MDM2 promoter del1518 polymorphism and cancer risk: evidence from 22,931 subjects

OncoTargets and Therapy, Jul 2017

MDM2 promoter del1518 polymorphism and cancer risk: evidence from 22,931 subjects Wenfeng Hua,1,* Anqi Zhang,2,* Ping Duan,2,* Jinhong Zhu,3 Yuan Zhao,2 Jing He,4 Zhi Zhang1 1Department of Laboratory Medicine and Central Laboratories, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, 2Department of Obstetrics and Gynecology, The Second Affiliated Hospital & Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 3Molecular Epidemiology Laboratory and Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 4Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China *These authors contributed equally to this work Abstract: Studies have shown that single-nucleotide polymorphisms in MDM2 gene may play important roles in the development of malignant tumor. The association of del1518 polymorphism (rs3730485) in the MDM2 promoter with cancer susceptibility has been extensively studied; however, the results are contradictory. To quantify the association between this polymorphism and overall cancer risk, we conducted a meta-analysis with 12,905 cases and 10,026 controls from 16 eligible studies retrieved from PubMed, Embase, and Chinese Biomedical (CBM) databases. We assessed the strength of the connection using odds ratios (ORs) and 95% confidence intervals (CIs). In summary, no significant associations were discovered between the del1518 polymorphism and overall cancer risk (Del/Del vs Ins/Ins: OR =1.01, 95% CI =0.90–1.14; Ins/Del vs Ins/Ins: OR =1.03, 95% CI =0.96–1.12; recessive model: OR =0.98, 95% CI =0.90–1.07; dominant model: OR =1.03, 95% CI =0.94–1.12; and Del vs Ins: OR =1.01, 95% CI =0.94–1.07). In the stratified analysis by source of control, quality score, cancer type, and ethnicity, no significant associations were found. Despite some limitations, the current meta-analysis provides solid statistical evidence of lacking association between the MDM2 del1518 polymorphism and cancer risk. Keywords: MDM2, del1518, polymorphism, cancer susceptibility, meta-analysis

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MDM2 promoter del1518 polymorphism and cancer risk: evidence from 22,931 subjects

OncoTargets and Therapy MDM2 promoter del1518 polymorphism and cancer risk: evidence from 22,931 subjects Ping Duan 1 Jinhong Zhu 0 Yuan Zhao 1 Zhi Zhang 2 0 Molecular epidemiology laboratory and Department of laboratory Medicine, h arbin Medical University cancer hospital , harbin, heilongjiang 1 Department of Obstetrics and gynecology, The s econd a ffiliated h ospital & Yuying c hildren's h ospital, Wenzhou Medical University , Wenzhou, Zhejiang 2 Department of laboratory Medicine and c entral l aboratories, g uangdong second Provincial general hospital , guangzhou, guangdong 3 Department of Pediatric surgery, guangzhou institute of Pediatrics, g uangzhou Women and c hildren's Medical center, guangzhou Medical University , guangzhou, guangdong, People's republic of china Studies have shown that single-nucleotide polymorphisms in MDM2 gene may play important roles in the development of malignant tumor. The association of del1518 polymorphism (rs3730485) in the MDM2 promoter with cancer susceptibility has been extensively studied; however, the results are contradictory. To quantify the association between this polymorphism and overall cancer risk, we conducted a meta-analysis with 12,905 cases and 10,026 controls from 16 eligible studies retrieved from PubMed, Embase, and Chinese Biomedical (CBM) databases. We assessed the strength of the connection using odds ratios (ORs) and 95% confidence intervals (CIs). In summary, no significant associations were discovered between the del1518 polymorphism and overall cancer risk (Del/Del vs Ins/Ins: OR =1.01, 95% CI =0.90-1.14; Ins/Del vs Ins/Ins: OR =1.03, 95% CI =0.96-1.12; recessive model: OR =0.98, 95% CI =0.90-1.07; dominant