ANESTHESIA/FACIAL PAIN

1 57
2 58
3 59
4
5
Association Between Polymorphisms 60
61
6
7 in the Genes of Estrogen Receptors and 62
63
8 64
9 the Presence of Temporomandibular 65
10 66
11 Disorders and Chronic Arthralgia 67
12 68
13 Q12 Valquiria Quinelato,* Letı́cia Ladeira Bonato,y Alexandre Rezende Vieira,z 69
14 Q1 Jos
e Mauro Granjeiro,x Ricardo Tesch,k and Priscila Ladeira Casado{ 70
15 71
Purpose: The high prevalence of painful temporomandibular disorders (TMDs) in women suggests that
16 72
17 estrogen and its receptors play a fundamental etiologic role in the development of this joint pathology 73
18 through complex action mechanisms. The aim of this study was to evaluate the possible association be- 74
19 tween polymorphisms in the ESR1 (estrogen receptor-1) and ESRRB (estrogen-related receptor-b) genes 75
20 and the risk of simultaneous development of TMDs and pain in other joints in the body. 76
21 Materials and Methods: All participants were clinically evaluated for the presence of TMD (Research 77
22 Diagnostic Criteria for TMD) and asked about the presence of chronic joint pain. The control group con- 78
23 sisted of 72 patients without TMD and without pain. Participants with arthralgia were divided into 3 79
24 groups: with muscular TMD (n = 42), with articular TMD (n = 16), and without TMD and with systemic 80
25 arthralgia (n = 82). Eight single-nucleotide polymorphisms in the ESR1 (rs12154178, rs1884051, 81
26 rs2273206, rs7774230) and ESRRB (rs1676303, rs4903399, rs10132091, rs7151924) genes were investi- 82
27 gated. The c2 test and Student t and Mann-Whitney tests were used to assess the relevance of nominal and 83
28 continuous variables, respectively. A P value less than .05 was considered significant. 84
29 Results: The TT (timin/timin) genotype for the ESR1 (rs2273206) gene was strongly associated with the 85
30 risk of developing muscle TMDs and temporomandibular joint pain (P = .04). For the ESRRB (rs1676303) 86
31 gene, an association was observed between the CC (cytosine/cytosine) genotype and the presence of artic- 87
32 ular TMDs associated with other chronic arthralgia (P = .02). These results were confirmed by the 88
33 increased risk of developing articular TMDs associated with the C allele (P = .04). 89
34 90
35 91
36 92
37 93
38 Q2 *Doctoral Student of Dentistry, Fluminense Federal University, {Doctor in Morphology and Adjunct Professor of Periodontics, 94
39 Niter

oi, RJ, Brazil. Fluminense Federal University, Niter

oi, RJ, Brazil. 95
40 yDoctor in Dentistry, Fluminense Federal University, Niter

oi; Financial support of this work was provided by the School of Med- 96
41 Specialist in Temporomandibular Disorders and Orofacial Pain, icine of Petr

opolis. 97
42 School of Medicine, Petr

opolis, RJ, Brazil. Conflict of Interest Disclosures: None of the authors have a rele- 98
43 zDoctor in Oral Biology, Departments of Oral Biology and vant financial relationship(s) with a commercial interest. 99
44 Pediatric Dentistry, School of Dental Medicine, University of Address correspondence and reprint requests to Dr Quinelato: 100
45 Pittsburgh, Pittsburgh, PA. School of Dentistry, Fluminense Federal University, Mario Santos 101
46 xDoctor in Chemistry and Cell Therapy Center, Clinical Research Braga Street, 28, Centro, Niter

oi, RJ, Brazil; e-mail: 102
47 Unit and Biology Institute, Fluminense Federal University, Niter

oi; valquiriaquinelato@yahoo.com.br 103
48 National Institute of Metrology, Quality and Technology, Rio de Received July 13 2017 104
49 Janeiro, RJ, Brazil. Accepted October 10 2017 105
50 kMaster of Health Sciences and Assistant Professor and Specialist Ó 2017 Published by Elsevier Inc on behalf of the American Association of Oral 106
51 in Temporomandibular Disorders and Orofacial Pain, School of and Maxillofacial Surgeons 107
52 Medicine, Petr

opolis, RJ, Brazil; Professor of Specialization Courses 0278-2391/17/31349-6 108
53 in Orthodontics, Brazilian Dental Association, Petr

opolis and https://doi.org/10.1016/j.joms.2017.10.023
109
54 Duque de Caxias, RJ, Brazil; Professor of Orthodontics of the 110
55 Specialization Course, Pontificia Universidad Cat

olica Madre y 111
56 Maestra, Santiago de los Caballeros, Dominican Republic. 112

