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Abstract

Objective

A meta-analysis to determine the association between chronic pancreatitis and glutathione-S transferase (GST) mu 1 (GSTM1) and theta 1 (GSTT1) deletions.

Methods

Case–control studies concerning the relationship between chronic pancreatitis and GSTM1 or GSTT1 deletions were identified (up to October 2013). Meta-analyses of the association between GSTM1 and GSTT1 genotype and chronic pancreatitis or alcoholic chronic pancreatitis (ACP) were performed.

Results

Seven studies were included in the meta-analysis (650 patients/1382 controls for GSTM1 and 536 patients/1304 controls for GSTT1). There were no significant relationships between GSTM1/GSTT1 and chronic pancreatitis or GSTT1 and ACP. There was a significant association between GSTM1 null genotype and ACP (odds ratio 1.16, 95% confidence intervals 1.03, 1.30).

Conclusion

The GSTM1 null genotype was significantly associated with ACP risk.

Keywords

Glutathione S-transferase M1 glutathione S-transferase T1 polymorphism chronic pancreatitis alcohol

Introduction

Chronic pancreatitis is a progressive inflammatory disease that may eventually lead to impairment of exocrine and endocrine functions and irreversible pancreatic damage.^1–3 Key aetiological factors include alcohol, smoking, genetic factors, and autoimmune, idiopathic and metabolic disorders.^4–8

Oxidative stress has been implicated in the pathogenesis of chronic pancreatitis,⁹ and upregulation of endogenous free-radical scavengers can limit oxidative stress. These include glutathione-S transferases (GSTs): a superfamily of phase II cytosolic, mitochondrial and microsomal enzymes. GSTs mediate the conjugation of reduced glutathione to electrophilic species on a variety of substrates, resulting in the elimination of toxic substances and protecting cells against electrophiles and products of oxidative stress.^10–12 Null genotypes of both the GST mu 1 (GSTM1) and GST theta 1 (GSTT1) genes exist, where a 15 or 50 kb sequence deletion occurs, leading to a lack of active isoforms when homozygous. The frequencies of GSTM1-null and GSTT1-null vary between 20 and 70%, and 11 and 38%, respectively.^11–13

The association between chronic pancreatitis and GSTM1/GSTT1 deletion has been studied in various populations, but the results remain inconclusive. The aim of the present meta-analysis was to perform a systematic review of studies evaluating GSTM1 and GSTT1 genotypes and the risk of chronic pancreatitis.

Materials and methods

Studies examining the association between GSTM1/GSTT1 genotypes and susceptibility to chronic pancreatitis were identified by searching PubMed, Science Citation Index and Chinese National Knowledge Infrastructure (CNKI) databases, without a language limitation. Studies published between January 1966 and October 2013 were identified using the keywords “GSTM1” or “GSTT1” in combination with “pancreatitis”. Inclusion criteria were: (i) studies concerning the relationship between chronic pancreatitis and GSTM1 or GSTT1 genotype; (ii) case–control studies; (iii) data must include sample size, odds ratios (OR) and 95% confidence intervals (CI), as well as genetic distribution or other information that could help infer these data.

When studies included several separate chronic pancreatitis types (including alcoholic chronic pancreatitis [ACP], hereditary chronic pancreatitis [HCP], nonhereditary chronic pancreatitis [NHCP] and idiopathic chronic pancreatitis [ICP]), pooled data were used to identify the association between GSTM1 and GSTT1 genotypes with CP. When studies included several separate control groups (including inpatients without pancreatic disease, healthy controls, healthy alcoholics, nonalcoholic healthy volunteers and blood donors), data from these control groups were pooled for analysis.

Meta-analysis

Newcastle–Ottawa Scale (NOS) criteria were used to assess study quality. Those studies that met five or more NOS criteria were considered high quality.¹⁴ Meta-analysis was performed using Stata® version 12.0 (StataCorp, College Station, TX, USA). For GSTM1 and GSTT1, unadjusted OR and 95% CI from each study were used to estimate summary OR. I²-value and χ²-based Q-test were performed to assess heterogeneity. OR were pooled according to the Mantel–Haenszel fixed-effect model, and the significance of pooled OR was determined using Z-test. Publication bias was assessed via funnel plot and Egger’s test. Sensitivity analysis was conducted by removing one study at a time, to evaluate the quality and consistency of the meta-analysis findings. P-values <0.05 were considered statistically significant.