model: OR =1.03, 95% CI =0.94-1.12; and Del vs Ins: OR =1.01, 95% CI =0.94-1.07). In the stratified analysis by source of control, quality score, cancer type, and ethnicity, no significant associations were found. Despite some limitations, the current meta-analysis provides solid statistical evidence of lacking association between the MDM2 del1518 polymorphism and cancer risk. MDM2; del1518; polymorphism; cancer susceptibility; meta-analysis - open access to scientific and medical research O r i g i n a l r e s e a r c h Wenfeng hua 1,* anqi Zhang 2,* Introduction Worldwide cancer incidence and mortality continues to increase greatly. More than 14.1 million cancer cases and 8.2 million cancer-associated deaths were reported by the latest GLOBOCAN estimates. The burden of cancer has become a serious global problem, particularly in economically developing countries, on account of aging society, smoking, nutritional status, obesity, and physical inactivity. Despite restriction on tobacco use, advocation on vaccination, early diagnosis, and treatment that can prevent cancer mortality effectively, the causes of cancer are still far from clear.1 According to molecular epidemiological researches, genetic polymorphisms have been implicated in diverse carcinogenesis mechanisms.2,3 p53, a tumor suppressor protein, is implicated in almost half of all human cancer. In response of genotoxic stress and oncogenic signals, p53 actives a transcriptional program to induce several cellular damage responses, including apoptosis, cell cycle halt, and autophagy.4,5 In certain cases, p53 activity is depressed by the overexpression of MDM2, a cellular antagonist. MDM2 acts as a major node in the P53 pathway. The MDM2 is an ubiquitin ligase E3 for p53, which promotes the degradation of P53 by the proteasome. There is a negative feedback loop between P53 and MDM2, in which activating p53 protein increases MDM2 transcription, and the resulting MDM2 protein interacts with p53, thereby causing p53 degradation.6 Previous reports have clearly shown that polymorphisms associate with diseases susceptibility by altering affected proteins structurally and functionally. Human MDM2 gene is located on chromosome 12q14.3–q15.1, which contains two promoters, an upstream constitutive promoter (P1) and an internal promoter (P2).7,8 The genetic variations within either of promoters may alter the expression of MDM2. For instance, MDM2 SNP309 (rs2279744, T.G) within promoter P2 enhances the affinity of promoter with the transcriptional activator SP1 to increase MDM2 transcription, thereby promoting tumor development in the different tissues.9 In addition, a del1518 polymorphism (rs3730485), a 40 bp insertion/deletion in the MDM2 promoter P1 region, could also affect promoter activity.10 Recently, several lines of evidence have indicated that the del1518 del-allele contributes to an increase in cancer risk;11–13 however, opposite results were also reported.14,15 To explore 8 1 0 2 l u J 3 1 n o 2 7 1 . 3 6 1 . 7 3 . 4 5 y b / m o c . rvpee l.yno tahned pcraencciesre rcisokr,rewlaetipoenrfobremtweedetnhidseml1e5ta1-8anpaolylysmisowrpithhisamll s s .dow lsue eligible publications. w a /w no / :s rs ttp pe h ro from F d e d a o l n w o d y p a r e h T d n a s t e g r a T o c n O Methods Publication search All possible publications related the association between MDM2 del1518 polymorphism and cancer risk were searched for from PubMed and Embase (up to March 29, 2017). The following items were used: “MDM2 or mouse double minute 2 homolog or human homolog of mouse double minute 2”, “del1518 or rs3730485”, “polymorphism or single-nucleotide polymorphism (SNP) or variant”, and “tumor or cancer or carcinoma or neoplasm”. The reference lists of all eligible studies in the initial search were searched manually to retrieve potentially relevant studies. To broaden our search to find the most relevant research, we also retrieved publications from