BR Biomedical Reports 2049-9434 2049-9442 D.A. Spandidos 10.3892/br.2018.1048 BR-0-0-1048 Articles Association between heme oxygenase-1 gene promoter polymorphisms and cancer susceptibility: A meta-analysis WangRui 1 ShenJun 2 YangRui 3 WangWan-Guo 3 YuanYe 3 GuoZhong-Hua 3 Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China Department of Cardiology, Renmin Hospital, Hubei University of Medicine Shiyan, Hubei 442000, P.R. China Department of Orthopedics, People's Hospital of Dongxihu District, Wuhan, Hubei 430040, P.R. China Correspondence to: Dr Zhong-Hua Guo, Department of Orthopedics, People's Hospital of Dongxihu District, 81 Ring Mountain Road, Wuhan, Hubei 430040, P.R. China, E-mail: yarer0@163.com 03 2018 25 01 2018 8 3 241 248 09062017 06112017 Copyright: © Wang et al. 2018 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Numerous studies have focused on the association between heme oxygenase-1 (HO-1) gene promoter polymorphisms and susceptibility to cancer; however, results remain ambiguous. The present systematic Human Genome Epidemiology review and meta-analysis aimed to clarify this association. A systematic search was used to assess the association of HO-1 gene polymorphisms with cancer susceptibility in the PubMed, Web of Science, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure databases, with all reviewed studies published before April 10, 2017. Review Manager 5.3 and Stata 12.0 software were used to perform the meta-analysis. A total of 14 studies were included in the analysis. Overall, no significant associations of the HO-1 (GT)n and T(−413)A polymorphisms with cancer susceptibility were identified. However, subgroup analyses by ethnicity and cancer type indicated that the LL and L-allele (LL+LS) genotypes of HO-1 (GT)n were associated with increased susceptibility to cancer compared with the SS+SL and SS genotypes in the following subgroups: East Asian [LL+LS vs. SS: odds ratio (OR)=1.51, 95% confidence interval (CI)=1.11–2.05, P=0.0003; LL vs. SS+SL: OR=1.44, 95% CI=1.04–2.01, P=0.03; LL vs. SS: OR=1.64, 95% CI=1.07–2.52, P=0.02]; squamous cell carcinoma (LL+LS vs. SS: OR=1.78, 95% CI=1.35–2.34, P<0.05; LL vs. SS+SL: OR=1.71, 95% CI=1.34–2.18, P<0.05; LL vs. SS: OR=2.26, 95% CI =1.62–3.14, P<0.05); and digestive tract cancer + East Asian (LL+LS vs. SS: OR=1.56, 95% CI=1.22–1.98, P<0.05; LL vs. SS: OR=1.80, 95% CI=1.06–3.05, P<0.05). These findings indicated that there was no association of the HO-1 (GT)n and T(−413)A polymorphisms with cancer susceptibility, while the L-allele genotypes (LL and LS) of HO-1 (GT)n may be susceptibility factors for cancer in East Asian, digestive tract cancer in East Asian and squamous cell carcinoma populations. Due to limitations of the reviewed studies, additional large-scale and refined studies are now required to confirm the present findings.

 cancer genetics polymorphism heme oxygenase-1 meta-analysis Introduction

Cancer has major impacts on public health and the economy in both developing and developed countries (1). In 2012, over 14.1 million new cases of cancer were diagnosed and 8.2 million people succumbed due to cancer worldwide (2). Certain susceptibility factors, including heavy alcohol intake, tobacco use, high calorific diet and chemical dyes, have been identified as potential susceptibility factors for cancer (3). An aging population, increased environmental pollution and longer life expectancy, have also contributed to increased incidence rates of cancer (4). However, the underlying pathogenic mechanisms of cancer remain to be fully elucidated.

Previous studies have indicated that the transition from normal to pre-cancer and cancer cells is a result of a multi-step accumulation of genetic and epigenetic modifications (5,6). Recent studies have focused on the interaction between heme oxygenase-1 (HO-1) gene polymorphisms and cancer (7,8). HO-1 is a subtype of HO, which serves an important role as a rate-limiting enzyme in the conversion of heme into biliverdin, CO and Fe2+ (9). HO-1 and its products may regulate the levels of reactive oxygen species (ROS) through anti-apoptotic, anti-oxidation, anti-inflammatory effects, and by mediating autophagy (10). In turn, ROS may modulate tumorigenesis by causing cell apoptosis/necrosis or an accumulation of DNA damage (11). Two loci of the HO-1 gene have been focused on when regarding its potential association with cancer, namely the (GT)n repeat length polymorphism [which according to repeat length is divided into two classes: S (short) and L (long)] and T(−413)A (rs2071746) (12–14); however, results so far are not conclusive. Both loci are localized on chromosome 22q12 and have been identified in the HO-1 gene promoter region (15).

