Interleukin-1β and Serotonin Transporter Gene Polymorphisms in Burning Mouth Syndrome Patients

The Journal of Pain, Vol 7, No 9 (September), 2006: pp 654-658 Available online at www.sciencedirect.com

Interleukin-1␤ and Serotonin Transporter Gene Polymorphisms in Burning Mouth Syndrome Patients André Luiz Sena Guimarães,* Alessandra Rosa de Sá,* Júnia Maria Netto Victoria,* Jeane de Fátima Correia-Silva,* Marcus Vinícius Gomez,† and Ricardo Santiago Gomez* *Department of Oral Surgery and Pathology, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, Brazil. † Department of Pharmacology, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Abstract: Burning mouth syndrome (BMS) is a chronic pain syndrome that encompasses all forms of burning sensations in the oral cavity when the oral mucosa is clinically normal. Neural, psychologic, and cytokine factors may be implicated in the pathogenesis of BMS. There are no studies of genetic factors associated with psychologic behavior and cytokine pain sensitivity in BMS patients. The purpose of the present study was to investigate a possible association between functional genetic polymorphisms, ⴙ3954 (C/T) interleukin-1␤, and the polymorphic site on promoter region of the serotonin transporter gene (5-HTTLPR) in a sample of Brazilian patients. Thirty patients affected by BMS and 31 healthy volunteers were genotyped for 5-HTTLPR and IL-1␤ gene. The chi-squared test was used for statistical analysis. There was no statistical difference in 5-HTTLPR genotypes between the case and control groups (P ⴝ .60), however a significant increase was observed in the IL-1␤ high production genotype CT in BMS subjects (P ⴝ .005). In conclusion, the present study shows association between BMS and IL-1␤ high producer genotype. Perspective: This article shows evidence that genetic polymorphisms associated with IL-1␤ high production genotype are implicated on the pathogenesis of BMS. The modulation of IL1␤ production may be an interesting tool in BMS management. © 2006 by the American Pain Society Key words: Interleukin-1␤, burning mouth syndrome, 5-HTTLPR, polymorphism.

B

urning mouth syndrome (BMS) is a chronic pain syndrome that mainly affects middle-aged and older female patients.13,14,18 The term encompasses all forms of burning sensations in the oral cavity when the oral mucosa is clinically normal.5 The prevalence of BMS ranges from .7% to 4.6% in various studies.5,17,20,28 This variability is likely due to the various criteria used for BMS diagnosis.47 BMS is 7 times more common in women than men.5 Received October 7, 2005; Revised February 15, 2006; Accepted February 21, 2006. Supported in part by grants from Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Programa de Excelência, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. Drs R. S. Gomez and M. V. Gomez are research fellows of CNPq. Address reprint requests to Prof Ricardo Santiago Gomez, Faculdade de Odontologia, Universidade Federal de Minas Gerais, Av Antonio Carlos, 6627, Belo Horizonte—MG, Brazil CEP 31270-901. E-mail: [email protected] 1526-5900/$32.00 © 2006 by the American Pain Society doi:10.1016/j.jpain.2006.02.011

654

Some studies have suggested that BMS may be a manifestation of somatization,10,13,50 and others have reported that BMS is more closely related to neuropathic pain than to psychosomatic factors.12,19,21,35 The role of psychogenic/psychosomatic factors in BMS has been questioned in the literature.47 The presence of anger, hostility, self-consciousness, impulsiveness, vulnerability, deliberation, and assertiveness were observed in the psychologic characterization of BMS patients.1,22,23,45 There is controversy as to whether depression and anxiety are primary42 or secondary17 events associated with the oral pain in BMS patients. Moreover, many BMS patients exhibiting high levels of anxiety, depression, and pain show improvement after suitable administrations of psychotropic medications such as antidepressants or benzodiazepines.16,32,34 However, tricyclic antidepressants have also been indicated for treatment of neuropathic pain.29,34 The gene for serotonin transporter (SLC6A4) is located on chromosome 17q12 and consists of a promoter and 14