Results

The literature search identified 16 relevant publications. Of these, one review article, ¹⁵ seven articles regarding other diseases^16–22 and one study regarding a different gene were excluded.²³ The remaining seven studies satisfied all inclusion criteria and were included in the meta-analysis (GSTM1, 650 cases/1382 controls; GSTT1, 536 cases/1304 controls) (Table 1).^24–30 All publications were written in English and evaluated the GSTM1 genotype; six also evaluated GSTT1.^25–30 All studies were considered high quality, according to NOS criteria.

Table 1.

Characteristics of studies included in the meta-analysis.

First author	Year	Region	Race	Cases male/female	Controls male/female	Case type	Control type	Age, years (cases/controls)	Gene
Bartsch²⁴	1998	America Europe	American European	114 (92/22)	78 (49/29)	ACP NACP	Healthy volunteers/ inpatients without pancreatic disease	NA	GSTM1
Frenzer²⁵	2002	Australia	Caucasian	71 (61/10)	257 (166/91)	ACP	Healthy alcoholics and blood donors	53 ± NA/68 ± NA	GSTM1 GSTT1
Verlaan²⁶	2003	Holland	Dutch	142 (80/62)	261 (118/143)	ACP, HCP ICP	Adult healthy subjects and alcoholics	NA	GSTM1 GSTT1
Burim²⁷	2004	Brazil	Brazilian	14 (NA)	262 (NA)	ACP	Healthy alcoholics and non-alcoholics	NA	GSTM1 GSTT1
Schneider²⁸	2004	America	Caucasian	135 (NA)	183 (NA)	HCP	Healthy controls	NA	GSTM1 GSTT1
Rahman²⁹	2005	England	White	121 (78/43)	245 (123/122)	ACP, HCP ICP	Healthy controls	51 (19–86)/58 (18–92)	GSTM1 GSTT1
Maruyama³⁰	2010	Japan	Japanese	53 (NA)	96 (NA)	ACP	Healthy controls and alcoholics without pancreatic dysfunction	59.4 ± 12.9/49.4 ± NA	GSTM1 GSTT1

ACP, alcoholic chronic pancreatitis; NACP, non-alcoholic chronic pancreatitis; NA, data not available; HCP, hereditary chronic pancreatitis; ICP, idiopathic chronic pancreatitis.

Results of the meta-analysis for GSTM1 and risk of chronic pancreatitis (650 cases/1382 controls) are shown in Figure 1. There was significant heterogeneity (P = 0.042), no significant association between GSTM1 and chronic pancreatitis, and no significant publication bias.

Figure 1.

(a) Meta-analysis for the association between glutathione S-transferase M1 (GSTM1) polymorphism and risk of chronic pancreatitis. (b) Funnel plot for publication bias.^24–30

Findings of the meta-analysis for GSTT1 and chronic pancreatitis (536 cases/1304 controls) are shown in Figure 2. There was no significant heterogeneity, no significant association between chronic pancreatitis and GSTT1 and no significant publication bias.

Figure 2.

(a) Meta-analysis for the association between glutathione S-transferase T1 (GSTT1) polymorphism and risk of chronic pancreatitis. (b) Funnel plot for publication bias.^{24–27,29.30}

Findings of the meta-analysis for the association between ACP and GSTM1 (597 cases/1286 controls) are shown in Figure 3. There was no significant heterogeneity or publication bias. There was a significant association between ACP and GSTM1 (OR 1.16, 95% 1.03, 1.30).

Figure 3.