Although numerous studies on the correlation between these two loci and cancer have been conducted, the results are ambiguous (11–14,16,17–29). Based on previous observations, two previous meta-analyses focused on the association of HO-1 gene polymorphisms with cancer susceptibility (30,31), though again the data appears inconclusive. Therefore, to clarify the associations between HO-1 gene polymorphisms and cancer susceptibility, an updated meta-analysis was performed in the present study.

 Materials and methods <sec> <title>Protocol

The current meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (32).

 Identification and eligibility of relevant studies

The electronic databases PubMed (https://www.ncbi.nlm.nih.gov/pubmed), Web of Science (http://isiknowledge.com), the Cochrane Library (http://www.cochranelibrary.com/), Wanfang Data (http://www.wanfangdata.com.cn) and China National Knowledge Infrastructure (http://www.cnki.net/) were searched for all studies published before April 10, 2017 that had examined the association between HO-1 gene polymorphisms and cancer. The search strategy was based on combinations of the key words ‘heme oxygenase-1 or HMOX1 or HO-1’, ‘polymorphism or susceptibility’ and ‘cancer or carcinoma or tumor or malignant or neoplasm’. English or Chinese-language studies were included in the literature search without any special restriction on the source of cases (cancer patients) and controls (normal subjects, free from cancer). Studies in the form of reviews or commentaries and studies in animals or those using cell lines were excluded.

 Inclusion criteria

Included studies met the following criteria: i) Case-control study or cohort study; ii) focus on the association of HO-1 (GT)n and T(−413)A polymorphisms with cancer; iii) provision of an odds ratio (OR) with 95% confidence intervals (CIs) or sufficient data for calculation of OR and 95% CIs.

 Data extraction

The following information were extracted from each eligible study: Name of author, year of publication, ethnicity or geographic location of study subjects, cancer type, study design, genotyping method, cohort age, cohort sex ratio, use of age and sex matching, and consistency of genotype frequencies with Hardy-Weinberg Equilibrium (HWE). Allele and genotype frequencies were extracted or calculated from the published data in the included studies. The bibliographic search and data extraction were carried out by two independent reviewers, and disagreements were resolved by discussion among the reviewers.

 Data synthesis and analysis

The meta-analysis was performed using Review Manager 5.3 (http://tech.cochrane.org/revman) and Stata 12.0 software (StataCorp LP, College Station, TX, USA). The χ2 test was applied to verify whether the genotype distribution of the control group in each study conformed to HWE. Four genetic models were used: An allele model (L vs. S); a dominant model (LL vs. SS+SL); a co-dominant model (LL vs. SS); and a recessive model (LL+LS vs. SS). To evaluate sources of heterogeneity across studies, subgroup analyses were conducted based on ethnicity, cancer type, tumor location and HWE. Heterogeneity was determined using I2 statistics; when I2 <50%, the fixed-effects model was used, while for I2 >50%, the random-effects model was used and meta-regression analysis was performed to detect the source of heterogeneity. Stratification analyses were performed based on the outcome of meta-regression analysis. Results were determined as ORs with 95% CIs and P-values. P<0.05 was considered to indicate statistical significance. Sensitivity analyses were conducted by omitting each study in turn and by excluding studies with departure from HWE. Funnel plots and Egger's/Begg's tests were used to visualize the overall effect and to evaluate publication bias, respectively.

 Results <sec> <title>Study characteristics

The systematic literature search identified 206 potentially relevant articles. After excluding duplications, 187 titles and abstracts were screened. A total of 165 articles were excluded due to irrelevance to the aim of the present study. The remaining 22 articles underwent full-text examination, and two studies (33,34) were excluded due to their analysis of the same subjects reported in two different studies (16,19), with the latter studies selected due to their inclusion of more data. Another two studies (20,35) were excluded as genotype data could not be obtained, one study (7) was not a case-control study, and two studies (8,36) used cancer patients in the control group. Thus, 14 studies (9,13,15,16,18–26) were included in the meta-analysis, among which were 12 studies (9,13,15,16,18–24) on (GT)n repeat length polymorphism and three studies (21,25,26) on T(−413)A single nucleotide polymorphism (SNP) associations with cancer susceptibility (Table I).