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 1.e2 ESTROGEN AND TEMPOROMANDIBULAR DISORDERS

113 Conclusions: This study supports the hypothesis that changes in the ESR1 and ESRRB genes influence 169
114 Q3 the presence of TMDs associated with chronic joint pain. 170
115 Ó 2017 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial 171
116 Surgeons 172
117 J Oral Maxillofac Surg -:1.e1-1.e9, 2017 173
118 174
119 175
The high prevalence of painful temporomandibular their sensitivity to glutamate through these mecha-
120 176
disorders (TMDs) in women, the pattern of onset nisms.15,16 Thus, ERs in the periaduqueal substance Q4
121 177
after puberty, and the lower prevalence rates in become influential in the pro-nociceptive pathways
122 178
the postmenopausal period suggest that female repro- of pain modulation.4
123 179
ductive hormones play a fundamental etiologic role Changes in estrogen levels also can increase the con-
124 180
in the development of this pathology.1,2 Although centration of serotonin and the inhibition of gene
125 181
involving different mechanisms, it is believed expression related to its reuptake, thus increasing
126 182
that the influence of these hormones occurs directly the time this neurotransmitter remains available in syn-
127 183
on the metabolism and homeostasis of the apses and interstitial spaces. Furthermore, ER activa-
128 184
temporomandibular joint (TMJ),2 but also on pain tion can influence the distribution and actions of
129 185
modulation, through their action on the central ner- serotonin receptors, with the activation of ER-b result-
130 186
vous system (CNS) and peripheral nervous system.3 ing in activation of serotonin receptors and the activa-
131 187
Estrogen is produced not only in the ovaries and ad- tion of ER-a leading to silencing of serotonergic
132 188
renal glands but also in nonendocrine tissues such as receptors.13 Serotonin in combination with estrogen
133 189
bone and the CNS.4 Its biological effects are based can exert central and peripheral effects. At the periph-
134 190
on genomic mechanisms (mediated by the interaction ery, it exerts a pro-nociceptive effect17 and is consid-
135 191
between estrogen receptors a and b [ER-a and ER-b]) ered an inflammatory mediator that is released from
136 192
and on non-genomic mechanisms that involve G platelets and mast cells after tissue injury and exerts
137 193
protein-coupled receptors capable of activating intra- direct action on C fibers.18 At the central level, this
138 194
cellular signaling cascades.4 substance is located in the superficial layers of the dor-
139 195
In human articular tissues, these 2 ER types are ex- sal horn and has an antinociceptive effect.17
140 196
pressed by chondrocytes,5 subchondral bone cells,6 It is believed that genetic and epigenetic alterations
141 197
synoviocytes,7 and ligament fibroblasts.8 However, might be related to estrogen and its receptors, influ-
142 198
ER-a predominates in cortical bone and ER-b predom- encing the development of TMDs and the precipita-
143 199
inates in cartilage, cancellous bone, and synovium.7 Es- tion and maintenance of painful conditions.19,20 The
144 200
trogen acts on osteoblast differentiation, decreasing gene encoding ER-a, ESR1, is located on
145 201
cell proliferation and altering the regulation of the chromosome 6q and includes 7 introns and 8 exons
146 202
extracellular matrix,9 and on the extracellular cartilage over a range of 140 kb. ESR1 gene polymorphisms
147 203
matrix, influencing its tolerance against overloads.10 It are correlated with endometriosis, uterine fibroids,
148 204
also produces increased sensitivity of joint structures breast cancer, osteoporosis, and osteoarthritis.21 The
149 205
to relaxin and activation of matrix metalloproteinases, large proportion of women with TMDs in various
150 206
resulting in ligament laxity and catabolism of the artic- studies suggests genetic alteration of the ESR1 gene
151 207
ular disc.11 All these mechanisms predispose the TMJ as a strong candidate associated with this disorder.22
152 208
to the development of degenerative changes.12 Estrogen-related receptor-b (ESSRB) is a group of
153 209
In relation to pain modulation, it is believed that es- orphan nuclear receptors that act on the establish-
154 210
trogen can interact with N-methyl-D-aspartate (NMDA) ment and maintenance of hormone production in
155 211
receptors and serotonin.4 NMDA receptors are gluta- various tissues, with expression in regions where
156 212
mate receptors (considered the main neurotransmitter estradiol has important physiologic functions, and
157 213
of the CNS) activated by ER-b after the neuronal sensi- share target genes in common with other ERs, such
158 214
tization process.4-13 These receptors mediate the rapid as osteopontin,23 lactoferrin,24 and pS2.25 It also has
159 215
depolarization in most synapses in the brain and spinal been identified as a cofactor of hypoxia-inducing fac-
160 216
cord and are associated with sodium ion influx tor in mediating adaptation to the hypoxic environ-
161 217
channels. Once activated, they play a key role in ment and oxygen homeostasis.26 In a recent study
162 218
central sensitization by depolarizing second-order conducted in 2015, polymorphisms in the ESRRB
163 219
neurons and activating calcium- and calmodulin- gene (rs6574293, rs4903399, rs10132091) were asso-
164 220
dependent kinases, which in turn phosphorylate ciated with the risk of damage developing in the TMJ
165 221
postsynaptic proteins, thus activating other NMDA re- and the shoulder joint.20
166 222
ceptors.14 It is believed that estrogen can increase the Thus, it is believed that the association between
167 223
hypothalamic excitability of the NMDA receptors and TMDs and other chronic systemic arthralgias is not
168 224