(a) Meta-analysis for the association between glutathione S-transferase M1 (GSTM1) polymorphism and risk of alcoholic chronic pancreatitis. (b) Funnel plot for publication bias.^25–30

The meta-analysis for GSTT1 and ACP (483 cases/1208 controls; Figure 4) found no significant heterogeneity, no significant association between ACP and GSTT1, and no significant publication bias.

Figure 4.

(a) Meta-analysis for the association between glutathione S-transferase T1 (GSTT1) polymorphism and risk of alcoholic chronic pancreatitis. (b) Funnel plot for publication bias.^25–27,29

Sensitivity analyses found that no individual study significantly altered the pooled results for any meta-analysis (data not shown).

Discussion

This meta-analysis is, to the best of our knowledge, the first systematic review of the association between chronic pancreatitis and GSTM1/GSTT1 genotype. Our findings indicate that GSTM1 is associated with ACP. Analysis of the association between GSTM1/GSTT1 and ACP indicated that GSTM1 null genotypes significantly decreased the risk of ACP.

This meta-analysis was based on a limited number of publications that studied several forms of chronic pancreatitis including ACP, HCP, NHCP and ICP. These types of chronic pancreatitis have different pathogeneses. For example, ACP is caused by alcohol consumption, and HCP is a rare chronic pancreatitis resulting from genetic factors.³¹ The inclusion of various forms of disease may be responsible for the lack of association between GSTM1/GSTT1 and the risk of chronic pancreatitis, but further studies are required to elucidate this.

Alcohol abuse is a serious medical and socio-economic problem.³² Consumption of large quantities of alcohol can cause severe oxidative stress in pancreatic cells, and lead to the production of superoxides and cytotoxic substances that cause DNA damage and cellular denaturation. Oxidative stress due to heavy drinking can cause chronic pancreatitis, with detoxification enzymes playing important roles in this process.³³ Polymorphisms in detoxification enzymes differ according to ethnicity.³⁴ GSTM1 and GSTT1 polymorphisms are associated with diseases including lung cancer,^35–37 type 2 diabetes mellitus³⁸ and acute leukaemia.³⁹ The present meta-analysis found a significant association between GSTM1 null genotypes and the risk of ACP. In contrast to our findings, another meta-analysis found that the GSTM1 null genotype was associated with a higher risk of oral cancer in Asians but not in Caucasians, and the GSTT1 null genotype was not related to oral cancer.⁴⁰ This apparent contradiction has several possible explanations: (i) our meta-analysis included a small number of studies; (ii) we observed significant heterogeneity; (iii) there was wide control-group variation in the included studies.

The present study found significant heterogeneity in the meta-analysis of the association between GSTM1 and chronic pancreatitis. Frequencies of GSTM1 and GSTT1 null genotypes differ widely according to ethnicity. GSTM1 null genotype frequencies are 42–60%, 42–54%, 16–36%, 54.6% and 55.5% in Caucasians, Asians, Africans, Middle East-Arabs and Egyptians, respectively; GSTT1 null genotype frequencies are 13–16%, 35–52%, 15–26%, 25% and 29.5% in these groups, respectively.⁴¹ Subgroup analyses according to ethnicity as well as meta-regression analyses are required to investigate the possible reasons for heterogeneity, but the present study did not include sufficient data to permit such an analysis.

Our meta-analysis has several limitations. First, although no evidence of publication bias was observed, our results were based on relatively few studies with small sample sizes, therefore publication bias cannot be definitively ruled out. Secondly, significant heterogeneity was observed in our analysis, and underlying heterogeneity may be due to subject age and sex, and variations in sample sizes, study design and genotyping methods. Thirdly, crude OR from each study were used to estimate summary OR and it is possible that some uncontrolled confounding was present. Finally, the majority of included studies did not test for Hardy–Weinberg equilibrium. Large, well-designed studies are required, in order to provide more accurate data.

In conclusion, the present meta-analysis revealed a significant association between the GSTM1 null genotype and the risk of ACP.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Kodydkova

Vavrova

Stankova

. Antioxidant status and oxidative stress markers in pancreatic cancer and chronic pancreatitis. Pancreas 2013; 42: 614–621.

