QUINTESSENCE INTERNATIONAL ORAL MEDICINE

Georgios S. Chatzopoulos Systematic review of cyclosporin A-induced gingival overgrowth and genetic predisposition

Georgios S. Chatzopoulos, DDS1/Vasiliki P. Koidou, DDS1/Larry F. Wolff, MS, PhD, DDS2

Objective: This systematic review aimed to investigate the not a meta-analysis of the data was performed. Fourteen articles influence of gene polymorphisms on the development of gin- meeting study inclusion criteria were selected for data extraction gival overgrowth in renal transplant patients treated with that examined the association between various genetic polymor- cyclospo rin A. Method and Materials: Electronic and hand phisms and gingival overgrowth in kidney transplant patients literature searches were conducted by two independent receiving cyclosporin A. Interleukin-1A, interleukin-10, trans- reviewers in MEDLINE-Pubmed, Cochrane Library, ISI Web of forming growth factor-β1 and androgen receptor gene polymor- Science, and SCOPUS Elsevier for prospective (case-control phisms may have a significant effect on an individual studies, cohort studies), cross-sectional, and retrospective susceptibility to cyclosporin A-induced gingival overgrowth in studies published up to June 2016 (first week) in any language. renal transplant patients. Conclusion: Genetic polymorphisms Data were reviewed and extracted in duplicate independently. seem to affect the development of cyclosporin A-induced gingi- Methodologic quality assessment of the included studies was val overgrowth in renal transplant patients. Pharmacogenetics performed during the data extraction process. Results: Due to and pharmacogenomics have the potential to determine the the estimated high risk of bias and the heterogeneity of the clinical outcome of a medication, the drug efficacy, and adverse included studies in regards to the variety of medications admin- drug reactions such as gingival overgrowth. (Quintessence Int istered to study patients, a systematic review of the literature and 2017;48: 711–724; doi: 10.3290/j.qi.a38120)

Key words: cyclosporin, gingival overgrowth, genetic predisposition

Medications for cardiovascular, respiratory, endocrine, oral health.1 These medications have the potential to hematologic, neurologic, urogenital, dermatologic, gas- impact susceptibility to periodontal diseases and may trointestinal, and musculoskeletal diseases may affect be divided into four categories including those that affect: ; the diagnosis of periodontal dis- ease; gingival and oral mucosa tissues; and alveolar bone metabolism.1 Gingival overgrowth may be inher- ited (hereditary gingival fibromatosis), idiopathic, or 1 Resident in , Advanced Education Program in Periodontology, Department of Developmental and Surgical Sciences, School of , Uni- even associated with systemic diseases, but drug-in- versity of Minnesota, Minneapolis, MN, USA. duced gingival overgrowth represents the majority of 2 Professor, Division of Periodontology, Department of Developmental and Surgi- cal Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA. these cases. Fibrotic enlargement of the gingival tissues

Correspondence: Dr Georgios S. Chatzopoulos, Advanced Education is a commonly observed adverse effect of various drug Program in Periodontology, Department of Developmental and Surgical categories such as anti-epileptic, calcium channel Sciences, School of Dentistry, University of Minnesota, 515 Delaware St. SE, Minneapolis, MN 55455, USA. Email: [email protected] blockers, and immunosuppressant drugs.2

VOLUME 48 • NUMBER 9 • OCTOBER 2017 711 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

Fig 2. Histologically, drug-induced gingival overgrowth consists of hyperplasia in the and hypertrophy in the keratinized epithelium as well as excessive connective tissue accumulation.10 Cyclosporin A is a widely used immunosuppressant used to prevent organ rejection after renal transplanta- tion, and gingival overgrowth is a frequently observed side effect.11 The reported prevalence of gingival over- growth among renal transplant patients treated with Fig 1 Clinical presentation of gingival overgrowth partially cyclosporin A varies from 13% to 84%, while the exact covering the teeth of a patient taking cyclosporin A. mechanism responsible for the cyclosporin A-induced gingival overgrowth still remains unclear.12-15 Age, sex, periodontal status prior to transplantation, poly-medi- cation, and local factors such as plaque accumulation For the patient, may result in are additional risk factors of drug-induced gingival emotional and social problems that are often underes- overgrowth.16 Combined treatment of cyclosporin and timated by the health professional.3,4 Transplant anti-re- a calcium channel blocker is more likely to lead to jection drugs have been reported to compromise the severe gingival overgrowth compared to cyclosporin quality of life of patients after transplantation.3,4 Clinical alone.12 However, it still remains unclear why a propor- presentation of gingival overgrowth varies and can tion of renal transplant patients are more prone to present as non-inflamed, firm, and fibrotic, or hemor- gingival overgrowth compared to others who maintain rhagic, edematous, and significantly inflamed tissue. well with unaffected gingival tissues. Recently, several Gingival enlargement of the anterior labial areas is studies aimed to investigate the influence of genetic usually the initial sign and the region of the canine is polymorphisms on cyclosporin A pharmacokinetics and often the most significantly affected.5,6 Gingival over- pharmacodynamics in recipients of renal transplanta- growth partially covering the teeth of a patient taking tion. The regulation of cytokine expression and the cysclosporin A is displayed in Fig 1. It usually initiates as unique aspects of gingival fibroblast metabolism are all interdental swelling that increases in size and may potential contributing factors in gingival overgrowth compromise mastication, occlusion, speech, and the and the development of synthetic or proliferative fibro- ability of patients to practice optimal oral hygiene. As blast phenotypes.17,18 There is an increased interest in the marginal and papillary gingival enlargement pro- the clinical application of genetics to guide prevention gresses, the deepening of periodontal pockets is asso- and treatment of oral diseases.19,20 This emerging field ciated with subgingival microbiota that may lead to of personalized/precision medicine involves a more gingival inflammation and progression of periodontal specific approach to health care of an individual in destruction.7 Moreover, increased concentrations of which genetic, environmental, and pharmacologic fac- disease-associated inflammatory cytokines have been tors are all taken into consideration in targeting ther- detected in individuals with gingival overgrowth.8 apy to an individual. Untreated cases of gingival overgrowth may advance A number of different polymorphisms of various to severe chronic due to the forma- genes have been tested as possible risk factors for gin- tion of a pathogenic biofilm, which the patient may be gival overgrowth. Interleukin-6 (IL-6) is a pro-inflamma- unable to remove.9 An example of the appearance of tory cytokine that plays an important role in the fibro- severe gingival overgrowth induced by cyclosporin A genic events of drug-induced gingival overgrowth.21,22 and aggravated by plaque accumulation is shown in Increased proliferation and positive regulation on col-

712 VOLUME 48 • NUMBER 9 • OCTOBER 2017 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

ab Figs 2a and 2b Severe gingival enlargement induced by cyclosporin A and aggravated by plaque accumulation in (a) the maxillary anterior teeth and (b) the mandibular anterior teeth (courtesy of Dr Aikaterini-Ellisavet Doufexi, Private practice, Thessaloniki, Greece).