ORIGINAL REPORT/Guimarães et al 25,44

exons spanning 31 kbp. A polymorphic region of SLC6A4, identified by a 44-bp insertion-deletion in the promoter region (5-HTTLPR), is known. The 2 alleles, termed long (L) and short (S), exhibit different phenotypes.25 In vitro studies have demonstrated that the S allele has been associated with reduced transcriptional efficiency which causes a reduced serotonin expression and uptake of the neurotransmitter.26 Some studies have suggested a possible involvement of the 5-HTTLPR genotype with suicidal behavior,4,6,8 depression,3 anxiety,49 alcoholism,43 and recurrent aphtous ulceration, an oral mucosal disorder related to stress.51 Interleukin-1 (IL-1) is a proinflammatory cytokine that plays a pivotal role in several chronic diseases.9,36 IL-1 has also been implicated in the modulation of pain sensitivity. Exogenous administration of IL-1, particularly IL-1␤, usually produces hyperalgesia.11,38,53 Genetic polymorphisms have been described for IL-1␤ gene. Polymorphism of the IL-1␤ gene at ⫹3954 (C/T) and at ⫺511 result in increased production of the cytokine and are found to be in linkage disequilibrium.2,41,46 In ⫹3954 IL-1␤ polymorphism, homozygous individuals for the T allele produce a 4-fold higher amount of IL-1␤ than individuals displaying the C/C genotype. The heterozygous individuals have the intermediary production of IL-1␤.41 It is interesting to note that IL-1␤ polymorphism has been related to psychosis susceptibility46 and early development of Alzheimer’s disease27 and Parkinson’s disease.48 Neural and psychologic factors may be implicated in the pathogenesis of BMS. This fact, together with the evidence that IL-1␤ levels are elevated in the blood or cerebrospinal fluid of depressed patients,30,31 that antidepressants are able to reduce peripheral release of this proinflammatory cytokine,37 and that 5-HTTLPR genotype is associated with depression and anxiety, prompted us to investigate a possible association between functional genetic polymorphisms, ⫹3954 (C/T) IL-1␤ and 5-HTTLPR, and BMS in a sample of Brazilian patients.

Material and Methods Subjects and Sample Collection Thirty-one consecutive subjects (mean age 55.7 yrs, range 25-79, SD 12.2) affected with BMS and 31 age- and gender-matched control subjects (mean age 50.2 yrs, range 24-84; SD 13.2) were included in this study. There were 5 (16.2%) men and 26 (83.8 %) women in the patient group. The patients were recruited from the Oral Diagnosis Clinic at the Universidade Federal de Minas Gerais. Both the patients and the control group were of the same geographic area and had identical socioeconomic status. No evaluation of the psychologic status of patients was performed. Ethnicity was not established, because the hazards of judging Brazilians by color, race, and geographical origin was recently demonstrated.40 All the patients diagnosed with BMS exhibited clinically normal oral mucosa associated with a burning oral sensation for at least 6 months, according to criteria described elsewhere.5 None of the patients presented any

655 evidence of malignancy, connective tissue, metabolic, or infectious disorders, or vitamin deficiency. Quantitative sensory testing of the tongue was not performed. The control group was composed of individuals without any history of BMS or systemic diseases. The study protocol was approved by local Ethical Committee, and informed consent was obtained from all patients. Oral mucosa swabs were taken once from the subjects on the buccal mucosa. The swabs were performed with sterile plastic tips abd placed immediately in Eppendorf microtubes containing 500 ␮L Krebs buffer, and the pellet obtained after 5 min of centrifugation at 13,000g was stored at ⫺20°C until processing.

