Associations Between I/ D polymorphism in the ACE gene and lung cancer: an updated systematic review and a meta-analysis

doi:10.21203/rs.3.rs-60841/v2

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Associations Between I/ D polymorphism in the ACE gene and lung cancer: an updated systematic review and a meta-analysis

https://doi.org/10.21203/rs.3.rs-60841/v2

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published 12 Feb, 2021

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Background: This study has evaluated the association between the I/D polymorphism in the ACE gene and lung cancer risk by constructing a meta-analysis.

Methods: The heterogeneity in the study was tested by the Cochran c²-based Q statistic test and I²test, and then the random ratio or fixed effect was utilized to merge the odds ratios (OR) and 95% confidence interval (CI), to estimate the strength of the association between ACE polymorphisms and susceptibility to lung cancer. We have performed Sensitivity analysis. Using funnel plot and Begg's rank test investigated the publication bias. All data Statistical analyses were performed using Stata 12.0 and Revman 5.3.

Results: A total of 4307 participants (2181 patients; 2126 controls) were included in twelve case-control studies selected. No significant association was found between the ACE I/D polymorphism and lung cancer risks (II vs ID + DD: OR = 1.22, 95% CI = 0.89–1.68; II + ID vs DD: OR = 1.21, 95% CI = 0.90–1.63; I vs D: OR =1.15, 95% CI = 0.95–1.39). In the subgroup analysis by ethnicity, no significant association between this polymorphism and lung cancer risks was also found among Asia and Caucasian populations for the comparison of II vs ID + DD, II + ID vs DD and I vs D genetic models.

Conclusion: Our study indicated that the ACE I/ D polymorphism was not associated with the risk of lung cancer.

Cancer Biology

Oncology

ACE

Polymorphism

Lung cancer

Meta-analysis

Lung cancer had become the largest malignant tumor in terms of harm to human health and life [1, 2]. The incidence and mortality of lung cancer were also increasing year by year, and its proportion in tumor mortality was also expanding[2]. Five-year survival rate of lung cancer was only about 15% [3].

The human angiotensin-converting enzyme (ACE) gene located on chromosome 17q23 and had a gene length of 21 kb, which was consisted of 26 exons and 25 introns [4]. The biological significance of the ACE gene was that the 16th intron had an insertion/deletion sequence, producing three genotypes, insertion homozygous (II), deletion homozygous (DD), and insertion/deletion of heterozygous type (ID) [5]. The level of ACE activity in serum was related to the I/D polymorphism of ACE gene [6]. The II genotype exhibits low activity, the DD gene exhibits high activity, and the heterozygous ID genotype has activity between the two [7].

In recent years, there have been many studies on the role of ACE I/D polymorphism in the risk of lung cancer, but there were some contradictions among the results of these studies. Some study showed an obviously trend of the ACE ‘II’ genotype with increased risk of lung cancer [8, 9], while the other study also showed the DD genotype of ACE may contribute to a higher risk of lung cancer [10-13], but additional one study showed ACE ‘ID’ genotypes might increase the risk of lung cancer [14] , and yet others displayed no association between ACE I/D polymorphism and lung cancer [15-19]. To more accurately assess the potential relationship between the ACE I/D polymorphism and the risk of lung cancer, we performed a meta-analysis using all eligibility published literature.

Search strategies

We conducted a comprehensive search of the literature in the Web of Science, Pubmed, Cochrane Library, Embase, China Nationa Knowledge Infrastructure (CNKI) electronic database, covering relevant studies published until June 31, 2019. The keywords for the search were as follows: (“angiotensin-converting enzyme” OR “ACE”) AND (“polymorphism” OR “variant” OR “mutation”) AND (“Lung cancer” OR “lung neoplasm”). The literature on relevant data was searched in English and Chinese respectively. In addition, the retrieved articles and references were performed manual searches. Referring to the Preferred Reporting Project (PRISMA) Guide for Systematic Evaluation and Meta-Analysis [20], an information flow diagram related to the final eligibility data was constructed by screening all retrieved literatures.

Inclusion and Exclusion Criteria

Screening for the studies of the relationship between ACE I/D polymorphism and the risk of Lung cancer according to the following inclusion criteria: (1) the design of study was case-control; (2) The full text can be found; (3) the genotype information of the ACE I/D polymorphism were available; (4) the relationship of the ACE I/D polymorphism and the risk of Lung cancer was evaluated; The major exclusion criteria were: (1) not a case–control study; (2) repeating early publications (studies used in different publications for the same sample data, including only the most complete samples after careful review); (3) Unpublished articles, conference papers, meta-analysis and systematic reviews; (4) family-based pedigree research. This meta-analysis strictly followed the requirements of the preferred reporting project for the systematic review and meta-analysis guidelines. [20].

