S-Containing Haplotype Is No Longer at Large
title_full	Chronic Pancreatitis: The True Pathogenic Culprit within the <i>SPINK1</i> N34S-Containing Haplotype Is No Longer at Large
title_fullStr	Chronic Pancreatitis: The True Pathogenic Culprit within the <i>SPINK1</i> N34S-Containing Haplotype Is No Longer at Large
title_full_unstemmed	Chronic Pancreatitis: The True Pathogenic Culprit within the <i>SPINK1</i> N34S-Containing Haplotype Is No Longer at Large
title_sort	chronic pancreatitis: the true pathogenic culprit within the <i>spink1</i> n34s-containing haplotype is no longer at large
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/deae52af45644327aa07400357a04fe0
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Chronic Pancreatitis: The True Pathogenic Culprit within the <i>SPINK1</i> N34S-Containing Haplotype Is No Longer at Large

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