Chan, AOO

Chi, HC

Chu, KM

Huang, C

Ko, S

Lam, KF

Rashid, A

Shiu, KL

Suet, YL

Wai, MH

Xia, HH

Yun, WS

HKU Scholars Hub

TitleAssociation between Helicobacter pylori infection andinterleukin 1β polymorphism predispose to CpG islandmethylation in gastric cancer [4]Author(s) Chan, AOO; Chu, KM; Huang, C; Lam, KF; Suet, YL; Yun, WS;Ko, S; Xia, HH; Chi, HC; Wai, MH; Shiu, KL; Rashid, ACitation Gut, 2007, v. 56 n. 4, p. 595-597Issued Date 2007URL http://hdl.handle.net/10722/57538Rights Gut. Copyright © B M J Publishing Group.doi:10.1136/gut.2006.113258  2007;56;595-597 Gut  and Asif Rashid Yun Wei Sun, Samuel Ko, Harry H Xia, Chi Hin Cho, Wai Mo Hui, Shiu Kum Lam Annie On On Chan, Kent-Man Chu, Camy Huang, Kwok Fai Lam, Suet Yi Leung,   island methylation in gastric cancerCpGand interleukin 1ß polymorphism predispose to  infectionHelicobacter pyloriAssociation between  http://gut.bmj.com/cgi/content/full/56/4/595Updated information and services can be found at:  These include: References   http://gut.bmj.com/cgi/content/full/56/4/595#BIBLThis article cites 9 articles, 7 of which can be accessed free at:  serviceEmail alertingtop right corner of the article Receive free email alerts when new articles cite this article - sign up in the box at the Notes    http://journals.bmj.com/cgi/reprintformTo order reprints of this article go to:  http://journals.bmj.com/subscriptions/ go to: GutTo subscribe to  on 2 October 2008 gut.bmj.comDownloaded from status and hepatic steatosis found in our studymay thus reflect the changes in fat distributionduring menopausal transition.Causal diagrams enable the accurate selec-tion of covariables from a variety of potentialvariables influencing the studied association. Ithas been shown that an arbitrary inclusion ofvariables in multivariable models may not onlylead to an underestimation of the associationof interest but also introduce bias in theanalyses.5 According to our directed acyclicgraphs, metabolic factors should be regarded asmediators rather than confounders for therelationship investigated.We conclude that menopausal status isassociated with hepatic steatosis. The prognos-tic relevance of this association with respect toincident cardiovascular disease and diabeteshas to be proved.Henry Vo¨lzkeInstitute of Epidemiology and Social Medicine,University of Greifswald, Greifswald, GermanySabine SchwarzClinical Research Center of Women’s Health, Charite´Universita¨tsmedizin, Berlin, GermanySebastian E BaumeisterInstitute of Epidemiology and Social Medicine,University of Greifswald, Greifswald, GermanyHenri WallaschofskiDepartment of Gastroenterology, Endocrinology andNutrition, University of Greifswald, Greifswald,GermanyChristian SchwahnInstitute of Epidemiology and Social Medicine,University of Greifswald, Greifswald, GermanyHans Jo¨rgen GrabeClinic of Psychiatry, University of Greifswald,Greifswald, GermanyThomas KohlmannInstitute for Community Medicine, University ofGreifswald, Greifswald, GermanyUlrich JohnInstitute of Epidemiology and Social Medicine,University of Greifswald, Greifswald, GermanyMartina Do¨renClinical Research Center of Women’s Health, Charite´Universita¨tsmedizin, Berlin, GermanyCorrespondence to: Dr Henry Vo¨lzke, Department ofEpidemiology and Social Medicine, Ernst Moritz ArndtUniversity, Walther Rathenau Street 48, D-17487Greifswald, Germany; voelzke@uni-greifswald.dedoi: 10.1136/gut.2006.115345References1 Bruno S, Maisonneuve P, Castellana P, et al.Incidence and risk factors for non-alcoholicsteatohepatitis: prospective study of 5408 womenenrolled in Italian tamoxifen chemoprevention trial.BMJ 2005;330:932.2 Nemoto Y, Toda K, Ono M, et al. Alteredexpression of fatty acid-metabolizing enzymes inaromatase-deficient mice. J Clin Invest2000;105:1819–25.3 John U, Greiner B, Hensel E, et al. Study of Health InPomerania (SHIP): a health examination survey inan east German region: objectives and design. SozPraventivmed 2001;46:186–94.4 Volzke H, Robinson DM, Kleine V, et al. Hepaticsteatosis is associated with an increased risk ofcarotid atherosclerosis. World J Gastroenterol2005;11:1848–53.5 Greenland S, Pearl J, Robins JM. Causal diagramsfor epidemiologic research. Epidemiology1999;10:37–48.6 Park SH, Jeon WK, Kim SH, et al. Prevalence andrisk factors of non-alcoholic fatty liver