lagen and glycosaminoglycan synthesis are commonly have been associated with altered IL-10 expression caused by IL-6 and it is noteworthy that with cyclospo- levels and periodontal disease.30-32 Excessive anti-in- rin A-induced gingival overgrowth, an increased IL-6 flammatory responses in conjunction with reduced expression has been reported.21,22 Multidrug resistance pathogen clearance within the gingival tissues can 1 (MDR1) gene has also been associated with drug enhance the development of cyclosporin A-induced resistance and encodes P-glycoprotein, which is a gingival overgrowth. Androgens are sex hormones that potential determinant of cyclosporin A excretion.23 The are found in high concentrations in men and are variability of P-glycoprotein expression could be the metabolized actively in gingival tissues. In healthy gin- reason for the adverse response to the association of giva of men, testosterone is metabolized to a greater cyclosporin A with hyperplastic gingival tissues. Trans- extent compared to women, while in inflamed gingival forming growth factor beta 1 (TGF-β1) is a multifunc- tissues the extent of the metabolism is similar in both tional growth cytokine that stimulates fibroblast prolif- sexes.33 Cyclosporin A-induced gingival overgrowth has eration and extracellular matrix formation.24 In clinical been associated with increased levels of androgen studies, transplant patients medicated with cyclosporin metabolism, while testosterone injection into dogs was A exhibited increased gingival crevicular fluid levels of associated with an increase of hyperplastic gingival TGF-β1,25 and this cytokine has also been associated tissues.34,35 Polymorphism in the repeat length of a CAG with an increased risk for gingival overgrowth.26 TGF- β1 trinucleotide may have a potential role in the patho- may play a pivotal role in the pathogenesis of cyclosporin genesis of benign prostatic hyperplasia, prostate can- A-induced gingival overgrowth. cer, polycystic ovary syndrome in women, and breast Interleukin-10 (IL-10) is an anti-inflammatory cyto- cancer in women.36-39 kine that regulates the inflammatory immune response IL-1A is considered an important cytokine involved and as a result tissue destruction.27 IL-10 has been in tissue destruction associated with periodontal dis- reported to hold a protective role in the inflammatory ease,40 while activation of MMPs is involved in tissue response, tissue destruction, and bone resorption by breakdown.41 In contrast, IL-1A has been shown to inhibiting a series of pro-inflammatory mediators promote fibroblast proliferation as a result of nifedip- including suppression of IL-1, IL-6, IL-8, tumor necrosis ine-induced gingival overgrowth.42 As IL-1A exhibits factor α, and matrix metalloproteinases (MMPs).28,29 The both anabolic and catabolic effects, regulation of its single nucleotide polymorphisms (SNPs) in the pro- levels by cyclosporin A may lead to a loss of homeo- moter region of IL-10 gene −592, −819, and −1,082 static balance in the gingival tissues. MMPs are host-de-

VOLUME 48 • NUMBER 9 • OCTOBER 2017 713 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

rived proteinases that play an important role in the Information sources degradation of different proteins of the extracellular Electronic and hand literature searches were conducted matrix such as collagen. MMP-1 initiates extracellular by two independent reviewers in MEDLINE-Pubmed, matrix destruction and a significant reduced expres- Cochrane Library, ISI Web of Science, and SCOPUS Else- sion of MMP-1 has been reported to be associated vier, for studies published up to June 2016 (first week) with overgrowth of gingival tissues of renal trans- in any language. The electronic search was performed planted patients medicated with cyclosporin A.43 utilizing the following key terms: (gingival over- Other investigators have shown that cyclosporin A growth[MeSH Terms] OR GO[All Fields] OR gingival inhibited the production of MMP-1 and MMP-3 by enlargement[All Fields] OR gingival hyperplasia[MeSH gingival fibroblasts at concentrations detected in the Terms] OR gingival fibromatosis[All Fields]) AND ((cyc- serum.44 Therefore, altered turnover of the extracellu- losporins[MeSH Terms] OR cyclosporine[MeSH Terms]) lar matrix could potentially affect periodontal pathol- OR cyclosporine [All Fields]) OR CsA[All Fields]) AND ogy leading to gingival hyperplastic tissues. Genetic ((genetic polymorphism[All Fields] OR polymor- polymorphisms are commonly associated with altered phism[All Fields]) OR (genotype[MeSH Terms] OR transcriptional activity and could possibly make indi- genetics[MeSH Terms])). A hand search of periodon- viduals more susceptible to disease development tics-related journals including Journal of Dental such as gingival overgrowth or increased disease Research, Journal of Clinical Periodontology, Journal of severity. The presence of genetic polymorphisms may Periodontology, and Journal of Periodontal Research explain cytokine and cell receptor production and was also performed. References of all relevant studies function. were hand-searched, with no language restriction to Therefore, the aim of this systematic review was to any of the searches. investigate the influence of gene polymorphisms on the development of gingival overgrowth in renal trans- Patient, Intervention, Comparison, Outcome plant patients treated with cyclosporin A. (PICO) question • P = patients with renal transplantation receiving cyclosporin A and manifesting gingival overgrowth METHOD AND MATERIALS • I = assessment of the soft tissues in regards to the This systematic review was conducted according to the presence of gingival overgrowth at least 6 months Cochrane handbook for systematic reviews and the after renal transplantation PRISMA-statement protocol has been utilized to ensure • C = patients with renal transplantation receiving cyc- appropriate reporting.45,46 The flowchart of the search losporin A and not manifesting gingival overgrowth strategy according to the PRISMA protocol is shown in • O = presence of gene polymorphisms Fig 3. Study selection Focused questions Two authors (GC, VK) performed the search and screen- • What is the effect of a gene polymorphism on the ing process independently. Titles and abstracts were clinical development of gingival overgrowth in first evaluated and analyzed for their eligibility. Selec- renal transplant patients receiving cyclosporin A? tion of full-text articles for reviewing was followed and • Is there any genetic predisposition among cyclo- analyzed with respect to the inclusion and exclusion sporin A-treated subjects who have undergone criteria that were set. Any disagreement between the renal transplantation with respect to the presence reviewers was resolved with discussion until agreement of gingival overgrowth? was reached. Cohen kappa test was utilized to test the inter-examiner variability.

714 VOLUME 48 • NUMBER 9 • OCTOBER 2017 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

Records identifi ed through Additional records identifi ed database searching through other sources* (n = 124) (n = 0) cation Identifi

Records after duplicates removed (n = 102)

Records screened Records excluded

Screening (n = 102) (n = 84)

Full-text articles assessed Full-text articles excluded for eligibility with reasons† (n = 18) (n = 4) Eligibility

Studies included in qualitative synthesis (n = 14)

Studies included in quantitative synthesis Included meta-analysis)‡ (n = 0)

Fig 3 Flowchart of the search strategy according to the PRISMA protocol.

*A hand search of periodontics-related journals including Journal of Dental Research, Journal of Clinical Periodontology, Journal of Periodontology, and Journal of Periodontal Research was also performed. References of all relevant studies were hand-searched, with no language restriction to any of the searches. †Four studies excluded were because of a lack of reported diagnostic criteria for gingival overgrowth, absence of clinical measurements and information surrounding the period between the transplantation and the examination,48 absence of information or inadequate time after the transplantation,49,50 and the absence of a control group, that is individuals on cyclosporin A without the presence of gingival overgrowth.51 ‡Due to the estimated high risk of bias and the heterogeneity of the included studies in regards to the variety of medications administered to study patients, a meta-analysis of the data was not performed.