 Meta-analysis HO-1(GT)n repeat length polymorphism and susceptibility to cancer

The association between the HO-1(GT)n repeat length polymorphism and cancer susceptibility was investigated in 12 relevant studies involving 2,471 patients with cancer and 2,654 normal controls. No significant associations were identified between susceptibility to overall cancer and the SNP in any of the four genetic models screened (L vs. S, LL+LS vs. SS, LL vs. SS+SL, LL vs. SS). However, subgroup analyses by ethnicity and cancer type indicated that the HO-1(GT)n repeat length polymorphism was associated with cancer susceptibility in the East Asian, squamous cell carcinoma and digestive tract cancer + East Asian subgroups (Table II).

The first subgroup analysis was conducted according to ethnicity. It was identified that the LL and L-allele (LL+LS) genotypes were associated with increased susceptibility to cancer compared with the SS+SL and SS genotypes in the East Asian subgroup (LL+LS vs. SS: OR=1.51, 95% CI=1.11–2.05, P=0.0003; LL vs. SS+SL: OR=1.44, 95% CI=1.04–2.01, P=0.03; LL vs. SS: OR=1.64, 95% CI=1.07–2.52, P=0.02). By contrast, no significant associations were identified in the genetic models with non-East Asian (Caucasian, American, West Asian) populations (Table II).

The second subgroup analysis was conducted according to cancer type. It was also identified that patients carrying the LL genotype and L-allele genotypes (LL+LS) had increased susceptibility to squamous cell carcinoma compared with SS+SL and SS genotype carriers (LL+LS vs. SS: OR=1.78, 95% CI=1.35–2.34, P<0.0001; LL vs. SS+SL: OR=1.71, 95% CI=1.34–2.18, P<0.0001; LL vs. SS: OR=2.26, 95% CI=1.62–3.14, P<0.0001). However, no associations were observed in any of the four allelic genetic models with digestive tract cancer (Table II).

The third subgroup analysis was conducted according to tumor location and ethnicity. It was observed that patients carrying the LL genotype and L-allele genotypes (LL+LS) had increased susceptibility to digestive tract cancer compared with SL+SS and SS genotype carriers in the East Asian subgroup (LL+LS vs. SS: OR=1.56, 95% CI=1.22–1.98, P=0.003; LL vs. SS: OR=1.80, 95% CI=1.06–3.05, P=0.03). However, no associations were observed in the allelic and co-dominant genetic models regarding cancer susceptibility in the digestive tract cancer + non-East Asian and squamous cell carcinoma + East Asian/non-East Asian subgroups (Table II).

Subgroup analysis was also conducted according to HWE. No significant associations were identified between susceptibility to overall cancer and HO-1(GT)n in any of the four genetic models for cases that met or deviated from HWE (Table II).

 HO-1 T(−413)A SNP and cancer susceptibility

There were 3 studies that investigated the association between the HO-1 T(−413)A SNP and digestive system neoplasms. The meta-analysis suggested that there were no significant associations between the HO-1 T(−413)A polymorphism and overall cancer susceptibility in any of the genetic models (Table II).

 Sensitivity analysis

The stability of the results was assessed by sensitivity analyses, which were conducted for all genetic comparisons by omitting each study in turn. It was determined that no study had substantial influence on the pooled ORs in all genetic models, suggesting the results were stable. In addition, the ORs were unaltered by omitting studies in which the genotype distribution in controls departed from HWE.

 Publication bias

Funnel plots and Begg's tests were used to evaluate the publication bias of the included studies. From the funnel plots and Begg's tests, no indication of publication bias was identified in the studies on the (GT)n repeat length polymorphism or T(−413)A SNP (Fig. 1 and Table III).

 Discussion

There are three isoforms of HO in human, namely HO-1, HO-2 and HO-3 (37). HO-1, also known as heat shock protein 32, is upregulated by a number of chemical and physical stresses (38). Animal experiments have confirmed that HO-1 localizes to endoplasmic reticulum, caveolae, mitochondria and the nucleus, indicating the possibility that HO-1 serves roles in addition to heme degradation (9). HO-1 expression is elevated in a variety of tumors and neoplasms (39). HO-1 and its products may promote tumor growth through anti-apoptotic, anti-oxidation, anti-inflammatory and proliferative effects, and by mediating autophagy (40–42). Thus, HO-1 activity is considered to be conducive to tumor growth (43).