Drenth

te Morsche

Jansen

. Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis. Gut 2002; 50: 687–692.

Witt

Luck

Hennies

. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000; 25: 213–216.

Tandan

Nageshwar Reddy

. Endotherapy in chronic pancreatitis. World J Gastroenterol 2013; 19: 6156–6164.

Spicak

Poulova

Plucnarova

. Pancreas divisum does not modify the natural course of chronic pancreatitis. J Gastroenterol 2007; 42: 135–139.

Maisonneuve

Lowenfels

Müllhaupt

. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005; 54: 510–514.

Howes

Lerch

Greenhalf

. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004; 2: 252–261.

Rebours

Boutron-Ruault

Schnee

. The natural history of hereditary pancreatitis: a national series. Gut 2009; 58: 97–103.

Etemad

Whitcomb

. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001; 120: 682–707.

10.

Strange

Spiteri

Ramachandran

. Glutathione-S-transferase family of enzymes. Mutat Res 2001; 482: 21–26.

11.

Hayes

Strange

. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 2000; 61: 154–166.

12.

Wang

Zhang

. Genetic polymorphisms of GSTT1, GSTM1, and NQO1 genes and diabetes mellitus risk in Chinese population. Biochem Biophys Res Commun 2006; 341: 310–313.

13.

Arruda

Grignolli

Gonçalves

. Prevalence of homozygosity for the deleted alleles of glutathione S-transferase mu (GSTM1) and theta (GSTT1) among distinct ethnic groups from Brazil: relevance to environmental carcinogenesis? Clin Genet 1998; 54: 210–214.

14.

Meng

Liu

. Glutathione S-transferase M1 null genotype meta-analysis on gastric cancer risk. Diagn Pathol 2014; 9: 122–122.

15.

Wang

Liao

. Researches on relationship between gene mutations and chronic pancreatitits. Int J Intern Med 2009; 36: 45–48 [In Chinese].

16.

Bekris

Shephard

Peterson

. Glutathione-s-transferase M1 and T1 polymorphisms and associations with type 1 diabetes age-at-onset. Autoimmunity 2005; 38: 567–575.

17.

Firozi

Zhang

. DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. Mutat Res 2002; 513: 37–48.

18.

Ladero

Martínez

García-Martin

. Polymorphisms of the glutathione S-transferases mu-1 (GSTM1) and theta-1 (GSTT1) and the risk of advanced alcoholic liver disease. Scand J Gastroenterol 2005; 40: 348–353.

19.

Hashemi

Eskandari-Nasab

Fazaeli

. Association of genetic polymorphisms of glutathione-S-transferase genes (GSTT1, GSTM1, and GSTP1) and susceptibility to nonalcoholic fatty liver disease in Zahedan, Southeast Iran. DNA Cell Biol 2012; 31: 672–677.

20.

Markova

Zotova

Savchenko

. Lymphocyte metabolism in patients with acute pancreatitis with different genotypes of GSTM1 and GSTT1 genes. Biomed Khim 2006; 52: 317–326. [in Russian, English Abstract].

21.

Khan

Husain

Choudhuri

. Association of polymorphism in alcohol dehydrogenase and interaction with other genetic risk factors with alcoholic liver cirrhosis. Drug Alcohol Depend 2010; 109: 190–197.

22.

Mazor

Koifman

Elkin

. Risk factors for serious adverse effects of thiopurines in patients with Crohn’s disease. Curr Drug Saf 2013; 8: 181–185.

23.

Nikolić

Stanković

Nišević

. GSTP1 Ile105Val polymorphism in Serbian patients with pancreatic diseases. J Med Biochem 2011; 30: 121–125.

24.

Bartsch

Malaveille

Lowenfels

. Genetic polymorphism of N-acetyltransferases, glutathione S-transferase M1 and NAD(P)H: quinone oxidoreductase in relation to malignant and benign pancreatic disease risk. The International Pancreatic Disease Study Group. Eur J Cancer Prev 1998; 7: 215–223.

25.

Frenzer

Butler

Norton

. Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis. J Gastroenterol Hepatol 2002; 17: 177–182.