Chinese Biomedical (CBM) database with items of “MDM2” and “cancer” in Chinese. inclusion/exclusion criteria Studies selected had to meet the following inclusion criteria: 1) evaluating the association between MDM2 del1518 polymorphism and cancer risk, 2) case–control studies, 3) supplying detailed genotype distribution data to estimate the odds ratio (OR) with 95% confidence interval (CI), and 4) published in English or Chinese. Only the latest study was selected from duplicate publications. In addition, studies with genotype frequency distribution of controls departed from Hardy–Weinberg equilibrium (HWE) were excluded from the final analysis. submit your manuscript | www.dovepress.com Dovepress Data extraction Information was extracted from studies by two authors (WH and AZ) independently. If two authors had disagreement, a third author would join in the discussion. A final decision would be made by voting. The following information was collected from each study: first author’s surname, year of publication, country of origin, ethnicity, cancer type, control source, total number of cases and controls, genotype methods, percent of males, and numbers of cases and controls with the Ins/Ins, Ins/Del, and Del/Del genotypes for del1518 polymorphism. The subgroup analysis was carried out by ethnicity (Asians and Caucasians), source of control (hospital based [HB] and population based [PB]), and cancer type. Cancer type investigated in only one study was classified into the “others” group. statistical methods Consistency with HWE in the control group was evaluated by Pearson’s goodness-of-fit χ2 test for each study (P,0.05 was considered as statistically significant deviation from HWE). OR and 95% CI were used to assess the strength of the association between the del1518 polymorphism and cancer risk. Pooled risk estimates were calculated under the alleles contrast (Del vs Ins), homozygous (Del/Del vs Ins/ Ins), heterozygous (Ins/Del vs Ins/Ins), dominant (Ins/Del and Del/Del vs Ins/Ins), and recessive (Del/Del vs Ins/Del and Ins/Ins) model. We used the chi square-based Q-test to determine the heterogeneity among studies. A P-value of ,0.1 means significant heterogeneity. Under such circumstances, the random-effects model would be taken to assess the pooled ORs; otherwise, the fixed-effects would be adopted.16–18 The quality assessment was also performed using the quality assessment criteria (Table S1) as described previously.19 All studies were scored from 0 to 15, and only studies with a score of $12 were regarded as high quality. Subgroup analysis was conducted by cancer type, source of control, quality score, and race. Begg’s funnel plots and Egger’s test were used to assess publication bias. The accuracy and reliability of results were verified by sensitivity analysis by sequentially removing one single study at a time to check the influence of deleted study on pooled ORs. All the statistical tests were conducted by STATA Version 11.0 (StataCorp LP, College Station, TX, USA). P,0.05 indicated statistical significance. Results study characteristics As shown in Figure 1, a total of 14 articles were retrieved from the initial literature search. After careful examination and assessment, three publications were excluded for the OncoTargets and Therapy 2017:10 following reasons: one had duplicate data with the previous research20andothertwowereirrelevantwithcancerrisk.21,22 All studies were in agreement with HWE, except for an article by Jin et al.11 We included this article for the further study because genotype distribution of the TP53 Arg72 Pro polymorphism was in accordance with HWE in the same study.11 Of these 11 publications, two publications involved twocancertypes14,23andonepublicationinvolvedfourcancer types.24Wedividedthesearticlesintodifferentindependent studies based on cancer type. And, the controls of these 1 E 1 3 0 0 00 8 1 6 5 7 5 5 5 5 9 9 n 3 6 9 9 . 