Data Extraction

The analysis data of the selected studies were independently extracted by two researchers using standard data-collection forms. Studies related information extracted from each literature were as follows: First author, Year of publication, Country of origin, Mean age and Gender in cases and controls, Numbers of cases and controls, Hardy-Weinberg equilibrium, Genotyping method, Source of controls, and available genotype frequency information for ACE I/D. If the same sample data appeared in multiple publications, only the publication with the largest sample size was included in the study. The differences between the two investigators were resolved through discussion. If the discussion could not resolve the objection between the two, the objection would be judged by the third investigator. All data were obtained from the full text of the published research and the author was not contacted for further information. All information on the participants in the selected studies were shown in table 1.

Study Quality Assessment

Two evaluators evaluated the quality of the included studies according to the Newcastle-Ottawa Scale (NOS) [21], which is applicable to the quality assessment of observational studies. The difference between the two evaluators was reported and resolved by the third evaluator. The scores of research quality mainly include the following three aspects: (1) Selection of the case groups and control groups (4 stars); (2) Quality of confounding factors correction in case and control population (2 stars); and (3) determination of the exposure of interest in the studies (3 stars). For each item numbered in the selection and exposure categories, one study can be rated as up to one star, and comparability can be assigned up to two stars. Higher scores indicate an increase in the quality of the research method. Studies with scores equal to or higher than 6 are considered high quality studies.

Data Analysis

The heterogeneity in the study was tested by the Cochran c²-based Q statistic test and I²test, and then the random ratio or fixed effect was utilized to merge the odds ratios (OR) and 95% confidence interval (CI). The significance of the pooled OR was analyzed by Z-test (P< 0.05 Judged statistically significant). To estimate the strength of the association between ACE polymorphisms and susceptibility to lung cancer, we have performed Sensitivity analysis. Using funnel plot and Begg's rank test investigated the publication bias. All data Statistical analyses were performed using Stata 12.0 (Stata Corp, College Station, TX, United States) and Revman 5.3.

Literature Search and Study Characteristics

The flow chart of the literature search was shown in Figure 1. 279 potentially relevant articles were selected in the preliminary online search. After verifying and deleting 104 duplicate articles, 175 articles entered the final review. Through the review of the title and abstract, 15 articles were included for full-text review. Finally, 12 articles were included in the final study. These studies were published between 2005 and 2018, and 12 articles included 2181 lung cancer patients and 2126 controls. Except for one study, the distribution of genotypes in controls in other studies followed Hardy Weinberg equilibrium (HWE). In addition, the NOS scores for all studies ranged from 6 to 8 points, so that the selected articles were considered to be good in methodological quality. The relevant feature information of the included articles was in tables 1 and table 2.

Meta-analysis results

The heterogeneity of the three genetic models was determined by Q test and I squared statistics. As shown in Figure 2, these were serious heterogeneity in the three models (II vs ID + DD: P<0.001, I² = 77.9%; II + ID vs DD: P=0.002, I² = 61.7%; I vs D: P<0.001, I² = 73.0%), thus the random- effect model was employed in analysis of the three models. Our results reveled that there were no significant associations between ACE I/D polymorphism and Lung cancer under the model of II vs ID + DD (OR = 1.22, 95% CI = 0.89–1.68, P=0.22), II + ID vs DD (OR = 1.21, 95% CI = 0.90–1.63, P=0.21) and I vs D (OR =1.15, 95% CI = 0.95–1.39, P=0.15). In subgroup analysis by Ethnicity, no significant association was found in three models in both Caucasian and Asian populations (Table 3). Sensitivity analysis was used to assess the impact of each individual study on the pooled OR by sequentially removing each eligible study. Our results suggest that none of the studies affected the overall outcome of the pooled OR (Figure 3). Begg's funnel plot was used to assess publication bias, and the results showed that publication bias was not reflected in the three genetic models. (II vs ID + DD: P=0.41; II + ID vs DD: P=0.34; I vs D: P=0.89) (Figure 4).