Eligibility criteria • The subject of interest was a patient that exhibited All articles that met the following inclusion and exclu- gingival overgrowth and a control or a patient sion criteria were included in the systematic review. receiving cyclosporin A and not manifesting gingi- Inclusion criteria were: val overgrowth. • All prospective (case-control studies, cohort stud- • The included study participants received treatment ies), cross-sectional, and retrospective studies with cyclosporin A for at least 6 months. The mini- reporting on the eff ect of genotype in renal trans- mum period of 6 months was defi ned as a period plant patients with and without gingival over- adequate to manifest adverse eff ects of cyclosporin growth were considered for inclusion. A treatment after renal transplantation.

VOLUME 48 • NUMBER 9 • OCTOBER 2017 715 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

• Studies had at least ten participants. experimental groups, CONSORT implementation, and • The definition of gingival overgrowth was reported ISRCTN registration. Overall risk of bias was classified and clinical measurements had been performed. into low, medium, or high. Low risk of bias was • Studies that included smokers were also included. reported in studies that fulfilled all the assessed com- • No language restriction was applied. ponents, medium risk when only a limited number of Exclusion criteria were studies that: assessed components were met, and high risk when • were letters, case reports, reviews, and case series the evaluated study fulfilled none of the assessed cat- • did not include a control group egories.47 • included patients who had been receiving treat- ment with cyclosporin A for less than 6 months RESULTS • did not include clinical examination of the gingival overgrowth. Study selection The flowchart of the search strategy according to Data extraction PRISMA protocol is shown in Fig 3. Initial screening of Detailed data extracted from the 14 evaluated cross- the electronic databases yielded 124 potentially eligi- sectional studies are shown in Table 1. ble articles: 97 were retrieved from Pubmed/MEDLINE, Data were reviewed and extracted in duplicate inde- 3 from SCOPUS, 1 article from The Cochrane Library pendently. The following information was retrieved and 23 articles from the Web of Science (n = 124). After from each full-text reviewed study: duplicate references were removed (n = 102), titles and • name of first author abstracts were reviewed and 18 articles were selected • year of publication for further analysis.48-65 After full-text reading and evalu- • country of origin for the study ation of these 18 articles, 14 articles52-65 that met the • ethnicity of the study participants study analysis criteria were finally included in this • genetic variants review based on the inclusion and exclusion criteria. • characteristics of the cases and controls (sex and The four studies that were excluded were because of a mean age) lack of reported diagnostic criteria for gingival over- • pharmacologic agents used in the study growth, absence of clinical measurements, and infor- • type of examiner mation surrounding the period between the transplan- • period of time between renal transplantation and tation and the examination,48 absence of information or examination. inadequate time after the transplantation,49,50 and the absence of a control group, that is individuals on cyclo- Quality assessment of the included studies sporin A without the presence of gingival overgrowth.51 Criteria used for the methodologic quality assessment Finally, 14 articles meeting study inclusion criteria were of the 14 individual studies are shown in Table 2. Meth- selected for data extraction that examined the associa- odologic quality assessment of the included studies tion between various genetic polymorphisms and gin- was performed independently by two study reviewers gival overgrowth in kidney transplant patients receiv- (GC, VK), during the data extraction process. The quality ing cyclosporin A. The inter-reviewer agreement assessment protocol assessed the following param- (kappa) was calculated at the first phase of selection of eters: presence of randomization, masking of examin- the articles from the databases as well as after full-text ers/therapist/patient/statistician, calibration, definition and citation mining. The agreement at both phases was of inclusion/exclusion eligibility criteria, follow-up, eth- very high, .90 and .98, respectively. ical considerations, funding sources, statistical analysis, and miscellaneous parameters such as comparable

716 VOLUME 48 • NUMBER 9 • OCTOBER 2017 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

Table 1 Detailed data extracted from the 14 evaluated cross-sectional studies

Cases Control Period between Country (n); M/F; (n); M/F; transplantation origin/ Gene mean mean and examination Study ethnicity polymorphisms age (y) age (y) Pharmacologic agents Examiner (mo) TGF-β1 −800, 84; 140; Cyclosporin A, azathioprine, Two independent Kozak et Poland/Polish −509, +896, 61/23; 91/49; prednisone, diltiazem, or periodontal 6 al52 +915 42.2 39.7 verapamil specialists 62; 124; Cyclosporin A, azathioprine, Two independent Drozdzik Poland/Polish SPARC 998 39/23; 65/59; prednisone, diltiazem, or periodontal 6 et al53 38.6 42.4 verapamil specialists 61; 121; Cyclosporin A, azathioprine, Two independent Kurzawski Poland/Polish MMP-1 −1,607 39/22; 62/59; prednisone, diltiazem, or periodontal 6 et al54 38.6 42.4 verapamil specialists 63; 125; Cyclosporin A, azathioprine, Two independent Drozdzik Poland/Polish MMP-3 −1,171 41/22; 65/60; prednisone, diltiazem, or periodontal 6 et al,55 38.6 42.4 verapamil specialists 64; 111; Cyclosporin A, diltiazem or Two independent Drozdzik Poland/Polish IL-6 −174 40/24; 60/51; verapamil, prednisone, and periodontal 6 et al56 38.6 42.4 azathioprine specialists 54; 120; Cyclosporin A, azathioprine, Two independent Drozdzik Poland/Polish MDR1, exon 26 36/18; 61/59; prednisone, diltiazem, or periodontal 6 et al57 39.5 43.7 verapamil specialists Bostanci et Turkey/ 25; 16/9; 26; 14/12; Cyclosporin A, predniso- IL-1A −889 Single investigator ≥ 6 al58 Turkish 30 36 lone, azathioprine 40; 114; Kazancio- Turkey/ MDR1 C3435T 26/14; 70/44; Cyclosporin A NR ≥ 6 glu et al59 Turkish 37.37 37.96 122; China/ IL-10 −1,082, 80; 48/32; Cyclosporin A, mycopheno- Luo et al60 83/39; NR ≥ 6 Chinese −819, −592 45 late mofetil, prednisolone 45 100; Al Sayed et Saudi Arabia/ 50; 41/9; AR1 83/17; Cyclosporin A Single investigator ≥ 6 al61 NR 34.9 31.1 Cyclosporin A, azathioprine, Radwan- prednisolone with or with- TGF-β1 +869, 50; NR; 42; NR; Oczko et Poland/NR out mycophenolate mofetil; One dentist 57.1 ± 42.6 +915 40.2 39.3 al62 verapamil, amlodipine, or nitrendipine 124; Gong et 80; 48/32; Cyclosporin A, mycopheno- Two trained and China/NR CD14 −260 84/40; ≥ 6 al63 45 late mofetil, prednisolone calibrated 45 Linden et United King- TGF-β1 +869, 46; NR; 118; NR; Cyclosporin A, calcium One blinded ≥ 12 al64 dom/NR +915 NR NR channel blocker 70; Cyclosporin A, predniso- Gürkan et 79; 42/37; Turkey/NR ITGA2 +807 40/30; lone, azathioprine, or myco- One periodontist > 6 al65 33.6 32.9 phenolate

AR1, androgen receptor, exon 1; CD14, cluster of differentiation 14; IL, interleukin; ITGA2, alpha 2 integrin gene; MDR1, multi-drug resistance 1; M/F, males/females; MMP, matrix metalloproteinase; n, sample size; NR, not reported; SPARC, secreted protein, acidic, and rich in cysteine; TGF-β1, transforming growth factor beta 1.