1 5 3 9 5 9 9 9 9 6 6 io W .6 .2 .0 .0 0 .3 .9 .7 .1 .2 .0 .0 .0 .0 .0 .0 ta H 0 0 0 0 , 0 0 0 0 0 0 0 0 0 0 0 lu p o p F , 0 0 0 0 9 0 0 7 3 2 2 2 2 2 3 3 B A .3 .3 .3 .3 .5 .3 .3 .2 .2 .7 .4 .4 .4 .4 .4 .4 P M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ;e l b a l 3 9 9 9 9 2 2 ia 4 4 7 7 v ll ,08 05 42 42 40 57 23 26 97 32 ,74 ,47 ,7 ,7 ,8 ,8 a A 1 6 6 6 8 2 4 2 1 1 3 3 3 3 1 1 to n ; y c n 7 7 7 7 e 7 7 u D 46 14 58 58 91 51 87 2 4 8 ,7 ,7 ,77 ,77 77 77 eq l I 4 2 2 2 3 1 1 9 6 4 1 1 1 1 8 8 fr , a 7 7 7 7 9 9 n o r t 5 5 5 5 n 8 8 o I 23 05 10 10 82 22 06 18 19 3 ,2 ,2 ,28 ,28 36 36 r C I 5 3 3 3 1 1 2 1 1 1 1 1 1 1 6 6 no i m 2 1 7 1 5 4 ,F 1 0 8 0 a A 7 3 3 2 2 2 4 2 1 1 1 1 1 2 1 1 ; a m o n 9 0 7 5 6 8 i D 1 0 4 5 9 2 5 3 6 7 6 2 2 4 4 c D 5 3 2 8 9 1 5 1 2 5 2 2 3 4 2 2 r a c 0 D 1 5 4 2 0 0 9 1 0 9 75 24 09 ,24 55 64 s 7 7 6 6 9 u I 3 1 1 7 8 1 1 9 6 5 7 6 8 1 6 6 o m e a s u 9 9 1 2 2 9 0 8 7 1 6 4 2 q a I 4 7 8 3 5 3 6 2 1 7 7 4 8 3 8 9 s C I 3 1 1 1 2 1 1 1 7 1 4 4 5 8 4 4 l a e g a l h o p , r o ) t s e 0 . l(sae% /scaeno ../75237 ../000 ../62476 ../62436 /aan ../000 ../67550 ../58558 ../000 ../58061 ../52901 ../57201 ../000 ./000100 ../000 ../000 ,;scce M c 7 0 6 6 n 0 6 5 0 5 4 6 0 1 0 0 m u i r b e lii u p q y d e t o e l e ll a ll e c –Wl. y e d D rah /s u J 3 1 n o 2 7 1 . 3 6 1 . y b / d n s t e g r a T o c n three publications were included into meta-analysis only o h rg n t e e e r r r r r r r r r r r r r r r r b once. Main characteristics of each study are summarized i G m P P P P P P P P P P P P P P P P i s c c c c c c c c c c c c c c c c n s e y in Table 1. Totally, there were 12,905 cases ranging from a l n n a g 132 to 2,501 and 10,026 controls ranging from 132 to 3,749 a s - i t e e included in the present meta-analysis. Three studies were m t hWl;e conducted on esophageal squamous cell carcinoma,14,15,25 e y D n t n n n n n n n ; l/ two studies were conducted on breast,24,26 colorectal,11,24 rrcu iicn n n n n n n n n isaac n isaac isaac isaac isaac isaac isaac aom ,eD ovarian cancer,23,27 and lung,24,28 and five studies were con- teh thE isaa isaa isaa isaa isaa isaa isaa isaa acu isaa acu acu acu acu acu acu iraccn ;sDD n ductedon“others”,suchasgastriccardiacadenocarcinoma,14 in lra i/s d ry lu in hepatocellular carcinoma,12 uterine leiomyoma,13 prostate ed tn ay ay ay ay ay ay lce i,i cancer,24 and endometrial cancer.23 Twelve studies were licun uoC iacnh iacnh iacnh iacnh iacnh iacnh iacnh iacnh iran iacnh rnow rnow rnow rnow rnow rnow taepo ;ayom h s , m PB,11–14,24–26,28andfourstudieswereHB.15,23,27Moreover,there ie c ieo l ch l were seven studies performed among Caucasians13,23,24 and tsud r ltac n ltac te n itrae ;ed iren sncinoeresstoufdsieesveanmsotundgieAsswiaenres.,11,1122,14a,1n5,d25s–2c8oIrnesaodfdtihtieorne,mqauianliintyg iftssco caenC tyep lgun tsraeB scce itsrgac lrceoo iraavO cch scce lU scce lrceoo lgun tsraeB tsraPo iraavO endom iltssaabp ,l;teunU i o r ho it studies were $12. t a 60 60 70 70 80 90 21 21 51 51 61 61 61 61 71 71 ,B ae e r c ac e 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 h r n o 1 . y b / d n s t e g r a T o c n huaetal . t .001 94 80 09 .001 29 56 .001 82 .001 59 25 03 21 saebd eh 0 .6 .7 .8 0 .0 .5 0 .0 0 .8 .0 .0 .9 n P , 0 0 0 , 0 0 , 0 , 0 0 0 0 io t a l u p o ) ) ) ) ) ) ) ) ) ) ) ) ) p 2 3 5 0 3 6 8 1 2 8 4 4 8 , t IIsv I)C .1–1 .1–1 .1–1 .1–1 .1–3 .2–3 .1–0 .1–2 .1–1 .1–1 .1–0 .1–1 .1–1 ;PoB iann DD (59% .(940 .(910 .(920 .(730 .(830 .(860 .(820 .(810 .(970 .(950 .(860 .(980 .