Recent studies have reported that ACE may be involved in the development of tumors [22- 24]. ACE was a key enzyme in the renin-angiotensin system, which converted angiotensin I to angiotensin II and inactivates bradykinin. The mechanism of action may be due to the fact that angiotensin II can stimulate the synthesis of DNA and protein in vascular smooth muscle cells, and promote the synthesis and secretion of vascular endothelial growth factor [25]. On the other hand, it may be because bradykinin can increase the permeability of the cell membrane to electrolytes and peptides. ACE can inactivate bradykinin [26] , but low expression of ACE in tumor tissues can promote invasive growth of malignant tumors. There are more and more published studies investigating the association between this polymorphism and lung cancer risk; however, there are inconsistencies and conflicts in the results. To further assess the association between ACE I/D polymorphism and lung cancer risk, we used a meta-analysis to analyze 12 case-control studies, including 2181 cases and 2126 controls.

The results of this meta-analysis showed no significant association was found in the three genetic models of comparison. Although previous studies have revealed that ACE may produce a certain effect in the etiology of lung cancer, our results suggest that these effects may not be caused by ACE gene mutations. The exact pathogenesis of AEC in the etiology of lung cancer remains unclear. Our results may suggest that ACE I/D polymorphism did not affect cancer risk. Moreover, considering that this polymorphism may affect serum ACE levels, and ACE levels may affect the risk of lung cancer, the risk of lung cancer is not directly caused by ACE gene mutation. Therefore, future research is necessary to determine the association between ACE polymorphism, ACE levels and cancer risk.

Previously, a meta-analysis was applied for eight published studies [8, 10, 11, 13, 15, 17-19] by Cheng et al [27], it included 1612 cases and 1442 controls, the results shown that the ACE gene I/D polymorphism was not associated with lung cancer. Wang et al [28] also conducted a meta-analysis of six published studies with 807 cases and 816 controls [8, 10, 13, 15, 18], the results also showed ACE I/D polymorphism may not be associated with lung cancer risk. In our study, a total of 12 studies were enrolled, including 2181 cases and 2126 controls. So the statistical power of the current analysis was better than the previous two meta-analyses. Compared with other studies, this study is more comprehensive about the relationship between ACE I/D polymorphism and lung cancer risk. Despite the differences between the studies included in the analysis, the results of our study suggest that the ACE I/D polymorphism may not lead to cancer risk, which is consistent with Cheng’s study and Wang ’s study.

However, there are certain limitations in our research. First, databases that include only published research in both Chinese and English are selected for analysis, and other language or unpublished potential research may be missed. Second, due to the lack of raw data, we were unable to assess potential interactions of gene-genes and genes-environments. Third, the meta-analysis includes data from Europeans and Asians, so the results of this item apply only to these two ethnic groups. Fourth, among the three models, heterogeneity may greatly influence the conclusion of the meta-analysis. Lastly, the power of our analysis with the sample size was not high enough, so the results obtained from this paper should be verified in the future.

In summary, our study showed that the ACE I/D polymorphism did not increase or decrease the risk of susceptibility to lung cancer. Further well-designed studies should be conducted to identify our findings in different populations and age groups, such as different races in Asia, Europe and other populations, or children and adults. Future research will also need to explore the ACE I/D gene-gene or the possible role of gene-environment interactions in susceptibility to lung cancer.

OR: odds ratios; CI: confidence interval; ACE: angiotensin-converting enzyme; CNKI: China Nationa Knowledge Infrastructure; NOS: Newcastle-Ottawa Scale; HWE: Hardy Weinberg equilibrium

Ethics approval and consent to participate: Not applicable.

Consent for publication: yes

Availability of data and material: yes

Competing interests: The authors declare that they have no competing interests

Funding: Not applicable.

Authors' contributions:

JC and RL: Conceptualization, data curation, formal analysis, methodology, writing and review and editing

MS and MZ: Software, supervision, validation, visualization.

All authors have read and approved the manuscript

Informed consent: NA

Acknowledgements

We appreciate the cooperation of the families and individuals who cooperated in this study.

