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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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Related in: MedlinePlus

Meta-analysis results for chronic pancreatitis all etiologies combined based on allelic frequency.Heterogeneity testing: Q-value = 41.05, df = 23, p = 0.01, I2 = 43.97 (95% CI: 10.56–64.90).
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pone-0002003-g003: Meta-analysis results for chronic pancreatitis all etiologies combined based on allelic frequency.Heterogeneity testing: Q-value = 41.05, df = 23, p = 0.01, I2 = 43.97 (95% CI: 10.56–64.90).

Mentions: Figure 3 summarizes the results of the initial meta-analysis with all etiologies of CP combined. The total number of patients from these studies was 2,421 with 4,857 controls. The mutation was detected in 469 of 4,842 patient alleles and in 96 of 9,714 control alleles. Significant heterogeneity was detected (Q = 41.05, df = 23, p = 0.01, I2 = 43.97%). The random effect model showed a combined OR of 11.00 (95% C.I. = 7.59–15.93). Both the Egger and the Begg-Mazumdar tests were not statistically significant with p = 0.65 and p = 0.94 respectively.


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)

Meta-analysis results for chronic pancreatitis all etiologies combined based on allelic frequency.Heterogeneity testing: Q-value = 41.05, df = 23, p = 0.01, I2 = 43.97 (95% CI: 10.56–64.90).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002003-g003: Meta-analysis results for chronic pancreatitis all etiologies combined based on allelic frequency.Heterogeneity testing: Q-value = 41.05, df = 23, p = 0.01, I2 = 43.97 (95% CI: 10.56–64.90).
Mentions: Figure 3 summarizes the results of the initial meta-analysis with all etiologies of CP combined. The total number of patients from these studies was 2,421 with 4,857 controls. The mutation was detected in 469 of 4,842 patient alleles and in 96 of 9,714 control alleles. Significant heterogeneity was detected (Q = 41.05, df = 23, p = 0.01, I2 = 43.97%). The random effect model showed a combined OR of 11.00 (95% C.I. = 7.59–15.93). Both the Egger and the Begg-Mazumdar tests were not statistically significant with p = 0.65 and p = 0.94 respectively.

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