Study characteristics the genetic variants analyzed, the total number of Detailed data extracted from the 14 evaluated cases/controls, males/females as well as mean age (in cross-sectional studies are shown in Table 1. The data years) for the two study groups, the pharmacologic include the country origin of the sample, the ethnicity, agents used in each study, the examiner, and the

VOLUME 48 • NUMBER 9 • OCTOBER 2017 717 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

Table 2 Methodologic quality assessment of the 14 included studies evaluated

Ethical Miscella- Random- Calibra- Eligibility consider- Statistical neous com- Study ization* Masking† tion‡ criteria§ Follow-up‖ ations¶ Funding# analysis** ments†† NR; NR; Yes; No; Patient; Kozak et al52 NA NR Yes; No NR Yes; Yes Ministry Yes; NR; NA NR Yes Drozdzik et Research No; Patient; NA NR NR Yes; No NR Yes; Yes Yes; NR; NA al53 foundation Yes Kurzawski No; Patient; NA NR NR Yes; No NR Yes; Yes NR Yes; NR; NA et al54 Yes Drozdzik et No; Patient; NA NR NR Yes; No NR Yes; Yes NR Yes; NR; NA al55 Yes Drozdzik et No; Patient; NA NR NR Yes; No NR Yes; Yes NR Yes; NR; NA al56 Yes Drozdzik et No; Patient; NA NR NR Yes; No NR Yes; Yes NR Yes; NR; NA al57 Yes Bostanci et No; Patient; NA NR NR Yes; Yes NR NR; Yes NR Yes; NR; NA al58 Yes Kazancioglu No; Patient; NA NR NR Yes; Yes NR Yes; Yes NR Yes; NR; NA et al59 Yes NR; NR; Yes; Research No; Patient; Luo et al60 NA NR Yes; Yes NR Yes; NR Yes; NR; NA NR foundation Yes Al Sayed et No ; Patient; NA NR NR Yes; Yes NR Yes; Yes Ministry Yes; NR; NA al61 Yes Radwan- No ; Patient; NA NR NR Yes; NoNR Yes; YesNR Yes; NR; NA Oczko et al62 Yes Research No; Patient; Gong et al63 NA NR NR Yes; Yes NR Yes; NR Yes; NR; NA foundation Yes Linden et NR; NR; Yes; No; Patient; NA NR Yes; No NR NR; Yes NR Yes; NR; NA al64 NR Yes University Gurkan et NR; NR; Yes; Yes; Patient; NA NR Yes; Yes NR Yes; Yes research Yes; NR; NA al65 NR Yes funds

NA, not applicable or not available; NR, not reported. All studies had an estimated risk of bias categorized as high. The risk of bias was classified as high when the evaluated study fulfilled none of the assessed categories. The quality assessment protocol assessed the following parameters: *presence of randomization (randomized, adequate sequence generation, allocation concealment, concealment adequate) †masking of: examiners; therapist; patient; statistician ‡calibration (intra-examiner, inter-examiner) §definition of inclusion; exclusion criteria ‖follow-up (percentage of completed follow-ups, adequate correction) ¶ethical considerations: ethics approval; informed consent #funding sources **statistical analysis: sample size calculation; unit analysis; appropriate statistics applied ††miscellaneous parameters: comparable experimental groups; CONSORT implementation; ISRCTN registration

period between the transplantation and the clinical overgrowth). The 14 included studies were published examination. Overall, included in the 14 studies of this between 2001 and 2014 and all were cross-sectional in systematic review were 915 individuals that received design. The study population in six studies consisted of treatment with cyclosporin A after renal transplanta- subjects who were of Polish origin,52-57 two of the stud- tion and presented with gingival overgrowth, while ies included a Turkish origin population,58,59 one study 1,380 subjects served as controls (received cyclosporin investigated a subject population of Chinese origin,60 A after renal transplant but did not manifest gingival while the remaining five reviewed articles did not

718 VOLUME 48 • NUMBER 9 • OCTOBER 2017 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

Table 3 Primary conclusions of the 14 studies in which data were extracted and evaluated

Year Study published Conclusion No association between the TGF-β1 gene polymorphism and gingival overgrowth was revealed in kidney trans- Kozak et al52 2011 plant patients administered cyclosporin A. No association between SPARC gene polymorphism and gingival overgrowth was revealed in kidney transplant Drozdzik et al53 2007 patients who were administered cyclosporin A. No association between the MMP-1 gene polymorphism and gingival enlargement was revealed in kidney trans- Kurzawski et al54 2006 plant patients who were administered cyclosporin A as a principal immunosuppressive agent. No association between MMP-3 gene polymorphism and gingival overgrowth was revealed in kidney transplant Drozdzik et al55 2010 patients administered cyclosporin A. No association between the IL-6 gene polymorphism and gingival overgrowth was revealed in kidney transplant Drozdzik et al56 2005 patients administered cyclosporin A as a principal immunosuppressive agent. No association between the MDR1 gene polymorphism and gingival overgrowth was revealed in kidney trans- Drozdzik et al57 2004 plant patients administered cyclosporin A as a principal immunosuppressive agent. Bostanci et al58 2006 IL-1A polymorphism might alter individual susceptibility to cyclosporin A. Kazancioglu et The MDR1 gene polymorphism is not associated with gingival hyperplasia frequency, but may be associated with 2013 al59 gingival hyperplasia severity. IL-10-819TT (−592AA) genotype and ATA haplotype are associated with susceptibility to cyclosporin A-induced Luo et al60 2013 gingival overgrowth. The findings suggest a link between cyclosporin A-induced gingival overgrowth and a smaller size of CAG repeat Al Sayed et al61 2014 in the AR gene. Radwan-Oczko et High and intermediate TGF-β1 producer phenotypes and heterozygous genotype 10T/C might be considered 2006 al62 risk factors for gingival overgrowth in patients treated with cyclosporin A. No association between CD14 −260 polymorphisms and the prevalence of gingival overgrowth was revealed in Gong et al63 2013 renal transplant patients administered cyclosporin A. Polymorphisms in the TGF-β1 gene influence the expression of gingival overgrowth in renal transplant recipients Linden et al64 2001 concomitantly treated with cyclosporin and a calcium channel blocker. ITGA2 +807 gene polymorphism is not associated with susceptibility to cyclosporin A-induced gingival Gurkan et al65 2014 overgrowth.

AR, androgen receptor; CD14, cluster of differentiation 14; ITGA2, alpha 2 integrin gene; IL, interleukin; MDR1, multi-drug resistance 1; MMP, matrix metalloproteinase; SPARC, secreted protein, acidic, and rich in cysteine; TGF-β1, transforming growth factor beta 1.

report the origin of their sample population.61-65 Cyclo- al.67 Relative to the gene polymorphisms examined, sporin A was the administered pharmacologic agent TGF-β1 polymorphisms were examined in three stud- used in all studies, and most investigators reported ies,52,62,64 MDR1 in two studies,57,59 and secreted protein administration of additional agents, such as azathio- (SPARC),53 MMP-1,54 MMP-3,55 IL-6,56 IL-1A,58 IL-10,60 prine, prednisone, diltiazem, verapamil, nitredipine, androgen receptor (AR), exon 1 (AR1),61 cluster of differ- amlodipine, and mycophenolate mofetil. The clinical entiation 14 (CD14),63 α2 integrin gene (ITGA2),65 all in examination was performed by one or two examiners, one study (Table 1). at least 6 months after the transplantation. All the included studies utilized the clinical scoring method Quality assessment according to Pernu et al,66 in which the included Methodologic quality assessment of the included 14 patients were ascribed a general whole-mouth score of evaluated studies is shown in Table 2. The quality between 0 and 3 based on the severity of the gingival assessment of these studies all demonstrated a high overgrowth, except for one study64 where plaster mod- estimated risk of bias.47 Due to the lack of consistent els were used and assessed as described by James et randomization and concealment, masking, sample size

