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

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  • Elie Aoun
  • Chung-Chou H Chang
  • Julia B Greer
  • Georgios I Papachristou
  • M Michael Barmada
  • David C Whitcomb

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 I2 = 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.

Suggested Citation

  • Elie Aoun & Chung-Chou H Chang & Julia B Greer & Georgios I Papachristou & M Michael Barmada & David C Whitcomb, 2008. "Pathways to Injury in Chronic Pancreatitis: Decoding the Role of the High-Risk SPINK1 N34S Haplotype Using Meta-Analysis," PLOS ONE, Public Library of Science, vol. 3(4), pages 1-8, April.
    • Handle: RePEc:plo:pone00:0002003
    DOI: 10.1371/journal.pone.0002003
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    References listed on IDEAS

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    1. John PA Ioannidis & Nikolaos A Patsopoulos & Evangelos Evangelou, 2007. "Heterogeneity in Meta-Analyses of Genome-Wide Association Investigations," PLOS ONE, Public Library of Science, vol. 2(9), pages 1-7, September.
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    Cited by:

    1. Marianges Zadrozny Gouvêa da Costa & Dulce Reis Guarita & Suzane Kioko Ono-Nita & Denise Cerqueira Paranaguá-Vezozzo & Guilherme Eduardo Gonçalves Felga & Martha Regina Arcon Pedroso & Marcelo Moreira, 2011. "Genetic Risk for Alcoholic Chronic Pancreatitis," IJERPH, MDPI, vol. 8(7), pages 1-11, June.

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