GENETIC POLYMORPHISMS IN ALCOHOL-METABOLIZING ENZYMES AND CHRONIC PANCREATITIS

Mariette Verlaan1,*, René H. M. Te Morsche1, Hennie M. J. Roelofs1, Robert J. F. Laheij1, Jan B. M. J. Jansen1, Wilbert H. M. Peters1 and Joost P. H. Drenth1,2

1 Department of Medicine, Division of Gastroenterology and Hepatology, University Medical Centre St Radboud, Nijmegen, The Netherlands and 2 Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

* Author to whom correspondence should be addressed at: Department of Medicine, Division of Gastroenterology and Hepatology, University Medical Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: +31 24 3616520; Fax +31 24 3540103; E-mail: m.verlaan{at}mdl.umcn.nl

(Received 16 January 2003; first review notified 13 March 2003; in revised form 18 August 2003; accepted 25 August 2003)


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims: Alcohol misuse is now regarded as an important risk factor for development of chronic pancreatitis (CP). However, not every alcohol misuser develops CP and it therefore might be suggested that susceptibility could be further influenced by inter-individual variations in the activities of alcohol-metabolizing enzymes. Several genetic polymorphisms that may affect the activities of alcohol-metabolizing enzymes have been described. Therefore we determined whether polymorphisms in the genes for alcohol dehydrogenase 3 (ADH3) or cytochrome P450 2E1 (CYP2E1) predispose to the development of CP. Methods: DNA samples were obtained from 142 adult CP patients with hereditary (n = 21), alcoholic (n = 82) or idiopathic (n = 39) CP. DNA from 128 healthy controls and from 93 alcoholic controls was analysed for comparison. Patients and controls were all of Caucasian origin. Genetic polymorphisms in ADH3 and CYP2E1 were determined by PCR, followed by restriction-fragment-length-polymorphism analyses in all subjects. Results: The frequencies of ADH3 and CYP2E1 c1c2 genotypes did not differ between CP patients and alcoholic and healthy controls. However, a trend for a higher frequency of the CYP2E1 intron 6 D allele was demonstrated in patients with alcohol-induced CP, compared to that of healthy controls (OR = 3.03, 95%CI = 1.0–9.1) or alcoholic controls (OR = 2.76, 95%CI = 0.9–8.7). Conclusions: These data suggest that the presence of the CYP2E1 intron 6 DD genotype might confer a higher risk of alcoholic CP.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chronic pancreatitis (CP) is a progressive inflammatory disease, which eventually leads to impairment of exocrine and/or endocrine function of the organ (Witt et al., 2000Go; Whitcomb and Somogyi, 2001Go; Drenth et al., 2002Go). Alcohol (ethanol) is regarded as the main cause of CP, in fact, alcohol misuse accounts for 70–80% of all cases of CP (Gastard et al., 1973Go; Mergener and Baillie, 1997Go). However, only 5–10% of heavy drinkers develop pancreatitis (Bisceglie and Segal, 1984Go), while the mechanism for how alcohol causes CP remains unknown (Sarles et al., 1989Go). In addition, other aetiological factors such as heredity, smoking, anatomical varia-tions and various metabolic disorders have been identified. However, in a substantial number of the patients there are no obvious risk factors and the disease in these patients is classified as idiopathic CP (Steer et al., 1995Go).

Modulating genetic factors underlying the susceptibility to CP remain elusive. Given the importance of alcohol consump-tion in the aetiopathogenesis of CP, we have focussed on genes involved in alcohol metabolism. Ethanol is mainly oxidized to acetaldehyde by alcohol dehydrogenases (ADH). Oxidation of alcohol by the cytochrome P450 2E1 (CYP2E1) enzyme is important especially in chronic alcohol misusers as it is inducible up to 10-fold by consumption of alcohol. Several polymorphisms in the genes encoding for these enzymes may influence the corresponding enzyme activities and may thus affect the toxicity of alcohol (Zavras et al., 2002Go).

ADH enzymes are encoded by at least six gene loci (ADH16) (Edenberg, 2000Go) and polymorphisms have been identified in two of these genes; ADH2 and ADH3 (Bosron and Li, 1986Go). In Caucasians, however, only the ADH3 locus is polymorphic. Two ADH3 alleles exist; ADH3*1 and ADH3*2, encoding the subunits {gamma}1 and {gamma}2 respectively, which differ by one amino acid (Day et al., 1993Go). The {gamma}1{gamma}1 isoenzyme metabolizes alcohol at a 2.5-fold higher rate than does the {gamma}2{gamma}2 isoenzyme (Bosron and Li, 1986Go).