VOLUME 48 • NUMBER 9 • OCTOBER 2017 719 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

calculation, and power analysis across studies, the data that gingival overgrowth was also independent of age, should be interpreted with caution. None of the gender, treatment duration, and cyclosporin A dos- included studies estimated with a low risk of bias due age.60 to the study protocol and design of the included stud- Frequency of distribution analysis was carried out ies. Therefore, due to the estimated high risk of bias by Al Sayed et al,61 who examined the association of the and the heterogeneity of the included studies in gingival overgrowth and the length of the CAG repeats regards to the variety of medications administered to in the AR gene. The difference in allele distribution was study patients, a meta-analysis of the data was not per- statistically significantly (P < .05) different among those formed. individuals with and without gingival overgrowth showing that only 4% of the gingival overgrowth group Results of the included studies participants exhibited an allele size of 8 or more as The primary conclusions of the evaluated studies are compared with 97% of those in the control group. A given in Table 3. significant difference (P < .05) was also reported in Results provided evidence that IL-1A,58 IL-10,60 AR,61 regards to the median of the allele size in the study and and TGF-β162,64 gene polymorphisms may influence the control group: 3.3 for the study group and 11.0 for the individual susceptibility to cyclosporin A-induced gin- control. In addition, gender, age, mean duration of cyc- gival overgrowth in renal transplant patients. In con- losporin A therapy, and dose of cyclosporin A were trast, in the present investigation, the gene polymor- confounders of this difference.61 phisms of SPARC,53 MMPs 1 and 3,54,55 IL-6,56 MDR1,57 The prevalence and severity of gingival overgrowth CD14,63 and ITGA265 revealed no association with the treated with cyclosporin A and a calcium channel cyclosporin A-induced gingival overgrowth, while blocker were associated with functional polymor- IL-1A, IL-10, AR1, and TGF-β1 correlated with drug-in- phisms of the TGF-β1 gene in a study by Linden et al.64 duced gingival overgrowth in renal transplant patients. Polymorphisms of this gene at position +869, codon 10 In a study by Bostanci et al59 that followed 51 individu- (leucine to proline substitution) and position +915, als on cyclosporin A treatment for 6 to 173 months, codon 25 (arginine to proline substitution) were exam- their results showed there were significant differences ined and it was found that the mean overgrowth score of genotypes IL-1A −889 C/T or TT and −889 C/T was highest in individuals that were homogenous for between patients with and without gingival over- proline compared to those who were heterozygotes growth. Carriage of the IL-1A −899T allele demon- (leucine/proline) and homozygotes for leucine. Hetero- strated a significant protective role against gingival zygotes (arginine/proline) for codon 25 showed the overgrowth in cyclosporin A-treated individuals with an highest mean overgrowth score and were more likely odds ratio of 0.26, while the presence of to exhibit severe overgrowth than those who were was not significantly (P > .05) associated with the pres- homozygous at codon 25.64 The same functional poly- ence of overgrowth. In addition, increased age showed morphisms of the TGF-β1 gene were investigated for a protective effect and the duration of the treatment their potential role in the incidence and severity of was not significantly associated with the development gingival overgrowth in renal transplant recipients of gingival overgrowth.58 IL-10 −819TT (−592AA) geno- treated with cyclosporin A and calcium channel block- type and ATA haplotype were found to be significantly ers. A group of 92 patients, 50 patients with and 42 (P < .05) associated with susceptibility to cyclosporin patients without gingival overgrowth, demonstrated A-induced gingival overgrowth, while no significant no significant differences in regards to the mean age, difference (P > .05) of the genotypes −1082AA and AG time after transplantation, TGF-β1 level, number of were detected in a study by Luo and coworkers.60 These teeth, and average total cyclosporin A dose.62 In con- same investigators reported in a cross-sectional study trast to Linden et al,64 Radwan-Oczko et al62 reported no

720 VOLUME 48 • NUMBER 9 • OCTOBER 2017 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

significant differences (P > .05) between heterozygous properties, that the polymorphisms highlighted in this and homozygous genotypes at codon 25 among the systematic review may alter the equilibrium in the gin- studied groups. With respect to codon 10, individuals gival tissues and direct the tissues towards a high- who were homozygous for proline displayed protective lighted, productive phenotype. effects against gingival overgrowth and were at least The present study also suggested a possible protec- half as likely to have gingival overgrowth (8% versus tive effect of increased age in incidence of cyclosporin 19.1%).62 It can be derived from the above that the role A-induced gingival overgrowth. This finding is in con- of the TGF-β1 polymorphisms in the cyclosporin A-in- trast with the investigation of Bondon et al,68 which duced gingival overgrowth continues to be controver- reported that drug-induced gingival overgrowth was sial and more studies are required to clarify their role in more common in male individuals and between the gingival homeostasis. ages of 40 and 69. Furthermore, Spratt et al69 in their investigation found that the age at the time of a renal transplant, the presence of plaque and gingival bleed- DISCUSSION ing, and the presence of probing depths all were The present systematic review aimed to determine the related to gingival overgrowth severity. effect of gene polymorphisms on the development of In regards to the limitations of the present study, it gingival overgrowth in renal transplant patients that should be taken into consideration that the majority of received cyclosporin A for at least 6 months after their the subjects included in the studies used in the present transplant. The results of this systematic search of the review were under administration of other medica- literature revealed that a number of cross-sectional tions, including calcium channel blockers, prednisone, studies have been conducted to evaluate the influence verapamil, amlodipine, diltiazem, azathioprine, myco- of IL-1A,58 IL-6,56 IL-10,60 SPARC,53 MMP-1,54 MMP-3,55 phenolate mofetil, and nitrendipine. The presence of TGF-β1,52,62,64 MDR1,59 ITAF2,65 CD14,63 and AR61 gene additional drug administration in the individuals exam- polymorphism relationships to the onset of the cyclo- ined introduces a further confounding aspect of the sporin A-induced gingival overgrowth. Due to the vari- results reported. For example, the available literature ous examined genetic polymorphisms, as well as the suggests that the combination treatment of cyclospo- different pharmacologic agents used after renal trans- rin A with nifedipine increases the prevalence as well as plantation in each study, it was not possible to perform the severity of gingival overgrowth in renal transplant a meta-analysis of the included data. The systematic individuals.70 In this context, the combination effect of review of the current literature, however, concluded such medications cannot be defined and separated. that IL-1A, IL-10, TGF-β1, and AR gene polymorphisms In addition, studies included in the present review may have a significant effect on individuals’ susceptibil- reported on different populations including Polish, ity to cyclosporin A-induced gingival overgrowth in Turkish, Chinese, and undefined population groups. It renal transplant patients. As previously discussed, IL-1A is possible that populations from different regions nor- has been shown to promote fibroblast proliferation, mally exhibit considerable differences in demographic, resulting in nifedipine gingival overgrowth,42 whereas environmental, and ecologic characteristics.71 These IL-10 inhibits pro-inflammatory mediators and different population groups typically vary in ethnicity MMPs.28,29 Furthermore, TGF-β1 similarly stimulates and other characteristics, such as genetic heterogene- fibroblast proliferation and extracellular matrix forma- ity, while at the same time presenting with significant tion,24 and androgens are metabolized in the gingival demographic and socioeconomic differences. In this tissues and their altered expression may be associated context, populations from different regions may pres- with hyperplastic gingiva. It can be derived from the ent with different levels of predisposition to gingival above, and the fact that those molecules hold anabolic overgrowth or periodontal diseases as shown in the