Numerous studies have demonstrated that the LL genotype of the HO-1(GT)n locus may increase cancer susceptibility (12,13,16,18,19,21). However, the associations identified between the HO-1 polymorphisms and cancer susceptibility are inconsistent, and other studies have come to other conclusions (15,17,26). Additionally, two previously published meta-analyses reported different conclusions (30,31). More recently, a number of studies on this topic have been published (19–25). Therefore, the present study conducted an update meta-analysis following different inclusion criteria to that used previously to evaluate the association of HO-1 polymorphisms with cancer susceptibility.

The present meta-analysis indicated that there was no significant association between the HO-1(GT)n repeat length polymorphism and overall cancer susceptibility. However, on subgroup analysis, the LL and L-allele (LL+LS) genotypes of the HO-1(GT)n locus were associated with a higher susceptibility to squamous cell carcinoma, digestive tract cancer in East Asian carriers and overall cancer in East Asian carriers compared with the SS and/or SL genotype. By contrast, this association with susceptibility was not observed in any of the four genetic models in non-East Asian (Caucasian, American and West Asian) populations. This may be due to differences in life styles, ethnicity, region, cancer type and tumor location, among other factors. The present study also identified no significant associations between the HO-1 T(−413)A SNP and overall cancer susceptibility. These results are consistent with a previous study by Luo et al (31).

However, the present analysis had a number of limitations, as follows: i) The language was restricted to English and Chinese, which excluded eligible studies in other languages; ii) the sample size of included studies on HO-1 T(−413)A SNP was markedly small; iii) the thresholds defined as class S (short) were not uniform in different studies; iv) to an extent, factors such as differences in age and condition of the patients may have affected the stability of results, though were unavoidable. Collectively, these limitations may have affected the final conclusions.

Nevertheless, the current results indicated that there was no association of the HO-1 (GT)n and T(−413)A polymorphisms with overall cancer susceptibility. However, the L-allele genotypes (LL and LS) may be susceptibility factors for cancer in East Asian, digestive tract cancer in East Asian and squamous cell carcinoma populations. Due to the limitations of the included studies, larger refined studies are now required to confirm these conclusions.