Yokota J, Shiraishi K, Kohno T. Genetic basis for susceptibility to lung cancer: Recent progress and future directions. Advances in cancer research. 2010; 109:51-72.
Schwartz AG, Cote ML. Epidemiology of Lung Cancer. Advances in experimental medicine and biology. 2016; 893:21-41.
Sculier JP, Berghmans T, Meert AP. Advances in target therapy in lung cancer. European respiratory review. 2015; 24(135):23-29.
Castellon R, Hamdi HK. Demystifying the ACE polymorphism: from genetics to biology. Current pharmaceutical design. 2007; 13(12):1191-1198.
Harrap SB, Davidson HR, Connor JM, Soubrier F, Corvol P, Fraser R, Foy CJ, Watt GC. The angiotensin I converting enzyme gene and predisposition to high blood pressure. Hypertension 1993; 21(4): 455-60
Rocken C, Lendeckel U, Dierkes J, et al. The number of lymph node metastases in gastric cancer correlates with the angiotensin I-converting enzyme gene insertion/deletion polymorphism. Clinical cancer research. 2005; 11(7):2526-2530.
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. Journal of clinical investigation. 1990; 86(4):1343-1346.
Nacak M, Nacak I, Sanli M, Ozkur M, Pektas M, Aynacioglu AS. Association of angiotensin converting enzyme gene insertion/deletion polymorphism with lung cancer in Turkey. Cancer genetics and cytogenetics. 2010; 198(1):22-26.
Phukan RK, Borah PK, Saikia BJ, Das M, Sekhon GS, Mahanta J. Interaction of tobacco smoking and chewing with Angiotensin converting enzyme (insertion/deletion) gene polymorphisms and risk of lung cancer in a high risk area from northeast India. Asian Pacific journal of cancer prevention. 2014; 15(24):10691-10695.
Devic Pavlic S, Ristic S, Flego V, Kapovic M, Radojcic Badovinac A. Angiotensin-converting enzyme insertion/deletion gene polymorphism in lung cancer patients. Genetic testing and molecular biomarkers. 2012; 16(7):722-725.
Gao M, Wang Y, Shi Y, et al. The relationship between three well-characterized polymorphisms of the angiotensin converting enzyme gene and lung cancer risk: a case-control study and a meta-analysis. Journal of the renin-angiotensin-aldosterone system. 2012; 13(4):455-460.
Shi G, Sun Y, Wu ED, Liang Z, Zhang B. Association of genetic polymorphism of angiotensin converting enzyme gene with lung cancer. China Medical Herald. 2014; 11(15):43-46.
Wang H, Nie ZH, Duan Y, et al. Angiotensin -converting Enzyme Gene Polymorphism in Patients with Lung Carcinoma. J ournal of Navy Medicine. 2000; (04):319-322.
Peddireddy V, Badabagni SP, Gundimeda SD, Mundluru HP. Association of eNOS and ACE gene polymorphisms and plasma nitric oxide with risk of non-small cell lung cancer in South India. The clinical respiratory journal. 2018; 12(1):207-217.
Cheon KT, Choi KH, Lee HB, Park SK, Rhee YK, Lee YC. Gene polymorphisms of endothelial nitric oxide synthase and angiotensin-converting enzyme in patients with lung cancer. Lung. 2000; 178(6):351-360.
Ozen F, Polat F, Arslan S, Ozdemir O. Combined germline variations of thrombophilic genes promote genesis of lung cancer. Asian Pacific journal of cancer prevention : APJCP. 2013; 14(9):5449-5454.
Yaren A, Oztop I, Turgut S, Turgut G, Degirmencioglu S, Demirpence M. Angiotensin-converting enzyme gene polymorphism is associated with anemia in non small-cell lung cancer. Experimental biology and medicine (Maywood, NJ). 2008; 233(1):32-37.
Zhang Q, Liu X, Zhang Z, Wang L. Analysis of the relationship between polymorphism of angiotensin-converting enzyme gene and lung cancer. Chinese journal of lung cancer. 2005; 8(3):211-214.
Ding X. Analysis of the Relationship Between the Polymorphism of Angiotensin- converting Enzyme Gene and Lung Cancer. Soochow University; 2008.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of internal medicine. 2009; 151(4):264-269.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European journal of epidemiology. 2010; 25(9):603-605.
Coulson R, Liew SH, Connelly AA, et al. The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma. Oncotarget. 2017; 8(12):18640-18656.
Pandith AA, Qasim I, Zahoor W, Shah P, Bhat AR. ACE I/D sequence variants but not MTHFR C677T, is strongly linked to malignant glioma risk and its variant DD genotype may act as a promising predictive biomarker for overall survival of glioma patients. Gene. 2018; 639:62-68.
Sugimoto M, Furuta T, Shirai N, Ikuma M, Sugimura H, Hishida A. Influences of chymase and angiotensin I-converting enzyme gene polymorphisms on gastric cancer risks in Japan. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2006; 15(10):1929-1934.
Walther T, Menrad A, Orzechowski HD, Siemeister G, Paul M, Schirner M. Differential regulation of in vivo angiogenesis by angiotensin II receptors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2003; 17(14):2061-2067.
Yang HY, Erdos EG, Levin Y. A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochimica et biophysica acta. 1970; 214(2):374-376.
Cheng Z, Ma R, Tan W, Zhang L, Tan Q. Lack of association between ACE insertion/deletion polymorphism and lung cancer: A meta-analysis. Journal of the renin-angiotensin-aldosterone system : JRAAS. 2015; 16(2):453-458.
Wang N, Yang D, Ji B, Li J. Angiotensin-converting enzyme insertion/deletion gene polymorphism and lung cancer risk: A meta-analysis. Journal of the renin-angiotensin-aldosterone system : JRAAS. 2015; 16(1):189-194.

