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Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis.

Aoun E, Chang CC, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC - PLoS ONE (2008)

Bottom Line: 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).The 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: The 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 findings: The 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 I(2) = 80.95%.

Conclusion: The 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.

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Flow diagram of the studies included in the meta-analysis.* The report by Bernardino et al was excluded from the meta-analysis because it did not detect the N34S haplotype in neither the cases nor the controls and was therefore assigned a weight of zero.
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pone-0002003-g002: Flow diagram of the studies included in the meta-analysis.* The report by Bernardino et al was excluded from the meta-analysis because it did not detect the N34S haplotype in neither the cases nor the controls and was therefore assigned a weight of zero.

Mentions: Figure 2 is a flow diagram illustrating the studies included. Thirty case-control studies evaluating the association of the SPINK1 N34S polymorphism with CP were identified (Table 1). Two studies were excluded because the prevalence of the polymorphism was not reported in the control population [13], [28]. An additional three studies were excluded due to data duplication in other publications [29], [30], [31]. Additionally, The report by Bernardino et al [32] was excluded from the analysis because it did not identify the N34S polymorphism in either cases or controls. A total of 24 studies were therefore evaluated.


Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis.

Aoun E, Chang CC, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC - PLoS ONE (2008)

Flow diagram of the studies included in the meta-analysis.* The report by Bernardino et al was excluded from the meta-analysis because it did not detect the N34S haplotype in neither the cases nor the controls and was therefore assigned a weight of zero.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2289874&req=5

pone-0002003-g002: Flow diagram of the studies included in the meta-analysis.* The report by Bernardino et al was excluded from the meta-analysis because it did not detect the N34S haplotype in neither the cases nor the controls and was therefore assigned a weight of zero.
Mentions: Figure 2 is a flow diagram illustrating the studies included. Thirty case-control studies evaluating the association of the SPINK1 N34S polymorphism with CP were identified (Table 1). Two studies were excluded because the prevalence of the polymorphism was not reported in the control population [13], [28]. An additional three studies were excluded due to data duplication in other publications [29], [30], [31]. Additionally, The report by Bernardino et al [32] was excluded from the analysis because it did not identify the N34S polymorphism in either cases or controls. A total of 24 studies were therefore evaluated.

Bottom Line: 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).The 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: The 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 findings: The 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 I(2) = 80.95%.

Conclusion: The 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.

Show MeSH
Related in: MedlinePlus