(730 itsrad m + 3 2 3 9 5 2 4 9 4 6 4 6 3 d oD ID RO .01 .01 .01 .80 .01 .41 .90 .90 .01 .01 .90 .01 .90 ,oR eh .0 .1 .3 .5 .0 .0 .9 .0 .1 .0 .5 .1 .0 .9 ,I P 0 0 0 0 0 0 0 0 0 0 0 0 0 0 l;I e k s i r 5 1 l e d f m ts n a a t e M s e 2 l e b l a b i r a a 3776 submityourmanuscript|www.dovepress.com Dovepress OncoTargetsandTherapy2017:10 Overall, the pooled risk estimates suggested that no statistically significant association was found between the polymorphism and cancer risk (Del/Del vs Ins/Ins: OR =1.01, 95% CI =0.90–1.14; Ins/Del vs Ins/Ins: OR =1.03, 95% CI =0.96–1.12; Del/Del vs Ins/Del + Ins/Ins: OR =0.98, 95% CI =0.90–1.07; Ins/ Del + Del/Del vs Ins/Ins: OR =1.03, 95% CI =0.94–1.12; Del vs Ins: OR =1.01, 95% CI =0.94–1.07). Moreover, the stratified analysis by source of control, quality score, cancer type, and ethnicity showed no evidence of the association between del1518 polymorphism and overall cancer risk. heterogeneity and sensitivity analysis As shown in Table 1, significant between-study heterogeneity was observed under the different models (homozygous model: P=0.003; heterozygous model: P=0.009; recessive model: P=0.049; dominant model: P,0.001; and allele comparing: P,0.001); therefore we adopted the randomeffects model to generate wider CIs. Sensitivity analysis suggested that ORs were not significantly altered by any single study, indicating that this meta-analysis result was stable and reliable. Publication bias The publication bias was performed by Begg’s funnel plot and Egger’s test. We found no asymmetry of funnel plot (Figure 3). In addition, the results of Egger’s test did not suggest any evidence of publications bias (homozygous: P=0.919; heterozygous: P=0.921; recessive model: P=0.920; dominant model: P=0.921; and allele comparing model: P=0.990). Discussion The tumor suppressor p53, a transcriptional factor, essentially controls the growth and development of normal cells. p53 instability may lead to cell cycle disorder and aberrant cellular apoptosis, thereby strongly contributing to malignant transformation and progression.29,30 The MDM2 gene, a genomic size of 34 kb, contains two promoters, such as a p53-responsive promoter and a p53-independent promoter.8 MDM2, as a major mechanism of genetic toxicity and carcinogenesis, is a principle regulator of the stabilization of 8 p53 in the no-stress condition.31 MDM2, functioning as an -102 E3 ligase, specifically complexes with p53 by the N-terminus l-Ju domain and induces its degradation through proteasomal n13 pathway.32,33 The expression of MDM2 is elevated by p532o7 positive regulation. Given a negative autoregulatory loop .163 between MDM2 and p53, the importance of MDM2 has .17 been proved in the central part of p53-assosiated signal .534 pathway.34,35 Genetic variations, including SNPs and other /yb types of polymorphisms, may modify genetic predisposition .com to diseases.36 Some genetic alterations located in the MDM2 ss gene, such as SN309,37 have been proved to be associated rvpee l.yno with cancer risk.16,38,39 As far as we know, there are at least .dow lsue 4,765 polymorphisms found in the MDM2 gene (http://www. /ww ano ncbi.nlm.nih.gov/projects/SNP). One of the frequently inves/ ttsp rspe tigated polymorphisms is MDM2 del1518, a common 40 bp : h ro Ins/Del polymorphism, located in constitutive promoter with from F a putative TATA motif.10,26 adde Due to the special location of del1518 polymorphism, its lon association with cancer risk has been a hot spot. Salimi et al dow suggested that women carrying del allele had an increased ryap risk of uterine leiomyoma compared with the women carrying ehT MDM2 40 bp insert allele.13 Jin et al reported that the 40 bp adn deletion allele had an important role in the oncogenesis of tsge colorectal cancer, specially for rectal cancer.11 In addition, raT a genetic association study by Dong et al have found that con the del1518 was significantly associated with an increased O risk of hepatocellular carcinoma.12 While some studies have considered del1518 del-allele as susceptibility loci for the risk of various cancer types,14,15 other studies failed to confirm its contribution to cancer risk.23–28 The discrepant results might be caused by small sample size, and variations among different study populations. Moreover, it is widely believed that malignancies arising from different tissue had completely