DNA Isolation DNA extraction was carried out as described by Boom et al7 and modified as below. We added 450 ␮L lysis buffer (1.0 mol/L GuSCN, 83 mmol/L Tris HCl (pH 6.4), 36 mmol/L EDTA, and 1.5% Triton X-100) and 20 ␮L silica (Sigma, St Louis, MO) to the microcentrifuge tube containing the oral mucosa swab pellet. The tube was mixed and incubated for 10 min at 56°C, centrifuged at 3,000g for 1 min and the supernatant discharged. The pellet with the DNA adsorbed into the silica was washed twice with 450 ␮L washing buffer (1.0 mol/L GuSCN and 83 mmol/L Tris HCl (pH 6.4)), twice with 70% ethanol, once with 450 ␮L acetone, and then dried at 56°C for 10 min. Finally, 100 ␮L TE buffer (10 mmol/L Tris-HCl (pH 8.0) and 1 mmol/L EDTA) was added and incubated at 56°C for 10 min to elute the DNA. After incubation the solution was vortexed and centrifuged at 5,000g for 2 min, and approximately 90 ␮L supernatant containing DNA was transfered to a new tube.

IL-1␤ Genotyping Interleukin-1␤ (⫹3954) polymorphisms were assessed by polymerase chain reaction (PCR) amplification and digestion. The sequences of PCR primers were 5=-CTCAGGTGTCCTCGAAGAAATCAAA-3= and 5=-GCTTTTTTGCTGTGAGTCCCG-3= with expected PCR product size of 194 bp, as described elsewhere.36 The PCR was carried out in a total volume of 50 ␮L, containing 10 ␮L of solution DNA (approximately 400 ng), primers (20 pmol/reaction), and 25 ␮L Pre-mix buffer (Phoneutria Biotecnologia, Belo Horizonte, Brazil). According to the manufacturer, the Pre-mix buffer contained 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.4), 0.1% Triton X-100, 1.5 mmol/L MgCl2, deoxynucleoside triphosphates, and 1.25 units of Taq DNA polymerase. The conditions for amplification consisted of 94°C for 3 min followed by 35 cycles of 94°C for 30 s, 54°C for 35 s, and 72°C for 30 s. The run was terminated by final elongation at 72°C for 5 min. Lid temperature was 103°C. The products were digested with 5 U Taq I restriction enzyme (Promega, Madison, WI) at 65°C for 4 h and obtained 97 ⫹ 85 ⫹ 12 bp DNA products for allele C and 182 ⫹ 12 bp DNA products for allele T. The visualization was performed in an 18 ⫻ 16 cm 10% polyacrylamide gel electrophoresis staining with ethidium bromide (0.5 ␮g/mL).

Interleukin-1␤ ⫹3954 and 5HTTLPR Polymorphism in BMS Patients

656

Distribution of Genotype and Allele Frequencies (%) of 5-HTTLPR in Patients With Burning Mouth Syndrome (BMS) and in Control Subjects Table 1.

5-HTTLPR Genotypes, n (%) LL LS SS Alleles L S

BMS (n ⫽ 30)

CONTROL (n ⫽ 31)

P

14 (46.6%) 10 (33.3%) 6 (20.1%)

11 (35.5%) 14 (45.1%) 6 (19.4%)

.60

63.0% 37.0%

58.0% 42.0%

.56

Abbreviations: L, long allele; S, short allele.