 References SiegelRLMillerKDJemalACancer Statistics, 2017CA Cancer J Clin67730201710.3322/caac.2138728055103 TorreLABrayFSiegelRLFerlayJLortet-TieulentJJemalAGlobal cancer statistics, 2012CA Cancer J Clin6587108201510.3322/caac.2126225651787 VerdoodtFKjaer HansenMKjaerSKPottegårdAFriisSDehlendorffCStatin use and mortality among ovarian cancer patients: A population-based cohort studyInt J Cancer141279286201710.1002/ijc.3073828411390 BragaSFMde SouzaMCCherchigliaMLTime trends for prostate cancer mortality in Brazil and its geographic regions: An age-period-cohort analysisCancer Epidemiol505359201710.1016/j.canep.2017.07.01628810175 CoppedèFEpigenetic biomarkers of colorectal cancer: Focus on DNA methylationCancer Lett342238247201410.1016/j.canlet.2011.12.03022202641 McCleary-WheelerALLomberkGAWeissFUSchneiderGFabbriMPoshustaTLDusettiNJBaumgartSIovannaJLEllenriederVInsights into the epigenetic mechanisms controlling pancreatic carcinogenesisCancer Lett328212221201310.1016/j.canlet.2012.10.00523073473 WuMMLeeCHHsuLIChengWFLeeTCWangYHChiouHYChenCJEffect of heme oxygenase-1 gene promoter polymorphism on cancer risk by histological subtype: A prospective study in arseniasis-endemic areas in TaiwanInt J Cancer13818751886201610.1002/ijc.2992626566708 GhadbanTMiroJTTrumpFTsuiTYUzunogluFGReehMGebauerFBachmannKWellnerUKalininVDiverse prognostic value of the GTn promoter polymorphism in squamous cell and adeno carcinoma of the oesophagusClin Genet90343350201610.1111/cge.1276526916598 DunnLLMidwinterRGNiJHamidHAParishCRStockerRNew insights into intracellular locations and functions of heme oxygenase-1Antioxid Redox Signal2017231742201410.1089/ars.2013.567524180287 ZhangMMZhengYYGaoYZhangJZLiuFYangYNLiXMMaYTXieXHeme oxygenase-1 gene promoter polymorphisms are associated with coronary heart disease and restenosis after percutaneous coronary intervention: A meta-analysisOncotarget78343783450201627825138 LuoHLiZQingYZhangSHPengYLiQWangDSingle nucleotide polymorphisms of DNA base-excision repair genes (APE1, OGG1 and XRCC1) associated with breast cancer risk in a Chinese populationAsian Pac J Cancer Prev1511331140201410.7314/APJCP.2014.15.3.113324606430 MurakamiAFujimoriYYoshikawaYYamadaSTamuraKHirayamaNTeradaTKuribayashiKTabataCFukuokaKHeme oxygenase-1 promoter polymorphism is associated with risk of malignant mesotheliomaLung190333337201210.1007/s00408-012-9371-222271370 KikuchiAYamayaMSuzukiSYasudaHKuboHNakayamaKHandaMSasakiTShibaharaSSekizawaKAssociation of susceptibility to the development of lung adenocarcinoma with the heme oxygenase-1 gene promoter polymorphismHum Genet116354360200510.1007/s00439-004-1162-215688187 AndersenVChristensenJOvervadKTjønnelandAVogelUHeme oxygenase-1 polymorphism is not associated with risk of colorectal cancer: A Danish prospective studyEur J Gastroenterol Hepatol23282285201110.1097/MEG.0b013e3283417f7621191307 KuwanoAIkedaHTakedaKNakaiHKondoIShibaharaSMapping of the human gene for inducible heme oxygenase to chromosome 22q12Tohoku J Exp Med172389392199410.1620/tjem.172.3897940528 ChangKWLeeTCYehWIChungMYLiuCJChiLYLinSCPolymorphism in heme oxygenase-1 (HO-1) promoter is related to the risk of oral squamous cell carcinoma occurring on male areca chewersBr J Cancer9115511555200410.1038/sj.bjc.660218615365571 OkamotoIKröglerJEndlerGKaufmannSMustafaSExnerMMannhalterCWagnerOPehambergerHA microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with risk for melanomaInt J Cancer11913121315200610.1002/ijc.2193716596642 LoSSLinSCWuCWChenJHYehWIChungMYLuiWYHeme oxygenase-1 gene promoter polymorphism is associated with risk of gastric adenocarcinoma and lymphovascular tumor invasionAnn Surg Oncol1422502256200710.1245/s10434-006-9290-717520317 HongCCAmbrosoneCBAhnJChoiJYMcCulloughMLStevensVLRodriguezCThunMJCalleEEGenetic variability in iron-related oxidative stress pathways (Nrf2, NQ01, NOS3, and HO-1), iron intake, and risk of postmenopausal breast cancerCancer Epidemiol Biomarkers Prev1617841794200710.1158/1055-9965.EPI-07-024717726138 SawaTMounawarMTatemichiMGilibertIKatohTOhshimaHIncreased risk of gastric cancer in Japanese subjects is associated with microsatellite polymorphisms in the heme oxygenase-1 and the inducible nitric oxide synthase gene promotersCancer Lett2697884200810.1016/j.canlet.2008.04.01518502573 HuJLLiZYLiuWZhangRGLiGLWangTRenJHWuGPolymorphism in heme oxygenase-1 (HO-1) promoter and alcohol are related to the risk of esophageal squamous cell carcinoma on Chinese malesNeoplasma578692201010.4149/neo_2010_01_08619895178 WangXWWangJNWangALAssociation study