distinct molecular mechanisms, and even the same cancer type could display significant heterogeneity among different individuals. In the current meta-analysis, we combined all eligible investigations comprising 12,905 cases and 10,026 controls from 16 studies on MDM2 del1518 polymorphism. We found no significant association between del1518 polymorphism in the overall analysis and stratification analyses by cancer submit your manuscript | www.dovepress.com Dovepress type, ethnicity, source of control, and scores. A latest metaanalysis conducted by Yu et al found that there was no significant difference between del1518 polymorphism and overall squamous cell carcinoma susceptibility with a total of 309 cases and 1,000 controls from three studies, results of which is consistent with the current study.22 To our knowledge, this investigation is the largest and most comprehensive meta-analysis regarding the association between del1518 polymorphism and all cancer type. However, there were still some limitations to be addressed. First, statistical power might be limited to certain degree, especially for stratified analyses, such as cancer type of gastric, hepatocellular, uterine leiomyoma, prostate, and endometrial. Hence, the results of this meta-analysis should be interpreted with caution. Second, because of the stratification analysis of ethnicity included Asians and Caucasians only, we could not take genetic and geographical differences into consideration. Further analysis should contain diverse area and ethnicities. Third, the results of this study were based on unadjusted estimates by the reason of insufficient data of individual such as age, gender, smoking, environment exposure, and lifestyles. Gene–gene and gene–environment interactions could not be explored. Fourth, there was obvious heterogeneity for the meta-analysis, which might owe to differences in cancer types, the populations, geographical area, and study designs. Finally, the included studies were mainly searched for from PubMed, Embase, and CBM; therefore, publication bias might exist in this metaanalysis for the unavailability of the unpublished studies with negative results. Conclusion Our present meta-analysis suggested no association between MDM2 gene del1518 polymorphism and overall cancer susceptibility. Further well-designed study with large sample sizes, different ethnicities, cancer types, and gene– environment interactions is needed to confirm our findings. Acknowledgments This study was supported by grants from the introduction of talent scientific research start-up fund of Guangdong Second Provincial General Hospital (YY2016-004), Scientific Research Foundation of Wenzhou (Y20100175), Zhejiang Provincial Medical and Health Science and Technology plan (2013RCA035), Project of Science and Technology Department of Zhejiang Province (2014C37003), and Zhejiang Provincial Natural Science Foundation of China (LY16H160054). 8 1 0 2 l u J 3 1 n o 2 7 1 . 3 6 1 . 7 3 . 4 5 y b / m o c . s s rvpee l.yno .dow lsue w a /w no / :s rs ttp pe h ro Disclosure The authors report no conflicts of interest in this work. submit your manuscript | www.dovepress.com Dovepress 3779 8 1 0 2 l u J 3 1 n o 2 7 1 . 3 6 1 . 7 3 . 4 5 y b / m o c . s s rvpee l.yno .do se w lu w a /w no / :s rs ttp pe h r o om F fr d e d a o l n w o d y p a r e h T d n a s t e g r a T o c n O Supplementary material Publish your work in this journal OncoTargets and Therapy is an international, peer-reviewed, open access journal focusing on the pathological basis of all cancers, potential targets for therapy and treatment protocols employed to improve the management of cancer patients. 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Wenfeng Hua, Anqi Zhang, Ping Duan, Jinhong Zhu, Yuan Zhao, Jing He, Zhi Zhang. MDM2 promoter del1518 polymorphism and cancer risk: evidence from 22,931 subjects, OncoTargets and Therapy, 2017, 3773-3780, DOI: 10.2147/OTT.S140424