5-HTT Genotyping The insertion/deletion in the 5HTT gene–linked polymorphic region (5-HTTLPR) was assessed only by PCR amplification. The sequences of PCR primers were 5=CCGCTCTGAATGCCAGCACCTAAC-3= and 5=- AGAGGGACTGAGCTGGACAACCAC-3=.24 The PCR was carried out in a 50 ␮L mixture containing 2 ␮L DNA solution (approximately 80 ng), 1 unit/reaction of Taq DNA polymerase (Phoneutria Biotecnologia), PCR buffer (50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.4), and 1.5 mmol/L MgCl2) (Phoneutria Biotecnologia), deoxynucleoside triphosphates (0.1 mmol/L/reaction of each dNTP) (Amersham, New Jersey), and primers (20 pmol/reaction). This solution was subjected to 2 min at 94°C, followed by 40 cycles of 30 sec at 94°C, 30 sec at 68°C, and 45 sec at 72°C. The run was terminated by final elongation at 72°C for 5 min. Lid temperature was 103°C. Allele sizes were determined by comparison of bands with size standards after electrophoresis in a 6.5% polyacrylamide gel and silver staining. Amplification of the 5-HTTLPR gave 2 alleles differing by 44 bp (L with 522 bp and S with 478 bp).51

Statistical Analysis Statistical significance of differences between case and control group distributions for alleles and genotypes were determined using chi-squared with Yates’s correction. A significance level of P ⱕ .05 was used. The evaluation of the Hardy-Weinberg equilibrium was performed by comparing observed and expected frequencies of heterozygotes and homozygotes. All the statistical analyses were performed using BioStat 3.0 software (Optical Digital Optical Technology, Belém, Brazil).

Results The genotype and allele frequencies of 5-HTTLPR polymorphism are shown in Table 1. The frequency of the SS genotype and of the allele S in the BMS cases and in the control group was not statistically different. The observed distribution of 5-HTTLPR genotypes in the patient group (LL:LS:SS, 14:10:6) was not statistically different from those expected from the Hardy-Weinberg equilibrium equation (12:14:4) (P ⫽ .12).

The distribution of genotype and allele frequencies of IL-1␤ polymorphism in patients with BMS and in the control group is shown in Table 2. A significant increase in the IL-1␤ high production genotype CT was observed in the group with BMS (P ⫽ .005). The distribution of IL-1␤ genotypes in the case group (TT:CT:CC, 0:22:9) was statistically different from those expected from the HardyWeinberg equilibrium equation (4:13:13) (P ⫽ .002).

Discussion The etiopathogenesis of BMS has generated considerable controversy in the literature. To date no study has attempted to investigate a genetic factor associated with psychologic behavior and pain sensitivity in a set of BMS patients. The SLC6A4 gene regulates the magnitude and duration of serotonergic neurotransmission, and polymorphism in this gene has been associated with anxiety-related traits.15,26 Because no association between 5-HTTLPR polymorphism and BMS was observed, it could be suggested that serotonin transport imbalance may not be important to the disease development. However, other mechanisms related to serotonin axis or associated with anxiety disorders should be further investigated. The potential of interleukins to initiate the hyperalgesia in inflammation and neuropathic conditions have been previously described.39 Those studies suggested that IL-1 plays an important role in pain sensibility, not only following the exposure to various environmental and pharmacologic challenges33,52 but also in setting pain sensitivity in the normal state.53 Interleukin-1␤ has also been associated with depression.30,31 In the present study, we observed association of the polymorphism at IL-1␤ ⫹3954 with BMS. Taken together, although it can not be determined whether IL-1␤ high producer genotype is associated with pain sensibility and/or depression symptoms associated with the syndrome, IL-1␤ modulation could be an interesting target in BMS patient management. Although further studies are necessary to delineate the importance of IL-1␤ to BMS pathogenesis, the present study shows association between BMS and IL-1␤ high producer genotype.

Table 2. Distribution of the Genotype and Allele Frequencies (%) of IL-1␤ ⴙ3954 Polymorphism in Patients With Burning Mouth Syndrome (BMS) and in Control Subjects IL-1␤ Genotypes, n (%) TT CT CC Alleles T C

BMS (n ⫽ 31)

CONTROL (n ⫽ 31)

P

0 (0%) 22 (71%) 9 (29%)

0 (0%) 10 (31.3%) 21 (68.7%)

.005

35.5% 64.5%

17.0% 83.0%

.0049

ORIGINAL REPORT/Guimarães et al

657

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