between the risk of esophageal squamous cell carcinoma and microsatellite polymorphism in promoter of heme oxygenase-1Hebei Mediacl J56686702014 HuBZhangJWangJZhuCChenBKongMZhangBZhuMThe risk of esophageal squamous cell carcinoma associated with microsatellite polymorphism in promoter of heme oxygenase-1Zhonghua Wai Ke Za Zhi532062102015(In Chinese)26269017 AndersenVKoppTITjønnelandAVogelUNo association between HMOX1 and risk of colorectal cancer and no interaction with diet and lifestyle factors in a prospective Danish case-cohort studyInt J Mol Sci1613751384201510.3390/ijms1601137525574604 HsuLIWuMMWangYHLeeCYYangTYHsiaoBYChenCJAssociation of environmental arsenic exposure, genetic polymorphisms of susceptible genes, and skin cancers in TaiwanBioMed Res Int2015892579201510.1155/2015/89257926295053 Motovali-BashiMHamidyMAssociation between GT-repeat polymorphism at heme oxygenase-1 gene promoter and gastric cancer and metastasisTumour Biol3647574762201510.1007/s13277-015-3125-825956277 TangDTangWJShiXLLiWPZhouHLuLMTaoLAssociation of the microsatellite (GT)n repeat polymorphisms of the HO-1 gene promoter and corresponding serum levels with the risk of laryngeal squamous cell carcinomaActa Otolaryngol136806811201610.3109/00016489.2016.115726527400252 SongLYAssociation of heme oxygenase-1 polymorphisms with hepatitis B-related liver diseaseGuangxi Med Univ241111202015 JiráskováANovotnýJNovotnýLVodickaPPardiniBNaccaratiASchwertnerHAHubácekJAPuncochárováLŠmerhovskýZAssociation of serum bilirubin and promoter variations in HMOX1 and UGT1A1 genes with sporadic colorectal cancerInt J Cancer13115491555201210.1002/ijc.2741222212955 ZhangLSongFFHuangYBZhengHSongFJChenKXAssociation between the (GT)n polymorphism of the HO-1 gene promoter region and cancer risk: A meta-analysisAsian Pac J Cancer Prev1546174622201410.7314/APJCP.2014.15.11.461724969894 LuoHShaoYYaoNChenXHuLHeTAssociation of heme oxygenase-1 polymorphisms with cancer risk: A systematic review and meta-analysisJ BUON2011421153201526416069 MoherDLiberatiATetzlaffJAltmanDReviews and Meta-Analyses: The PRISMA statement reprint - Preferred reporting items for systematicPhys Ther89873880200919723669 LinSCLiuCJYehWILuiMTChangKWChangCSFunctional polymorphism in NFKB1 promoter is related to the risks of oral squamous cell carcinoma occurring on older male areca (betel) chewersCancer Lett2434754200610.1016/j.canlet.2005.11.01916387424 LiYAmbrosoneCBMcCulloughMJAhnJStevensVLThunMJHongCCOxidative stress-related genotypes, fruit and vegetable consumption and breast cancer riskCarcinogenesis30777784200910.1093/carcin/bgp05319255063 IshikawaMKajimuraMAdachiTMaruyamaKMakinoNGodaNYamaguchiTSekizukaESuematsuMCarbon monoxide from heme oxygenase-2 is a tonic regulator against NO-dependent vasodilatation in the adult rat cerebral microcirculationCirc Res97e104e114200510.1161/01.RES.0000196681.34485.ec16293786 VashistYKUzungoluGKutupAGebauerFKoenigADeutschLZehlerOBuschPKalininVIzbickiJRHeme oxygenase-1 germ line GTn promoter polymorphism is an independent prognosticator of tumor recurrence and survival in pancreatic cancerJ Surg Oncol104305311201110.1002/jso.2192621495030 BoucheDChauveauCRousselJCMathieuPBraudeauCTessonLSoulillouJPIyerSBuelowRAnegonIInhibition of graft arteriosclerosis development in rat aortas following heme oxygenase-1 gene transferTranspl Immunol9235238200210.1016/S0966-3274(02)00037-012180836 HadzijusufovicERebuzziLGleixnerKVFerencVPeterBKondoRGruzeAKneidingerMKrauthMTMayerhoferMTargeting of heat-shock protein 32/heme oxygenase-1 in canine mastocytoma cells is associated with reduced growth and induction of apoptosisExp Hematol3614611470200810.1016/j.exphem.2008.06.00218723263 MainesMDAbrahamssonPAExpression of heme oxygenase-1 (HSP32) in human prostate: Normal, hyperplastic, and tumor tissue distributionUrology47727733199610.1016/S0090-4295(96)00010-68650873 LiYXLiGDongWPChenJWangYFChenXBLuDRTanJMTransduction of heme oxygenase-1 gene to human Islet cells via adenovirus vector enhances anti-apoptosis function and insulin releaseZhonghua Yi Xue Za Zhi869159182006(In Chinese)16759519 NemethZLiMCsizmadiaEDömeBJohanssonMPerssonJLSethPOtterbeinLWegielBHeme oxygenase-1 in macrophages controls prostate cancer progressionOncotarget63367533688201510.18632/oncotarget.528426418896 ChauLYHeme oxygenase-1: Emerging target of cancer therapyJ Biomed Sci2222201510.1186/s12929-015-0128-025885228 NittiMPirasSMarinariUMMorettaLPronzatoMAFurfaroALHO-1 induction in cancer progression: A matter of cell adaptationAntioxidants66201710.3390/antiox6020029