VOLUME 48 • NUMBER 9 • OCTOBER 2017 721 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

classic studies by Löe et al72,73 in Sri Lankan tea laborers cells and tissues or the presence of unique fibroblast when compared to a Norwegian population group. sub-populations in the oral tissues, such as myofibro- The mechanisms underlying the drug-induced gin- blasts.75 gival overgrowth were addressed by Trackman and Furthermore, future research may wish to examine Kantarci.16 These investigators highlighted the pres- the potential relationship of cyclosporin A with the ence of an increased production of fibroblast, cyto- expression of MMPs. Hyland et al76 also assessed the kines, and prostaglandin E2 that altered the normal effect of cyclosporin A on MMP-1 and TIMP-1 expres- balance of cytokines in the gingival tissues, such as IL-6, sion in mRNA, protein, and enzyme activity levels. Cyc- IL-1β, platelet-derived growth factor subunit B, fibro- losporin A was found to inhibit the expression of blast growth factor 2, TGF-β, and connective tissue MMP-1 in a dose- and time-dependent manner in gin- growth factor (CTGF). Interestingly, the authors’ find- gival tissues at both the mRNA and protein levels, as ings supported a stimulatory effect of TGF-β on CTGF Thomason et al43 and Bolzani et al44 concluded in their that may enhance extracellular matrix production in studies. This could explain the reduced remodeling and gingival fibroblasts. CTGF is an autocrine and paracrine turnover of the extracellular matrix in tissues present- signaling molecule that stimulates fibroblast prolifera- ing with gingival overgrowth. Furthermore, the pres- tion and extracellular matrix synthesis and is strongly ence of different fibroblast cell populations may be induced by TGF-β. Furthermore, increased presence of associated with the reported variation in tissue over- CTGF and TGF-β has been observed in phenytoin and growth among individuals receiving cyclosporin A. nifedipine users, but not in cyclosporin A-treated indi- However, in the two included studies by Kurzawski et viduals, who present with an inflammatory and less al54 and Drozdzik et al,55 no association was found fibrotic phenotype of gingival overgrowth.16 between MMP-1 and MMP-3 gene polymorphisms and Uzel et al74 examined the presence and localization the development of gingival overgrowth among kidney of CTGF in drug-induced gingival overgrowth tissues transplant patients who were treated with cyclosporin utilizing 27 individuals and biopsies from phenytoin, A as a principal immunosuppressive agent. The small nifedipine, cyclosporin A, and control/healthy tissues. sample size in both studies may have influenced the The authors concluded that the degree of inflammation study results, and investigations with a greater number present in the tissues (number of mononuclear and of gingival overgrowth subjects should be considered polymorphonuclear cells per unit area) was higher in in the future to confirm or reject these findings. cyclosporin A users, further reinforcing the hypothesis Drug-induced gingival overgrowth has a complex of the inflammatory rather than fibrotic component of pathology in which multiple genes, genetic back- overgrowth in cyclosporin A users. Furthermore, the grounds, and environmental factors interact. MMP-1 synthesis and extracellular accumulation of CTGF was and MMP-3 may increase their expression in response found increased only for phenytoin users compared to other growth factors and cytokines, while the pres- with controls, nifedipine, and cyclosporin A users. ence of MMP-1 −1,607 and MMP-3 −1,171 polymor- These reported studies further strengthen the phisms may not affect their expression levels in fibro- hypothesis that different mechanisms of gingival over- blasts.77 Both included cross-sectional studies consisted growth are responsible for the different drugs involved of Polish participants.54,55 Association of cyclosporin in gingival overgrowth. The question that can be raised, A-induced gingival overgrowth with polymorphisms in however, is why do these individuals present with gin- the MMP-1 and MMP-3 genes may be dependent on gival fibrosis or overgrowth in the oral tissues and not ethnicity and further investigation is needed in differ- in any other body tissues since the administration of ent ethnic groups. the medication is systemic? Possibly this observation Genetics, environmental factors such as tobacco relates to the unique metabolic pathways of gingival smoking, alcohol drinking, and dietary constituents, as

