Analysis of the Alcohol Dehyrogenase (ADH3) and the Serine Protease Inhibitor, Kazal type 1 (SPINKl) Genes in Alcohol-Induced Pancreatitis

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Kilar, Margaret A.
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Alcohol dehydrogenase (ADH3) polymorphisms and serine protease inhibitor, Kazal type 1 (SPINK1) mutations, particularly N34S, have been examined in pancreatitis patients, although no study has analyzed both genes in the same patient. Previous studies suggested a possible association between ADH3 or SPINKI and alcohol induced pancreatitis; however, a statistically significant association was not proven. We hypothesize that ADH3 polymorphisms and SPINK 1 mutations are associated with alcohol-induced pancreatitis. Three groups were analyzed in this study: Patients with alcohol-induced pancreatitis (N = 45), non-alcohol associated pancreatitis with a positive family history of pancreatitis (N = 8) and non-alcohol associated pancreatitis with a negative family history of pancreatitis (N = 51). The ADH3 * 1 and *2 polymorphisms were analyzed by restriction fragment length polymorphism (RFLP) analysis. SPINKI exon 3 was analyzed by direct DNA sequencing to identify previously known mutations including N34S, P55S and IVS3+2T →C. The ADH3 * 1 and *2 allele frequency among Caucasian alcohol associated and non-alcohol associated pancreatitis patients was 0.5 and 0.5, respectively. The ADH3 *1 and *2 allele frequency among African American alcohol associated and non-alcohol associated pancreatitis patients was 0.8 and 0.2, respectively. The ADH3*2 allele, associated with a lower rate of alcohol metabolism, was detected at a higher frequency among African American pancreatitis patients (regardless of alcohol intake status), compared to the expected allele frequency, based on normal controls. SPINKI mutations were only identified among patients with non-familial, non-alcohol induced pancreatitis. Six of fifty-one patients (11.8%) had at least one SPINKl mutation, including N34S, P55S, IVS3+2T →C, and a novel V 46D mutation. One individual was compound heterozygous for N34S and IVS3+ 2T →C. Our SPINK1 results are in agreement with previous findings, that SPINK1 mutations are associated with non-familial idiopathic pancreatitis but are not likely involved in alcohol-induced pancreatitis among Caucasians or African Americans. Our ADH3 results differ from previous studies of alcohol-induced pancreatitis, suggesting an association of this disease with the ADH3 *2 allele in African Americans. This study, and similar studies, may be clinically relevant for future pancreatitis genetic testing.
viii, 29 p.
Kalamazoo College
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