Pathways to Injury in Chronic Pancreatitis: Decoding the Role of the High-Risk SPINK1 N34S Haplotype Using Meta-Analysis

Abstract

BackgroundThe complex interactions between recurrent trypsin-mediated pancreatic injury, alcohol-associated pancreatic injury and SPINK1 polymorphisms in chronic pancreatitis (CP) are undefined. We hypothesize that CP occurs as a result of multiple pathological mechanisms (pathways) that are initiated by different metabolic or environmental factors (etiologies) and may be influenced differentially by downstream genetic risk factors. We tested this hypothesis by evaluating the differences in effect size of the high risk SPINK1 N34S haplotype on CP from multiple etiologies after combining clinical reports of SPINK1 N34S frequency using meta-analysis.Methods and FindingsThe Pubmed and the Embase databases were reviewed. We studied 24 reports of SPINK1 N34S in CP (2,421 cases, 4,857 controls) using reported etiological factors as surrogates for pathways and multiple meta-analyses to determine the differential effects of SPINK1 N34S between alcoholic and non-alcoholic etiologies. Using estimates of between-study heterogeneity, we sub-classified our 24 studies into four specific clusters. We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59–15.93), but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16–7.85) was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09–24.67) or tropical CP (OR 19.15, 95% C.I. = 8.83–41.56). Studies analyzing familial CP showed very high heterogeneity suggestive of a complex etiology with an I2 = 80.95%.ConclusionThe small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent. The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint.

Genetics of Pancreatitis: The 2014 Update

“…The following studies have shown that mutations in the SPINK1 gene are associated with CP of various etiologies including idiopathic, familial, and tropical (Witt et al 2000;Pfützer et al 2000;Chen et al 2001;Bhatia et al 2002;Kume et al 2005;Aoun et al 2008). The p.N34S mutation has been found worldwide in CP patients and healthy controls, with an average allele frequency of 9.7% and 1%, respectively (Witt et al 2000;Pfützer et al 2000;Chen et al 2001;Bhatia et al 2002;Kume et al 2005;Aoun et al 2008). In addition to CP, we and others have reported that the p.N34S mutation is strongly associated with recurrent acute pancreatitis, but does not increase the risk of the first or sentinel acute pancreatitis event (Aoun et al 2010;Masamune et al 2011).…”

The Role of SPINK1 Gene Mutation in Chronic Pancreatitis Development and Progression

“…Наличие мутации N34S определяет низкий риск развития любой этиологии ХП, умеренный риск токсического ХП, высокий риск идиопатического ХП; низкий риск ранней клинической манифестации ХП любой этиологии, умеренный риск для токсического ХП, высокий риск -для идиопатического ХП. Полученные нами данные условно укладываются в наиболее доказательные результаты крупного метаанализа 24 исследований, включающих 2421 случай ХП (и 4857 контроль), свидетельствующие о высоком риске развития ХП у носителей мутации N34S -ОШ развития ХП достигает 11,00 (95% доверительный интервал (ДИ) 7,59-15,93), а для идиопатического ХП еще выше -14,97 (95% ДИ 9,09-24,67) [30].…”

“…Наиболее специфичной оказалась группа идиопатического ХП, в которой отмечена максимальная частота данной мутации, наиболее тяжелое и осложненное течение ХП, больший риск неблагоприятных исходов. Хотя роль мутаций гена ПИТ в развитии ХП была оценена в нескольких западных исследованиях [12][13][14][15]30], наше исследование -первое, в котором была изучена частота мутации N34S у больных ХП в Москве и Московской области, и пока единственное в России, в котором удалось доказать, что данная мутация играет существенную роль в развитии, по крайней мере, токсических и идиопатических панкреатитов.…”

Phenotypic Variability of the Homozygous IVS3+2T>C Mutation in the Serine Protease Inhibitor Kazal Type 1 (SPINK1) Gene in Patients with Chronic Pancreatitis

“…Serine protease inhibitor Kazal type 1 (SPINK1) provides the first line of defense against prematurely activated trypsinogen by physically blocking the active site of trypsin (Rinderknecht 1986;Witt et al 2000). Mutations in the SPINK1 gene are thought to diminish the protection against prematurely activated trypsin, and are thereby linked to trypsin-related pancreatic injury (Pfützer et al 2000;Witt et al 2000;Chen et al 2001;Bhatia et al 2002;Kume et al 2005Kume et al , 2006Aoun et al 2008).…”

“…Previous studies have shown that mutations in the SPINK1 gene are associated with CP of various forms including idiopathic, familial, and tropical (Pfützer et al 2000;Witt et al 2000;Chen et al 2001;Bhatia et al 2002;Kume et al 2005Kume et al , 2006Aoun et al 2008). The p.N34S (c.101A>G) mutation has been found worldwide in CP patients and healthy controls, with an average allele frequency of 9.7% and 1%, respectively (Pfützer et al 2000;Witt et al 2000;Aoun et al 2008;Kereszturi et al 2009).…”