722 VOLUME 48 • NUMBER 9 • OCTOBER 2017 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

well as physiologic factors such as age, gender, and 13. Hefti AF, Eshenaur AE, Hassell TM, Stone C. Gingival overgrowth in cyclospo- rine A treated multiple sclerosis patients. J Periodontol 1994;65:744–749. exercise have the potential to cause different drug 14. Boltchi FE, Rees TD, Iacopino AM. Cyclosporine A-induced gingival over- responses.78 Individual variability of drug responses has growth: a comprehensive review. Quintessence Int 1999;30:775–783. been reported since the 1950s and has led to the devel- 15. Afonso M, Bello Vde O, Shibli JA, Sposto MR. Cyclosporin A-induced gingival overgrowth in renal transplant patients. J Periodontol 2003;74:51–56. opment of the field of pharmacogenetics.78 Genetic 16. Trackman PC, Kantarci A. Connective tissue metabolism and gingival over- polymorphisms seem to affect protein functions and growth. Crit Rev Oral Biol Med 2004;15:165–175. 17. Schmitt-Gräff A, Desmoulière A, Gabbiani G. Heterogeneity of myofibroblast drug metabolism, which may play an important role in phenotypic features: an example of fibroblastic cell plasticity. Virchows Arch an individual’s drug response. The current goal of phar- 1994;425: 3–24. 18. Vaughan MB, Howard EW, Tomasek JJ. Transforming growth factor-beta1 macogenetics and pharmacogenomics is to determine promotes the morphological and functional differentiation of the myofibro- the clinical outcome of a medication, the drug efficacy blast. Exp Cell Res 2000;257:180–189. 19. Kornman KS, Polverini PJ. Clinical application of genetics to guide prevention and adverse drug reactions. Therefore, future studies and treatment of oral diseases. Clin Genet 2014;86:44–49. are needed to identify the effect of several gene poly- 20. Schmieder R, Edwards R. Insights into antibiotic resistance through metage- nomic approaches. Future Microbiol 2012;7:73–89. morphisms on the onset and development of drug-in- 21. Myrillas TT, Linden GJ, Marley JJ, Irwin CR. Cyclosporin A regulates interleu- duced gingival overgrowth. The use of genetic tests to kin-1beta and interleukin-6 expressions in gingival: implications for gingival overgrowth. J Periodontol 1999;70:294–300. predict the risk of cyclosporin A-induced gingival over- 22. Chae HJ, Ha MS, Yun DH, et al. Mechanism of cyclosporine-induced over- growth may make it possible to individualize therapy growth in gingiva. J Dent Res 2006;85:515–519. 23. Meisel P, Giebel J, Kunert-Keil C, Dazert P, Kroemer HK, Kocher T. MDR1 gene (personalized/precision medicine), with the intent of polymorphisms and risk of gingival hyperplasia induced by calcium antago- reducing the incidence of adverse drug effects and nists. Clin Pharmacol Ther 2006;79:62–71. 19 24. Barnard JA, Lyons RM, Moses HL. The cell biology of transforming growth increasing a drug’s effectiveness. factor b. Biochim Biophys Acta 1990;1032:79–87. 25. Buduneli N, Kutukculer N, Aksa G, Atilla G. Evaluation of transforming growth factor-beta1 level in crevicular fluid of cyclosporin A-treated patients. J Peri- odontol 2001;72:526–531. 26. Ellis JS, Morgan CI, Kirby JA, Taylor JJ, Thomason JM. Plasma TGF-b1 as a risk REFERENCES factor for gingival overgrowth. J Clin Periodontol 2004;31:863–868. 1. Ciancio SG. Medications: a risk factor for periodontal disease diagnosis and 27. de Waal Malefyt R, Yssel H, Roncarolo MG, Spits H, de Vries JE. Interleukin-10. treatment. J Periodontol 2005;76(11 Suppl):2061–2065. Curr Opin Immunol 1992;4:314–320. 2. Dongari-Bagtzoglou A; Research, Science and Therapy Committee, American 28. Oliveira AP, Faveri M, Gursky LC, et al. Effects of periodontal therapy on GCF Academy of Periodontology. Drug-associated gingival enlargement. J Peri- cytokines in generalized subjects. J Clin Periodontol odontol 2004;75:1424–1431. 2012;39: 295–302. 3. Peters TG, Spinola KN, West JC, et al. Differences in patient and transplant 29. Garlet GP. Destructive and protective roles of cytokines in periodontitis: A professional perceptions of immunosuppression-induced cosmetic side re-appraisal from host defense and tissue destruction viewpoints. J Dent Res effects. Transplantation 2004;78:537–543. 2010;89: 1349–1363. 4. Fiebiger W, Mitterbauer C, Oberbauer R. Health-related quality of life out- 30. Larsson L, Rymo L, Berglundh T. Sp1 binds to the G allele of the –1087 poly- comes after kidney transplantation. Health Qual Life Outcomes 2004;2:2. morphism in the IL-10 promoter and promotes IL-10 mRNA transcription and protein production. Genes Immun 2010;11:181–187. 5. Daley TD, Wysocki GP. Cyclosporine therapy. Its significance to the periodon- tist. J Periodontol 1984;55:708–712. 31. Albuquerque CM, Cortinhas AJ, Morinha FJ, Leitao JC, Viegas CA, Bastos EM. Association of the IL-10 polymorphisms and periodontitis: a meta-analysis. 6. Thomason JM, Kelly PJ, Seymour RA. The distribution of gingival overgrowth Mol Biol Rep 2012;39:9319–9329. in organ transplant patients. J Clin Periodontol 1996;23:367–371. 32. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An 7. Seymour RA, Ellis JS, Thomason JM. Risk factors for drug-induced gingival investigation of polymorphism in the interleukin-10 gene promoter. Eur J overgrowth. J Clin Periodontol 2000;27:217–223. Immunogenet 1997;24:1–8. 8. Ruhl S. Salivary Proteins and cytokines in drug-induced gingival overgrowth. 33. Vittek J, Rappaport SC, Gordon GG, Hagedoorn J, Southren AL. Metabolism of J Dent Res 2004;83:322–326. androgens by human periodontal ligament. J Dent Res 1982;61:1153–1157. 9. Fischer RG, Edwardsson S, Klinge B, Attström R. The effect of cyclosporin-A on 34. Sooriyamoorthy M, Gower DB, Eley BM. Androgen metabolism in gingival hyper- the oral microflora at of the ferret. J Clin Periodontol 1996;23: plasia induced by nifedipine and cyclosporin. J Periodontal Res 1990;25:25–30. 853–860. 35. Dayan D, Kozlovsky A, Tal H, Kariv N, Shemesh M, Nyska A. Castration prevents 10. Ayanoglou CM, Lesty C. Cyclosporin A-induced gingival overgrowth in the rat: calcium channel blocker-induced gingival hyperplasia in beagle dogs. Hum a histological, ultrastructural and histomorphometric evaluation. J Periodon- Exp Toxicol 1998;17:396–402. tal Res 1999;34:7–15. 36. Roberts RO, Bergstralh EJ, Cunningham JM, et al. Androgen receptor gene 11. Faulds D, Goa KL, Benfield P. Cyclosporin. A review of its pharmacodynamic polymorphisms and increased risk of urologic measures of benign prostatic and pharmacokinetic properties, and therapeutic use in immunoregulatory hyperplasia. Am J Epidemiol 2004;159:269–276. disorders. Drugs 1993;45:953–1040. 37. Paz-Y-Miño C, Robles P, Salazar C, et al. Positive association of the androgen 12. King GN, Fullinfaw R, Higgins TJ, Walker RG, Francis DM, Wiesenfeld D. Gingi- receptor CAG repeat length polymorphism with the risk of prostate cancer. val hyperplasia in renal allograft recipients receiving cyclosporin-A and calci- Mol Med Rep 2016;14:1791–1798. um antagonists. J Clin Periodontol 1993;20:286–293.

VOLUME 48 • NUMBER 9 • OCTOBER 2017 723 QUINTESSENCE INTERNATIONAL Chatzopoulos et al