diseaseamong Korean adults. J Gastroenterol Hepatol2006;21(Part 1):138–43.7 Clark JM, Brancati FL, Diehl AM. Nonalcoholic fattyliver disease. Gastroenterology 2002;122:1649–57.8 Krotkiewski M, Bjorntorp P, Sjostrom L, et al.Impact of obesity on metabolism in men andwomen. Importance of regional adipose tissuedistribution. J Clin Invest 1983;72:1150–62.9 Poehlman ET, Toth MJ, Gardner AW. Changes inenergy balance and body composition atmenopause: a controlled longitudinal study. AnnIntern Med 1995;123:673–5.10 Busetto L, Tregnaghi A, De Marchi F, et al. Livervolume and visceral obesity in women with hepaticsteatosis undergoing gastric banding. Obes Res2002;10:408–11.Association between Helicobacterpylori infection and interleukin 1bpolymorphism predispose to CpGisland methylation in gastriccancerInterleukin1b (IL1b) is upregulated in thepresence of Helicobacter pylori infection.1 IL1bpolymorphisms with T/T and T/C genotypesenhance IL1b production, and are associatedwith an increased risk of H pylori-inducedhypochlorhydria2 and gastric cancer.3 Therelationship between H pylori and CpG islandmethylation has been repeatedly reported.4–6 Ithas been reported that IL1b can modulate CpGisland methylation through activation of DNAmethyltransferase and hence repress geneexpression.7 We therefore hypothesised thatpatients with H pylori infection and IL1 poly-morphism, by the production of IL1b, arepredisposed to gastric cancer developmentthrough the CpG island methylation pathway.We obtained surgical specimens and theircorresponding peripheral blood from 98 con-secutive patients with gastric cancer admittedto Queen Mary Hospital, Hong Kong. Thisstudy was approved by the ethics committee.The methylation status of the death-associatedprotein-kinase, O6-methyl-guanine methyl-Figure 1 Causal diagram for the association between menopause and hepatic steatosis. (A) A minimum set of confounders would include age, smokingstatus and unmeasured confounders such as common genetic factors. (B) In contrast with (A), the diagram considers additional causal effects of alcoholconsumption and nutrition on menopausal status (dotted arrows). In this scenario, a minimum set of confounders would include age, smoking status,nutritional factors, alcohol consumption and unmeasured confounders such as common genetic factors.Funding: This work is part of the Community MedicineResearch (CMR) net of the University of Greifswald,Germany, which is funded by the Federal Ministry ofEducation and Research (grant no. ZZ9603), theMinistry of Cultural Affairs and the Social Ministry ofthe Federal State of Mecklenburg-West Pomerania. TheCMR encompasses several research projects, which aresharing data of the population-based Study of Health inPomerania (http://www.community-medicine.de).Competing interests: None.PostScript 595www.gutjnl.com on 2 October 2008 gut.bmj.comDownloaded from transferase, p16 genes8 and E-cadherin9 pro-moter was determined by methylation-specificpolymerase chain reaction. Genotyping of IL1polymorphism was performed as reportedpreviously.2 10 H pylori status was determinedby serology using a commercially availableELISA kit (pylori DTect ELISA, DiagnosticTechnology Pty, New South Wales, Australia)and histology using Giemsa stain. H pyloristatus was considered to be positive if eithertest showed a positive result.H pylori infection was present in 65% (64) ofpatients. In the IL1b gene, the T and C alleles atthe -511 locus of the IL1b gene were in neartotal linkage disequilibrium with the C and Talleles at the -31 locus. Analysis was thereforerestricted to the IL1b-511 locus, but theassociations with the -31 locus were identical.The allele frequencies at IL1b-511 were 16%(16), 59% (58) and 25% (24) for C/C, C/T and T/T genotypes, respectively. Methylation ofmethylguanine-DNA methyltransferase, E-cad-herin, death-associated protein and p16 waspresent in 30% (29), 59% (58), 43% (42) and45% (44) of patients, respectively (examplesshown in fig 1). Patients with the T/T or T/Cgenotype showed an increased odds ratio (OR)of 6.4 and 3.7, respectively, with respect to theC/C genotype for developing methylation attwo or more genes (table 1). This OR fordeveloping methylation at two or more geneswas markedly increased in patients with Hpylori infection and with the T/T (12.5) or T/C(5.6) genotype