CYP2E1, a microsomal enzyme, is also able to oxidize ethanol and particularly contributes to ethanol metabolism in chronic alcohol consumers. Genetic polymorphisms in CYP2E1 have been demonstrated in the transcription-regulation region (alleles c1 and c2) and in intron 6 (alleles D and C) (Hayashi et al., 1991Go; Uematsu et al., 1991Go). The presence of the c2 or C alleles was associated with enhanced enzyme activity (Hayashi et al., 1991Go; Uematsu et al., 1991Go; Watanabe et al., 1994Go).

In the present study we investigated the association between CP and the ADH3 and CYP2E1 gene polymorphisms, described above, in cohorts of non-selected adult Caucasian patients with CP and alcoholic and non-alcoholic Caucasian controls.


    SUBJECTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The study was approved by the local medical ethical review committee and all subjects gave their written informed consent. All subjects studied were Caucasians of Dutch extraction. The CP group consisted of 142 adult patients (80 males; 62 females). Twenty-one patients (15%) had a family history of CP (HCP), 82 patients (58%) had alcohol-induced CP (ACP) and 39 patients (27%) were classified as having idiopathic chronic pancreatitis (ICP).

The clinical diagnosis of CP was based on one or more of the following criteria: (1) presence of typical complaints (recurrent upper abdominal pain, radiating to the back, relieved by leaning forward or sitting upright and increased after eating); (2) suggestive radiological findings, such as pancreatic calcifications or pseudocysts, and (3) pathological findings (pancreatic ductal irregularities and dilatations) revealed by endoscopic retrograde pancreaticography or magnetic resonance imaging of the pancreas before and after stimulation with secretin. Diagnosis of HCP was made on the basis of two first-degree relatives or three or more second-degree relatives in two or more generations, who suffered from recurrent acute pancreatitis or chronic pancreatitis for which there was no precipitating factor. ACP was diagnosed in patients who consumed more than 60 g (women) or 80 g (men) ethanol per day for more than 2 years. Two of the 82 ACP patients also suffered from other alcohol-associated organ damage, namely liver cirrhosis. Patients were classified as having ICP when precipitating factors such as alcohol misuse, trauma, medication, infection, metabolic disorders or a positive family history were all absent.

For comparison, we discerned two control groups: a group consisting of 128 adult healthy subjects (75 males; 53 females) recruited by advertisement in a local paper, and a group of 93 alcoholic subjects (64 males; 29 females), who were being treated in a detoxification unit because of their addiction. We defined alcoholics as subjects who consumed in excess of 60 g (women) or 80 g (men) ethanol per day for more than 2 years. None of the alcoholics had CP or other known end-organ disease because of their alcoholism.

Genotyping
DNA was isolated from whole blood using the Pure Gene DNA isolation kit, and the isolation was performed according to the instructions from the manufacturer (Gentra systems). The genotyping for the polymorphism in ADH3 was carried out by polymerase chain reaction (PCR) amplification according to the method of Xu et al. (1988)Go. Subsequently, the PCR product was digested using restriction enzyme SspI (PCR/RFLP). The ADH3*1 allele contains an additional restriction site for SspI, yielding fragments of 63 and 67 bp, which is not present in the ADH3*2 allele.

The CYP2E1 genotypes were determined by PCR/RFLP methods as described elsewhere (Stephens et al., 1994Go). The restriction enzymes RsaI and PstI were used to discern the c1 and c2 alleles of the 5'-flanking region, while the enzyme DraI was used to detect the D and C polymorphisms in intron 6.

Statistical analyses
Data were analysed by SAS version 8.0. Differences in the baseline characteristics of patients and control groups were estimated with Fisher's exact test and Student's t-test. Chi-squared statistics were used to estimate differences in the presence of genetic polymorphisms in ADH3, CYP2E1 c1 and c2 or D and C polymorphisms among the different study groups. (When one of the genotypes has expected counts of less than 5, Chi-squared may not be a valid test, we therefore used Fisher's exact test instead in these cases.) The distribution of each polymorphism among the control population was tested for whether it fitted the Hardy–Weinberg equilibrium.

We compared the genotypes of ACP patients to those of alcoholic controls in order to correct for alcoholism for the D and C polymorphism in CYP2E1. Odds ratios (OR) with 95% confidence intervals (95%CI) were calculated by logistic regression analysis.