38. Yuan C, Gao C, Qian Y, et al. Polymorphism of CAG and GGN repeats of andro- 58. Bostanci N, Ilgenli T, Pirhan DC, et al. Relationship between IL-1A polymor- gen receptor gene in women with polycystic ovary syndrome. Reprod phisms and gingival overgrowth in renal transplant recipients receiving cyc- Biomed Online 2015;31:790–798. losporin A. J Clin Periodontol 2006;33:771–778. 39. Mao Q, Qiu M, Dong G, et al. CAG repeat polymorphisms in the androgen 59. Kazancioglu HO, Ak G, Turkmen A, Ozbek U, Tuncer FN, Karabulut A. The role receptor and breast cancer risk in women: a meta-analysis of 17 studies. Onco of MDR1 C3435T gene polymorphism on gingival hyperplasia in Turkish renal Targets Ther 2015;8:2111–2120. transplant patients treated with cyclosporine in the absence of calcium chan- 40. Rasmussen L, Handytom L, Lerner U.H. Characterization of bone resorbing nel blockers. Transplant Proc 2013;45:2233–2237. activity in gingival crevicular fluid from patients with periodontitis. J Clin 60. Luo Y, Gong Y, Yu Y. Interleukin-10 gene promoter polymorphisms are asso- Periodontol 2000;27:41–52. ciated with cyclosporin A-induced gingival overgrowth in renal transplant 41. Saito S, Katoh M, Masumoto M, Matsumoto S, Masubo Y. Collagen degrada- patients. Arch Oral Biol 2013;58:1199–1207. tion induced by the combination of IL-1alpha and plasminogen in rabbit 61. Al Sayed AA, Al Sulaiman MH, Mishriky A, Anil S. The role of androgen receptor articular cartilage explant culture. J Biochem 1997;122:49–54. gene in cyclosporine induced gingival overgrowth. J Periodontal Res 2014;49: 42. Sato N, Matsumoto H, Akimoto Y, Fujii A. The effect of IL-1alpha and nifedip- 609–614. ine on cell proliferation and DNA synthesis in cultured human gingival fibro- 62. Radwan-Oczko M, Boratyńska M, Zietek M, Zołedziewska M, Jonkisz A. The blasts. J Oral Sci 2005;47:105–110. relationship of transforming growth factor-beta1 gene polymorphism, its 43. Thomason JM, Sloan P, Seymour RA. Immunolocalization of collagenase plasma level, and gingival overgrowth in renal transplant recipients receiving (MMP-1) and stromelysin (MMP-3) in the gingival tissues of organ transplant different immunosuppressive regimens. J Periodontol 2006;77:865–873. patients medicated with cyclosporin. J Clin Periodontol 1998;25:554–560. 63. Gong Y, Bi W, Cao L, Yang Y, Chen J, Yu Y. Association of CD14-260 polymor- 44. Bolzani G, Coletta RD, Martelli Junior H, Almeida OP, Graner E. Cyclosporin A phisms, red-complex periodontopathogens and gingival crevicular fluid inhibits production and activity of matrix metalloproteinases by gingival cytokine levels with cyclosporine A-induced gingival overgrowth in renal fibroblasts. J Periodont Res 2000;35:51–58. transplant patients. J Periodontal Res 2013;48:203–212. 45. Furlan AD, Pennick V, Bombardier C, van Tulder M, Editorial Board, Cochrane 64. Linden GJ, Haworth SE, Maxwell AP, et al. The influence of transforming Back Review Group. 2009 updated method guidelines for systematic reviews growth factor-beta1 gene polymorphisms on the severity of gingival over- in the Cochrane Back Review Group. Spine (Phila Pa 1976) 2009;34:1929–1941. growth associated with concomitant use of cyclosporin A and a calcium channel blocker. J Periodontol 2001;72:808–814. 46. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin 65. Gürkan A, Emingil G, Afacan B, Berdeli A, Atilla G. Alpha 2 integrin gene Epidemiol 2009;62:1006–1012. (ITGA2) polymorphism in renal transplant recipients with and without drug induced gingival overgrowth. Arch Oral Biol 2014;59:283–288. 47. Dereka X, Mardas N, Chin S, Petrie A, Donos N. A systematic review on the association between genetic predisposition and biological 66. Pernu HE, Pernu HM, Huttunen KR, Nieminen PA, Knuuttila ML. Gingival complications. Clin Oral Implants Res 2012;23:775–788. overgrowth among renal transplant recipients related to immunosuppressive medication and possible local background factors. J Periodontol 1992;63: 48. García M, Macías RM, Cubero JJ, Benítez J, Caravaca F, Gervasini G. ABCB1 548–553. polymorphisms are associated with cyclosporine-induced nephrotoxicity and gingival hyperplasia in renal transplant recipients. Eur J Clin Pharmacol 67. James JA, Marley JJ, Jamal S, et al. The calcium channel blocker used with 2013;69: 385–393. cyclosporin has an effect on gingival overgrowth. J Clin Periodontol 2000;27: 109–115. 49. Cota LO, Viana MB, Moreira PR, et al. Gingival overgrowth in cyclosporine, tacrolimus, or sirolimus-based immunosuppressive regimens and the single 68. Bondon-Guitton E, Bagheri H, Montastruc JL. Drug-induced gingival over- nucleotide IL-6 (−174 G/C) gene polymorphism. Arch Oral Biol 2010;55: growth: a study in the French Pharmacovigilance Database. J Clin Periodontol 494–501. 2012;39: 513–518. 50. Kusztal M, Radwan-Oczko M, Kościelska-Kasprzak K, Boratyńska M, Patrzałek 69. Spratt H, Boomer S, Irwin CR, et al. Cyclosporin associated gingival over- D, Klinger M. Possible association of CTLA-4 gene polymorphism with cyclo- growth in renal transplant recipients. Oral Dis 1999;5:27–31. sporine-induced gingival overgrowth in kidney transplant recipients. Trans- 70. López-Pintor RM, Hernández G, de Arriba L, Morales JM, Jiménez C, de Andrés plant Proc 2007;39:2763–2765. A. Amlodipine and nifedipine used with cyclosporine induce different effects 51. De Iudicibus S, Castronovo G, Gigante A, et al. Role of MDR1 gene polymor- on gingival enlargement. Transplant Proc 2009;41: 2351–2353. phisms in gingival overgrowth induced by cyclosporine in transplant patients. 71. Albandar JM. Global risk factors and risk indicators for periodontal diseases. J Periodontal Res 2008;43:665–672. Periodontology 2000 2002;29:177–206. 52. Kozak M, Kurzawski M, Wajda A, et al. TGF-β1 gene polymorphism in renal 72. Löe H, Anerud A, Boysen H, Smith M. The natural history of periodontal dis- transplant patients with and without gingival overgrowth. Oral Dis 2011;17: ease in man. The rate of periodontal destruction before 40 years of age. J 414–419. Periodontol 1978:49:607–620. 53. Drozdzik A, Kurzawski M, Kozak M, Banach J, Drozdzik M. SPARC gene poly- 73. Löe H, Anerud A, Boysen H, Morrison E. Natural history of periodontal disease morphism in renal transplant patients with gingival overgrowth. J Periodon- in man. Rapid, moderate and no loss of attachment in Sri Lankan laborers tol 2007;78:2185–2189. 14–46 years of age. J Clin Periodontol 1986:13:431–445. 54. Kurzawski M, Drozdzik A, Dembowska E, Pawlik A, Banach J, Drozdzik M. 74. Uzel MI, Kantarci A, Hong HH, et al. Connective tissue growth factor in Matrix metalloproteinase-1 gene polymorphism in renal transplant patients drug-induced gingival overgrowth. J Periodontol 2001;72:921–931. with and without gingival enlargement. J Periodontol 2006;77:1498–1502. 75. Dill RE, Iacopino AM. Myofibroblasts in phenytoin-induced hyperplastic con- 55. Drozdzik A, Kurzawski M, Lener A, Kozak M, Banach J, Drozdzik M. Matrix nective tissue in the rat and in human gingival overgrowth. J Periodontol metalloproteinase-3 gene polymorphism in renal transplant patients with 1997;68: 375–380. gingival overgrowth. J Periodontal Res 2010;45:143–147. 76. Hyland PL, Traynor PS, Myrillas TT, et al. The effects of cyclosporin on the col- 56. Drozdzik M, Kurzawski M, Drozdzik A, Kotrych K, Banach J, Pawlik A. Interleu- lagenolytic activity of gingival fibroblasts. J Periodontol 2003;74:437–445. kin-6 gene polymorphism in renal transplant patients with and without gin- 77. Wyatt CA, Coon CI, Gibson JJ, Brinckerhoff CE. Potential for the 2G single gival overgrowth. J Clin Periodontol 2005;32:955–958. nucleotide polymorphism in the promoter of matrix metalloproteinase to 57. Drozdzik M, Mysliwiec K, Lewinska-Chelstowska M, Banach J, Drozdzik A, enhance gene expression in normal stromal cells. Cancer Res 2002;62: Grabarek J. P-glycoprotein drug transporter MDR1 gene polymorphism in 7200–7202. renal transplant patients with and without gingival overgrowth. J Clin Peri- 78. Kalow W, Staron N. On distribution and inheritance of atypical forms of odontol 2004;31:758–763. human serum cholinesterase, as indicated by dibucaine numbers. Can J Bio- chem Physiol 1957;35:1305–1320.

724 VOLUME 48 • NUMBER 9 • OCTOBER 2017