with respect to the C/C genotypebut was not present in patients without H pyloriinfection. However, no association of thegenotype on an individual methylation markerwas seen (table 1). Also, there was noassociation between the number of genesmethylated and H pylori status, no differencein age between those with or without methyla-tion at two or more genes, and anatomical site,except that lower stages (stages I and II) wereassociated with more frequent methylation attwo or more genes (table 1).The underlying mechanisms or the environ-mental factors governing the simultaneousmethylation of multiple genes in gastric cancerare still unclear. Hmadcha et al7 have reportedgene silencing due to methylation at the CpGisland in the presence of IL1b. We havepreviously reported that eradication of H pylorimay result in reversal of methylation at tumoursuppressor genes in non-lesional gastricmucosa.5 Our study may further support theidea that H pylori infection stimulates theproduction of IL1b, and the presence ofthe proinflammatory T allele further enhancesthe production of IL1b. The synergistic effect ofthese two factors was observed in our study tocorrelate with the increased frequency ofmethylated genes. Thus, patients with H pyloriinfection and IL1b-511 T/T genotype may bepredisposed to gastric cancer through the CpGisland methylation pathway.AcknowledgementsThis work was supported by the GastrointestinalCancer Research Fund, University of Hong Kong.Annie On On ChanDepartment of Medicine, The University of Hong Kong,Hong KongKent-Man ChuDepartment of Surgery, Statistics & Actuarial Science,The University of Hong Kong, Hong KongCamy Huang, Kwok Fai LamDepartment of Medicine, The University of Hong Kong,Hong KongSuet Yi LeungDepartment of Pathology, The University of Hong Kong,Hong KongYun Wei SunDepartment of Medicine, The University of Hong Kong,Hong KongSamuel KoDepartment of Surgery, Statistics & Actuarial Science,The University of Hong Kong, Hong KongHarry H XiaDepartment of Medicine, The University of Hong Kong,Hong KongChi Hin Cho, Wai Mo Hui, Shiu Kum LamDepartment of Medicine, The University of Hong Kong,Hong KongAsif RashidDepartment of Pathology, MD Anderson Cancer Center,TX, USATable 1 Correlation between methylation at two or more genes and IL1b-511 genotype, and other tumour characteristicsLess than two genes methylated Two or more genes methylated OR 95% CILocus at IL1b-511 (whole group, n = 98), overall p = 0.02C/C 56.2% (9) 43.8% (7) 1C/T 25.9% (15) 74.1% (43) 3.7 1.2 to 12.1T/T 16.7% (4) 83.3% (20) 6.4 1.6 to 30.7Locus at IL1b-511 (H pylori positive, n = 64) overall p = 0.03C/C 62.5% (5) 37.5% (3) 1C/T 23.1% (9) 76.9% (30) 5.6 1.2 to 31.7T/T 11.8% (2) 88.2% (15) 12.5 1.8 to 125.7Locus at IL1b-511 (H pylori negative, n = 34), overall p = 0.61C/C 50% (4) 50% (4) 1C/T 31.6% (6) 68.4% (13) 2.2 0.4 to 12.4T/T 28.6% (2) 71.4% (5) 2.5 0.3 to 25.9H pylori status, overall p = 0.29+ 25% (16) 75% (48) 1.6 0.7 to 42 35% (12) 65% (22) 1Patient age (years), overall p = 0.44(60 23% (7) 77% (23) 1.60 31% (21) 69% (47) 0.7 0.2 to 1.7Tumour stage, overall p = 0.004I and II 12.8% (5) 87.2% (34)III and IV 39% (23) 61% (36) 0.23 0.07 to 0.63Anatomical site, overall p = 0.55Antrum 27% (20) 73% (54) 1Non-antrum 33.3% (8) 66.7% (16) 0.7 0.3 to 2Histology (Lauren’s classification), overall p = 0.09Intestinal 21.2% (11) 78.8% (42) 1Diffuse 32.3% (10) 67.7% (21) 0.55 0.2 to 1.5Mixed 50.0% (7) 50.0% (7) 0.26 0.1 to 0.9Methylation status stratified by genotypeH pylori positive H pylori negativeC/C 62.5% (5/8) 50% (4/8) 0.6 0.07 to 4.4 (p = 0.61)C/T 23% (9/39) 68% (13/19) 1.5 0.4 to 5.2 (p = 0.49)T/T 11.7% (2/17) 71% (5/7) 3 0.3 to 31.1 (p = 0.33)*ORs of two or more genes methylated, with the first group being the referent group.596 PostScriptwww.gutjnl.com on 2 October 2008 gut.bmj.comDownloaded from Correspondence to: Dr A On On Chan, Department ofMedicine, Division of Gastroenterology andHepatology, University of Hong Kong, China;aoochan@hku.hkdoi: 10.1136/gut.2006.113258References1 Yamaoka Y, Kita M, Kodama T, et al. Induction ofvarious cytokines and development of severemucosal inflammation by cag A gene positiveHelicobacter pylori strains. Gut 1997;41:442–51.2 Furuta T, El-Omar EM, Xiao F, et al. Interleukin1beta polymorphisms increase risk ofhypochlorhydria