Because the mean age in the ACP group did not match that of the alcoholic controls, a multiple logistic regression analysis was performed in the group of ACP patients to study the association between the CYP2E1 DC polymorphism and the variable age to estimate an adjusted OR with 95%CI.

Finally, for the allele frequencies in ADH3, CYP2E1 c1 and c2 or D and C polymorphisms, OR with 95%CI were calculated by logistic regression analysis.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Characteristics of patients and controls
Characteristics of patients with CP and controls are denoted in Table 1. There was a difference in sex distribution between the HCP or ICP patients versus the healthy controls, with relatively more female subjects in the former two groups (both P < 0.05). Age distribution was dissimilar in HCP patients, as these patients develop CP at a younger age than do the other CP patients, explaining why this separate group was significantly younger than the normal control group (P < 0.05; Table 1). The mean age of ACP patients was higher than that of the alcoholic control group (P < 0.05; Table 1), but was not different compared to the healthy controls.


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Table 1. Main characteristics of patients with chronic pancreatitis and controls

 
There were no differences in smoking habits between patients and healthy controls or between ACP patients and alcoholic controls, but unfortunately the information about smoking is only available from a limited number of subjects.

ADH3 genotyping
There were no statistical differences in the distribution of the homozygous {gamma}1{gamma}1 genotype, the homozygous {gamma}2{gamma}2 genotype and the heterozygous {gamma}1{gamma}2 genotype among patients with HCP, ACP, ICP vs. the healthy control subjects (Table 2) or ACP patients versus alcoholic controls (Table 3). The genotype distribution of all groups studied followed the Hardy–Weinberg equilibrium. The ratio of the {gamma}1 and {gamma}2 allele in the different patient and control groups did not demonstrate any statistical difference either (Tables 4 and 5).


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Table 2. Distribution of ADH3, CYP2E1 c1c2 and CYP2E1 DC genotypes in patients with chronic pancreatitis and healthy controls

 

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Table 3. Distribution of ADH3, CYP2E1 c1c2 and CYP2E1 DC genotypes in patients with alcohol-induced chronic pancreatitis and alcoholic control subjects

 

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Table 4. Allele frequencies of ADH3, CYP2E1 c1c2 and CYP2E1 DC in patients with chronic pancreatitis and healthy controls

 

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Table 5. Allele frequencies of ADH3, CYP2E1 c1c2 and CYP2E1 DC in patients with alcohol-induced chronic pancreatitis and alcoholic control subjects

 
CYP2E1 c1c2 genotyping
There were no statistical differences in the distribution of CYP2E1 c1c2 genotype among groups (Table 2). None of the subjects investigated had the homozygous c2c2 genotype. Most subjects studied (95%), both patients and controls, carried the homozygous c1c1 genotype, while the remaining 5% was heterozygous (c1c2 genotype). The distribution of CYP2E1 c1c2 genotype followed the Hardy–Weinberg equilibrium. The c1 and c2 allele frequencies showed no statistical differences between different CP patient groups and control subjects (Tables 4 and 5).

CYP2E1 DC genotyping
There were no significant statistical differences in the distribution of the CYP2E1 DC genotype between HCP patients, ACP patients, ICP patients and healthy controls (Table 2). However, a slight tendency of a higher frequency of the CYP2E1 DD genotype was detected. The distribution of CYP2E1 DC genotype followed the Hardy–Weinberg equilibrium.

Comparison of the ACP patients with the alcoholic control group, in order to control for alcoholism, demonstrated a similar tendency of a higher frequency of the CYP2E1 DD genotype in the former group, however significance was not reached (P = 0.11; OR = 2.89, 95%CI: 0.9–9.3; Table 3). As the mean age of ACP patients was higher compared with that of alcoholic controls, we controlled for this confounding factor. We estimated an adjusted OR for age, which showed the same tendency of a higher frequency of the CYP2E1 DD genotype in the ACP patient group (adjusted OR = 2.31, 95%CI: 0.7–7.7).

The ratio of allele frequencies showed, in accordance with the genotype distribution of CYP2E1 DC, a trend of a higher frequency of the CYP2E1 D allele between ACP patients and healthy controls (P = 0.07; OR = 3.03, 95%CI: 1.0–9.1; Table 4). Comparison of the allele frequencies in ACP patients with that of alcoholic control subjects, demonstrated a similar tendency of a higher frequency of the D allele in the ACP patient group, but here again, significance was not reached (P = 0.12; OR = 2.76, 95%CI: 0.9–8.7; Table 5).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this study, frequencies of genetic polymorphisms in ADH3 or in the transcription-regulation region of CYP2E1 (c1c2) in control groups were similar to those in CP patients of various aetiologies. However, we detected a trend of a higher frequency of the CYP2E1 intron 6 D allele in patients with alcohol-induced CP as compared to that of healthy controls (OR = 3.03, 95% CI = 1.0–9.1) or alcoholic controls (OR = 2.76, 95%CI = 0.9–8.7). This suggests a weak positive association between the homozygous CYP2E1 DD genotype in Caucasians and the development of ACP.