Table 1 Characteristic of studies included in the meta-analysis

Author	year	country	Ethnicity	Age group	Genotype Methods	Source of control	NOS score	HWE
Peddireddy et al	2018	South Indian	Asia	Adult	PCR	PB	8	0.726
Phukan et al	2014	Northeast India	Asia	Adult	PCR	PB	8	0.227
Ozen et al	2013	Turkey	Caucasians	Adult	PCR	PB	7	0.920
Shi et al	2014	China	Asia	Adult	PCR-SSP	PB	6	0.308
Cheon et al	2000	Korea	Asia	Adult	PCR	-	6	0.133
Yaren et al	2008	Turkey	Caucasians	Adult	PCR	-	7	0.470
Nacak et al	2010	Turkey	Caucasians	Adult	PCR	PB	8	0.268
Wang et al	2000	China	Asia	Adult	PCR	-	6	0.861
Zhang et al	2005	China	Asia	Adult	PCR	HB	7	0.109
Gao et al	2012	China	Asia	Adult	PCR	HB	6	0.018
Devic Pavlic et al	2012	Croatia	Caucasians	Adult	PCR	HB	7	0.909
Ding et al	2008	China	Asia	Adult	PCR	HB	7	0.175

Table 2 The genotype distribution of ACE I/ D

Author	Sample size (case/control)	Female (%) (case/control)	case					control
Author	Sample size (case/control)	Female (%) (case/control)	I/I	I/D	D/D	I	D	I/I	I/D	D/D	I	D
Peddireddy et al	246/250	28.0/28.0	48	161	37	257	235	111	113	26	335	165
Phukan et al	151/151	45.7 /45.7	61	62	28	184	118	44	68	39	156	146
Ozen et al	52/212	11.5/-	10	30	12	50	54	67	105	40	239	185
Shi et al	120/62	39.2/-	47	49	24	143	97	26	31	5	83	41
Cheon et al	218/121	26.6/42.1	72	116	31	260	178	48	50	23	146	96
Yaren et al	75/85	8.0/9.4	4	39	32	47	103	14	37	34	65	105
Nacak et al	125/165	12.0/48.5	37	50	38	124	126	29	72	64	130	200
Wang et al	34/38	23.5/44.7	10	6	18	26	42	13	18	7	44	32
Zhang et al	47/54	14.9 /29.6	21	21	5	63	31	20	30	4	70	38
Gao et al	684/602	27.2/33.6	351	271	62	973	395	320	253	29	893	311
Devic Pavlic et al	308/353	29.5/38.5	64	148	96	276	340	78	177	98	333	373
Ding et al	121/33	31.4/30.3	55	56	10	166	76	19	10	4	48	18

Table 3 Summary of pooled OR in different ethnicities

Genetic model	group	Pooled OR (95% CI)	Heterogeneity		Test for overall effect
Genetic model	group	Pooled OR (95% CI)	P	I²	Z	P
II vs ID+DD	Caucasians	1.22 (0.75-2.00)	0.007	71.9%	0.80	0.423
II vs ID+DD	Asia	1.21(0.76-1.94)	<0.01	82.9%	0.81	0.419
II+ID vs DD	Caucasians	0.98(0.79-1.23)	0.284	20.5%	0.15	0.881
II+ID vs DD	Asia	1.56(0.94-2.59)	0.005	67.3%	1.71	0.088
I vs D	Caucasians	1.05(0.82-1.34)	<0.01	73.0%	0.39	0.694
I vs D	Asia	1.24(0.92-1.66)	<0.01	77.9%	1.41	0.159

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Associations Between I/ D polymorphism in the ACE gene and lung cancer: an updated systematic review and a meta-analysis

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