(A-H) Funnel plots representing the association between (GT)n polymorphism in heme oxygenase-1 (HO-1) gene and cancer susceptibility. (A and E) The allele model (L vs. S; T vs. A); (B and F) the dominant model (LL vs. SS+SL; TT vs. AA+AT); (C and G) the co-dominant model (LL vs. SS; TT vs. AA); (D and H) the recessive model (LL+LS vs. SS; TT+AT vs. AA).

Demographic characteristics of studies included in the meta-analysis of heme oxygenase-1 gene promoter polymorphisms and cancer (2004–2017).

Genotype, SS/SL/LL or AA/AT/TT, n Frequency of class L or T allele, % Sex of subjects, total, n (M/F) years (SD)
Author, year Ethnicity, origin Cancer type Study design and genotyping method Definition of S allele length, nt Cases Controls Cases Controls Cases Controls Cases Controls HWE Refs.
GT(n) repeat length polymorphism
Chang, 2004 East Asian, Taiwan Oral squamous cell carcinoma CC, PCR ≤25 29/64/54 17/40/26 58.5 55.4 147 (147/0) 83 (83/0) 51.3 (9.8) 47.1 (10.0) 0.82 (16)
Okamoto, 2006 Caucasian, Austria Melanoma CC, PCR <25 32/50/70 46/177/175 62.5 66.2 152 (82/70) 398 (206/192) 56.0 (15.0) 48.0 (14.0) 0.90 (17)
Lo, 2007 East Asian, Taiwan Gastric adenocarcinoma CC, PCR ≤25 34/101/48 47/116/87 53.8 58.0 183 (130/53) 250 (176/74) 67.5 (12.8) 51.1 (16.6) 0.22 (18)
Hong, 2007 American, USA Postmenopausal breast cancer CC, PCR ≤25 52/183/243 47/217/228 70.0 68.4 505 (0/505) 502 (0/502) N/A N/A 0.65 (19)
Hu, 2010 East Asian, China Esophageal squamous cell carcinoma CC, PCR <25 29/69/45 90/117/57 55.6 43.8 143 (N/A) 264 (N/A) 61.3 (10.4) 58.1 (10.0) 0.11 (21)
Jirásková, 2012 Caucasian, Republic Czech Sporadic colorectal cancer CC, PCR   <27 100/386/291 133/454/399 62.3 63.5 777 (453/324) 986 (571/415) 61.8 (11.0) 49.2 (11.0) 0.83 (29)
Murakami, 2012 East Asian, Japan Malignant mesothelioma CC, PCR <24   2/29/47 6/19/19 78.8 64.8 78 (58/20) 44 (33/11) 64.8 (8.5) 66.7 (9.0) 0.72 (12)
Wang, 2014 East Asian, China Esophageal squamous cell carcinoma CC, PCR ≤25 1/51/41 2/63/33 71.5 86.2 93 (48/45) 98 (51/47) 61.0 (8.0) 58.0 (8.0) 0.01 (22)
Hsu, 2015 East Asian, Taiwan Skin cancers CC, PCR ≤28 17/34/14 47/111/41 52.3 51.5 65 (N/A) 199 (N/A) 56.1 (6.9) 54.4 (6.3) 0.10 (25)
Hu, 2015 East Asian, China Esophageal squamous cell carcinoma CC, PCR <25 34/50/42 57/46/31 53.2 40.3 126 (83/43) 134 (77/57) 61.0 (8.0) 57.0 (10.0) 0.01 (23)
Motovali-Bashi, 2015 West Asian, Iran Gastric cancer CC, PCR ≤28 31/18/11 22/21/57 33.3 67.5 60 (40/20) 100 (60/40) 60.1 (10.9) 54.1 (12.0) <0.01 (26)
Tang, 2015 East Asian, China Laryngeal squamous cell carcinoma CC, PCR   <25 24/71/47 27/57/14 58.1 43.4 142 (140/2) 98 (97/1) 61.5 (9.6) 68.3 (11.9) 0.07 (27)
T(−413)A (rs2071746) single-nucleotide polymorphism
Song, 2015 East Asian, China Hepatocellular carcinoma CC, PCR N/A 62/136/69 43/131/75 51.3 56.4 267 (237/30) 249 (135/114) 49.4 (11.1) 46.6 (7.0) 0.27 (28)
Andersen, 2015 Caucasian, Denmark Colorectal cancer CS, PCR N/A 310/446/172 587/864/275 42.6 41.0 928 (521/407) 1726 (922/804) 57.8 (3.3) 56.5 (3.5) 0.15 (24)
Jirásková, 2012 Caucasian, Republic Czech Sporadic colorectal cancer CC, PCR   <27 253/372/152 311/497/177 43.5 43.2 777 (453/324) 986 (571/415) 61.8 (11.0) 49.2 (11.0) 0.39 (29)

CC, case-control; CS, case-cohort study; PCR, polymerase chain reaction; M, man; F, female; HWE, Hardy-Weinberg equilibrium; N/A, not available.