The CYP2E1 DD genotype may be associated with a less efficient microsomal alcohol-metabolizing enzyme, which may either delay the formation of acetaldehyde, the highly toxic metabolite of alcohol, and so permits higher intake of alcohol, or may result in a higher pressure on the cytosolic ADH-oxidizing system in patients with CP. It is possible that a shift from microsomal to cytosolic oxidation of alcohol might generate more damage to vital cellular systems.

So far, only a few studies have focussed on the association between various genotypes of alcohol-metabolizing enzymes and susceptibility to pancreatitis in Caucasians. In their review, Haber et al. (1995)Go argued that the genotypes of ADH3 were not significantly associated with the development of alcoholic pancreatitis. In contrast, some studies reported a positive association between the ADH3*1 allele and alcohol-induced CP (Day et al., 1991Go; Dumas et al., 1995Go). In more recent studies, polymorphisms in both ADH3 and CYP2E1 did not affect the risk of CP (Grove et al., 1998Go; Frenzer et al., 2002Go). Also Klingenberg et al. (2002)Go did not find an association between ADH3 polymorphisms and alcohol-associated pancreatitis. However, there appears to be an association between ADH genotypes with less active alcohol-metabolizing enzymes and alcoholic liver cirrhosis (Frenzer et al., 2002Go), whereas Grove et al. (1998)Go reported that the c2 allele of CYP2E1, possibly resulting in enhanced enzyme activity, was associated with a higher risk of alcoholic liver disease. In similar studies with Japanese CP patients and controls, no associations between variant ADH3 or CYP2E1 genotypes and CP were found (Matsumoto et al., 1996Go; Maruyama et al., 1999Go). However, a positive association between alcoholic CP and the ADH2(2) allele in the Japanese population was detected (Matsumoto et al., 1996Go; Maruyama et al., 1999Go).

The relative importance of the ADH3 and CYP2E1 enzyme activities to overall ethanol metabolism is unknown, although CYP2E1 by virtue of its inducibility by chronic intake of ethanol, is probably important in chronic alcohol misusers only (Bosron and Li, 1986Go; Takahashi et al., 1993Go). Other enzymes involved in the metabolism of ethanol, are enzymes of the aldehyde dehydrogenase (ALDH) family and the other members of the ADH family. In this study, genotype patterns of ADH2 and ALDH2 were not examined, because the relative common genetic polymorphisms in ADH2*2 and ALDH2*2 as often described in Japanese individuals (Matsumoto et al., 1996Go; Maruyama et al., 1999Go) are very rare in Caucasians.

Because of the low frequency of the CYP2E1 C allele, we were unable to define which CP subtype is most associated with the CYP2E1 D allele. However, when comparing the alcoholic CP patients with the alcoholic control group without CP, in order to control for alcohol misuse, a trend for the positive association between CP and the CYP2E1 DD genotype was still present.

Our finding has to be viewed in the perspective of potential limitations. First, we are lacking information on the nature of the alcoholic beverages consumed, and it might be argued that differences reported here are caused by differences in the types of alcoholic consumption. This seems unlikely, however, as ACP patients and alcoholic controls both stem from a cultural homogeneous population. Second, we do not have precise data on potential confounding factors for the alcoholic and healthy controls, such as dietary habits and use of medication or drugs. Third, the most important confounding factor, smoking, was not fully investigated. Although data on smoking habits were not available for every subject, our data suggest that smoking was similar among groups and did not influence the results of this study. In conclusion, our data suggest that the risk of ACP might be weakly associated with a genetic polymorphism in intron 6 of CYP2E1, whereas associations with other polymorphisms in ADH3 and CYP2E1 are lacking. This result might point to a higher risk for ACP in individuals with chronic alcohol consumption and a slow microsomal ethanol-oxidizing genotype.


    ACKNOWLEDGEMENTS
 
This work was supported by a grant of the Dutch foundation of digestive diseases (MLDS). Dr Joost P. H. Drenth is an investigator for the Royal Netherlands Academy of Arts and Sciences.


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 ABSTRACT
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 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
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