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Identification of a functional enhancer variant within the chronic pancreatitis‐associated SPINK1 c.101A>G (p.Asn34Ser)‐containing haplotype
Author(s) -
Boulling Arnaud,
Masson Emmanuelle,
Zou WenBin,
Paliwal Sumit,
Wu Hao,
Issarapu Prachand,
Bhaskar Seema,
Génin Emmanuelle,
Cooper David N.,
Li ZhaoShen,
Chandak Giriraj R,
Liao Zhuan,
Chen JianMin,
Férec Claude
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23269
Subject(s) - biology , haplotype , genetics , single nucleotide polymorphism , linkage disequilibrium , enhancer , dna binding site , indel , computational biology , transcription factor , gene , promoter , genotype , gene expression
The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser) variant (also known as rs17107315:T>C) represents the most important heritable risk factor for idiopathic chronic pancreatitis identified to date. The causal variant contained within this risk haplotype has however remained stubbornly elusive. Herein, we set out to resolve this enigma by employing a hypothesis‐driven approach. First, we searched for variants in strong linkage disequilibrium (LD) with rs17107315:T>C using HaploReg v4.1. Second, we identified two candidate SNPs by visual inspection of sequences spanning all 25 SNPs found to be in LD with rs17107315:T>C, guided by prior knowledge of pancreas‐specific transcription factors and their cognate binding sites. Third, employing a novel cis‐regulatory module (CRM)‐guided approach to further filter the two candidate SNPs yielded a solitary candidate causal variant. Finally, combining data from phylogenetic conservation and chromatin accessibility, cotransfection transactivation experiments, and population genetic studies, we suggest that rs142703147:C>A, which disrupts a PTF1L‐binding site within an evolutionarily conserved HNF1A−PTF1L CRM located ∼4 kb upstream of the SPINK1 promoter, contributes to the aforementioned chronic pancreatitis risk haplotype. Further studies are required not only to improve the characterization of this functional SNP but also to identify other functional components that might contribute to this high‐risk haplotype.