Results from the meta-analysis of the association between cancer susceptibility and heme oxygenase-1 gene promoter polymorphisms.

Genetic model
L vs. S LL+LS vs. SS LL vs. SS+SL LL vs. SS
Polymorphism and subgroup No. of studies Cases/controls, n OR (95% CI) P1-value I2 (%) OR (95% CI) P1-value I2 (%) OR (95% CI) P1-value I2 (%) OR (95% CI) P1-value I2 (%)
(GT)n polymorphism with cancer
  Total 12 2,444/3,146 1.00 (0.79,1.27) 0.99 87 1.08 (0.77,1.51) 0.67 76 1.14 (0.87,1.51) 0.34 79 1.16 (0.76,1.79) 0.49 81
  East Asian   8 977/1,170 1.19 (0.87,1.64) 0.27 82 1.51 (1.11,2.05) 0.0003 38 1.44 (1.04,2.01) 0.03 64 1.64 (1.07,2.52) 0.02 66
  Non-East Asian   4 1,467/1,976 0.73 (0.50,1.07) 0.10 91 0.63 (0.37,1.07) 0.08 83 0.77 (0.49,1.22) 0.27 87 0.58 (0.31,1.08) 0.09 85
  Meeting HWE   9 2,165/2,814 1.14 (0.96,1.36) 0.14 72 1.12 (0.82,1.52) 0.49 68 1.21 (0.95,1.54) 0.13 68 1.26 (0.86,1.84) 0.24 73
  Deviating from HWE   3 279/332 0.55 (0.16,1.93) 0.35 96 0.91 (0.17,4.75) 0.91 91 0.78 (0.21,2.89) 0.71 92 0.84 (0.09,7.64) 0.83 93
(GT)n polymorphism with squamous cell carcinoma   5 651/677 1.21 (0.79,1.87) 0.38 85 1.78 (1.35,2.34) <0.0001 0 1.71 (1.34,2.18) <0.0001 0 2.26 (1.62,3.14) <0.0001 4
(GT)n polymorphism with digestive tract cancer
  Total   8 1,671/2,013 0.93 (0.65,1.33) 0.68 91 1.17 (0.77,1.76) 0.46 77 1.08 (0.71,1.65) 0.72 85 1.20 (0.66,2.19) 0.55 85
  East Asian   6 834/927 1.14 (0.78,1.67) 0.51 86 1.56 (1.22,1.98) 0.003 26 1.44 (0.96,2.17) 0.08 72 1.80 (1.06,3.05) 0.03 66
  Non-East Asian   2 837/1086 0.49 (0.13,1.87) 0.30 97 0.55 (0.14,2.13) 0.39 92 0.40 (0.08,2.03) 0.27 94 0.38 (0.06,2.59) 0.32 95
T vs. A TT+TA vs. AA TT vs. AA+TA TT vs. AA
No. of studies Cases/controls, n OR (95% CI) P1-value I2 (%) OR (95% CI) P1-value I2 (%) OR (95% CI) P1-value I2 (%) OR (95% CI) P1-value I2 (%)
T(−413)A polymorphism with digestive system neoplasms
  Total   3 1,972/2,961 1.02 (0.94,1.10) 0.70 48 0.97 (0.86,1.10) 0.61 29 1.10 (0.95,1.27) 0.20 36 1.00 (0.76,1.33) 0.98 57

P1-values were obtained from Z tests for random or fixed-effects models.

Eggers and Beggs test results.

Association Genetic model P1-value P2-value
(GT)n polymorphism and cancer L vs. S 0.072 0.732
LL+LS vs. SS 0.023 0.244
LL vs. SS+SL 0.744 0.631
LL vs. SS 0.397 0.945
(GT)n polymorphism and squamous cell carcinoma L vs. S 0.673 0.806
LL+LS vs. SS 0.653 0.806
LL vs. SS+SL 0.917 0.806
LL vs. SS 0.691 1.000
(GT)n polymorphism and digestive tract cancer L vs. S 0.107 1.000
LL+LS vs. SS 0.024 0.386
LL vs. SS+SL 0.543 0.174
LL vs. SS 0.300 0.902
T(−413)A polymorphism and digestive system neoplasms T vs. A 0.491 1.000
TT+TA vs. AA 0.157 1.000
TT vs. AA+TA 0.675 1.000
TT vs. AA 0.285 0.296

P1-value, Eggers test result; P2-value, Beggs test result.