26.

Verlaan

te Morsche

Roelofs

. Glutathione S-transferase Mu null genotype affords protection against alcohol induced chronic pancreatitis. Am J Med Genet A 2003; 120A: 34–39.

27.

Burim

Canalle

Martinelli Ade

. Polymorphisms in glutathione S-transferases GSTM1, GSTT1 and GSTP1 and cytochromes P450 CYP2E1 and CYP1A1 and susceptibility to cirrhosis or pancreatitis in alcoholics. Mutagenesis 2004; 19: 291–298.

28.

Schneider

Tögel

Barmada

. Genetic analysis of the glutathione s-transferase genes MGST1, GSTM3, GSTT1, and GSTM1 in patients with hereditary pancreatitis. J Gastroenterol 2004; 39: 783–787.

29.

Rahman

Nanny

Ibrahim

. Genetic polymorphisms of GSTT1, GSTM1, GSTP1, MnSOD, and catalase in nonhereditary chronic pancreatitis: evidence of xenobiotic stress and impaired antioxidant capacity. Dig Dis Sci 2005; 50: 1376–1383.

30.

Maruyama

Harada

Yokoyama

. Association analyses of genetic polymorphisms of GSTM1, GSTT1, NQO1, NAT2, LPL, PRSS1, PSTI, and CFTR with chronic alcoholic pancreatitis in Japan. Alcohol Clin Exp Res 2010; 34(Suppl 1): S34–S38.

31.

Rosendahl

Bödeker

Mössner

. Hereditary chronic pancreatitis. Orphanet J Rare Dis 2007; 2: 1–1.

32.

Greenfield

Midanik

Rogers

. A 10-year national trend study of alcohol consumption, 1984-1995: is the period of declining drinking over? Am J Public Health 2000; 90: 47–52.

33.

Sreeja L Syamala V Hariharan S . Possible risk modiﬁcation by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population. J Hum Genet 2005; 50: 618–627.

34.

Verlaan

Harbers

Pap

. Paraoxonase 1-192Q allele is a risk factor for idiopathic chronic pancreatitis. Mol Diagn 2005; 9: 9–15.

35.

Carlsten

Sagoo

Frodsham

. Glutathione S-transferase M1 (GSTM1) polymorphisms and lung cancer: a literature-based systematic HuGE review and meta-analysis. Am J Epidemiol 2008; 167: 759–774.

36.

Shi

Zhou

Wang

. CYP1A1 and GSTM1 polymorphisms and lung cancer risk in Chinese populations: a meta-analysis. Lung Cancer 2008; 59: 155–163.

37.

Raimondi

Paracchini

Autrup

. Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review. Am J Epidemiol 2006; 164: 1027–1042.

38.

Saadat

. Null genotypes of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms increased susceptibility to type 2 diabetes mellitus, a meta-analysis. Gene 2013; 532: 160–162.

39.

Tang

Zhang

Cheng

. Glutathione-S-transferase polymorphisms (GSTM1, GSTT1 and GSTP1) and acute leukemia risk in Asians: a meta-analysis. Asian Pac J Cancer Prev 2014; 15: 2075–2081.

40.

Zhang

Hao

Shi

. Glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null polymorphisms, smoking, and their interaction in oral cancer: a HuGE review and meta-analysis. Am J Epidemiol 2011; 173: 847–857.

41.

Zaki MA, Moghazy TF, El-Deeb MMK, et al. Glutathione S-transferase M1, T1 and P1 gene polymorphisms and the risk of developing type 2 diabetes mellitus in Egyptian diabetic patients with and without diabetic vascular complications. Alex J Med 2014. DOI: 10.1016/j.ajme.2014.03.003.

Glutathione S-transferase M1 and glutathione S-transferase T1 genotype in chronic pancreatitis: A meta-analysis

Abstract

Objective

Methods

Results

Conclusion

Keywords

Introduction

Materials and methods

Meta-analysis

Results

Discussion

Footnotes

Declaration of conflicting interest

Funding

References