and atrophic gastritis and reducerisk of duodenal ulcer recurrence in Japan.Gastroenterology 2002;123:92–105.3 El-Omar EM, Carrington M, Chow WH, et al.Interleukin-1 polymorphisms associated withincreased risk of gastric cancer. Nature2000;404:398–402.4 Chan AO, Lam SK, Wong BC, et al. Promotermethylation of E-cadherin gene in gastric mucosaassociated with Helicobacter pylori infection and ingastric cancer. Gut 2003;52:502–6.5 Chan AO, Peng JZ, Lam SK, et al. Disappearing ofE-cadherin promoter hypermethylation status afterHelicobacter pylori eradication in patients withchronic gastritis. Gut 2006;55:463–8.6 Maekita T, Nakazawa K, Mihara M, et al. Highlevels of aberrant DNA methylation in Helicobacterpylori-infected gastric mucosae and its possibleassociation with gastric cancer risk. Clin Cancer Res2006;12:989–95.7 Hmadcha A, Bedoya FJ, Sobrino F, et al.Methylation-dependent gene silencing induced byinterleukin 1beta via nitric oxide production. J ExpMed 1999;190:1595–604.8 Kang GH, Lee HJ, Hwang KS, et al. Aberrant CpGisland hypermethylation of chronic gastritis, inrelation to aging, gender, intestinal metaplasia, andchronic inflammation. Am J Pathol2003;163:1551–6.9 Herman JG, Graff JR, Myohanen S, et al.Methylation-specific PCR: a novel PCR assay formethylation status of CpG islands. Proc Natl AcadSci U S A 1996;93:9821–66.10 Tarlow JK, Blakemore AI, Lennard A, et al.Polymorphism in human IL-1 receptor antagonistgene intron 2 is caused by variable numbers of an86-bptandem repeat. Hum Genet 1993;9:403–4.Restricted use of albumin forspontaneous bacterial peritonitisSpontaneous bacterial peritonitis (SBP) mayprecipitate deterioration of circulatory functionwith severe hepatic insufficiency, hepatic ence-phalopathy, and type-1 hepatorenal syndrome(HRS) and has 30% hospital mortality despiteinfection resolution.1 Predictors of this acute-on-chronic liver failure include ascitic fluidconcentrations of granulocytes and cytokinesand renal and hepatic insufficiency at diag-nosis.1–3 Endotoxemia and the inflammatoryresponse precipitate renal failure (RF) byaccentuating splanchnic vasodilatation andimpairing cardiac function.3–5 Compensatoryactivation of the renin-angiotensin and sympa-thetic nervous systems further decrease renalperfusion. Volume expansion with albumin(1.5 g/kg day one, 1 g/kg day three) signifi-cantly reduces the incidence of HRS andhospital mortality.2In the sole reported trial, only patients withserum bilirubin (bili) .68.4 mmol/l, blood ureanitrogen (BUN).30 mg/dl or serum creatinine(Cr) .88.4 mmol/l appeared to benefit fromalbumin.2 In this report we describe a ther-apeutic protocol involving 38 episodes in 28patients at the Mount Sinai Medical CenterNew York and the Barcelona Hospital Clinic inwhich albumin (1.5 g/Kg on the day ofdiagnosis, 1 g/Kg on the third day; HumanAlbumin 25%, ZBL Bioplasma AG, Berne,Switzerland) was restricted to those at highrisk for RF (bili . 68.4 mmol/l or Cr.88.4 mmol/l) (table 1). Diagnosis and treat-ment of SBP were based on established guide-lines.6 Cardiovascular and splanchnichemodynamics and the activity of the renin-angiotensin system and inflammatory responsewere assessed in 6 low-risk cases fromBarcelona at SBP diagnosis and resolution.3 7 8ABCDS22 S23 S24 S25U M U MU MU MU MU MMGMT MFECAD MFP16 MFDAPK MFP16 151 bp (U)150 bp (M)DAPK 106 bp (U)100 bp (M)MGMT 93 bp (U)81 bp (M)ECAD 97 bp (U)116 bp (M)Positive  ddH2OS19 S20 S21 S22U M U MU MU MU MU MPositive  ddH2OS20 S21 S22 S23U M U MU MU MU MU MPositive  ddH2OFigure 1 Examples of polymerase chain reaction products of P16, DAPK, E-cadherin (ECAD) and O2-methyl-guanine methyl transferase (MGMT) genes. The lower panel shows segments of the methylatedsequences of these gene products. Methylated cytosine residues that are unchanged are shown asunderlined.Competing interests: None.PostScript 597www.gutjnl.com on 2 October 2008 gut.bmj.comDownloaded from 

Association between Helicobacter pylori infection and interleukin 1β polymorphism predispose to CpG island methylation in gastric cancer [4]

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Association between Helicobacter pylori infection and interleukin 1β polymorphism predispose to CpG island methylation in gastric cancer [4]

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