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 QUINELATO ET AL 1.e3

225 random. There is a genetic and clinical basis for the co- STAGE 2—ASSESSMENT OF PRESENCE AND 281
226 morbid development of these 2 disorders. The pres- DURATION OF OTHER ARTHRALGIA 282
227 ence of polymorphisms in genes associated with In this stage, each participant completed a question- 283
228 estrogen metabolism could be related to the develop- naire considering the presence of pain in the knee, 284
229 ment of multiple-joint pain. Thus, the aim of this study hip, ankle, shoulder, wrist, and elbow joints and pain 285
230 was to evaluate the possible association of polymor- duration (days, months, or years). The questionnaire 286
231 phisms in the ESR1 and ESRRB genes with the risk was administered exclusively by a second examiner 287
232 of simultaneous development of TMDs and pain in who had no prior knowledge of the presence or 288
233 other joints in the body. absence of TMDs in the participants being assessed. 289
234 Arthralgia duration longer than 3 months was consid- 290
235 ered chronic.29,30 291
236 Materials and Methods According to the diagnosis of TMDs and other as- 292
237 sessed arthralgia, participants were divided into 4 293
238 This is a descriptive cross-sectional randomized 294
groups: 1) with muscular TMDs and chronic pain in
239 study that was approved on May 30, 2013 by the 295
another joint in the body, 2) with joint disorders and
240 research ethics committee of the Salgado de Oliveira 296
chronic pain in some other joint in the body, 3) no
241 Q5 University (S~ao Goncalo, RJ, Brazil; opinion number 297
TMD but some other type of chronic arthralgia, and
242 286.354). Free and informed consent was obtained 298
4) no TMD and no other type of joint pain (con-
243 from participants in writing before conducting the 299
trol group).
244 research. Recommendations from the Strengthening 300
245 the Reporting of Observational Studies in Epidemi- 301
STAGE 3—GENOTYPING
246 ology (STROBE)27 statement were followed for the 302
design and development of this study. Genomic DNA was obtained from saliva samples
247 303
Study subjects included patients seeking care and from all participants, as previously described.31 The
248 304
their companions who were in the waiting rooms of concentration and purity of DNA were analyzed using
249 305
the Fluminense Federal University (Niter
oi, RJ, Brazil). the NanoDrop spectrophotometer (Thermo Scientific,
250 306
Randomly selected participants were 18 to 65 years Wilmington, DE). All samples had to present an A260-
251 307
old and had no history of macrotrauma to the TMJs nm to A280-nm ratio greater than 1.9.20
252 308
or knee, hip, ankle, shoulder, wrist, and elbow joints. Eight single-nucleotide polymorphisms (SNPs) in
253 309
They were solicited at random over a 2-year period. the ESR1 (rs12154178, rs1884051, rs2273206,
254 310
Exclusion criteria were joint surgery; diagnosis of rs7774230) and ESRRB (rs1676303, rs4903399,
255 311
rheumatoid arthritis, systemic lupus erythematosus, fi- rs10132091, rs7151924) genes were selected accord-
256 312
bromyalgia, and other types of systemic joint diseases; ing to linkage disequilibrium relations and gene struc-
257 313
and previous treatment for TMDs. The study method- ture. These SNPs were previously identified and
258 314
ology was divided into 4 stages. included in the National Center for Biotechnology In-
259 315
formation database (http://www.ncbi.nlm.nih.gov/
260 316
SNP), with the lowest allelic frequency having to be
261 317
STAGE 1—CLINICAL DIAGNOSIS OF TMD greater than 0.12. All procedures followed the recom-
262 318
mendations of the Strengthening the Reporting of Ge-
263 All participants were examined clinically by the 319
netic Association Studies (STREGA) statement.32
264 same evaluator using the Research Diagnostic Criteria 320
265 for Temporomandibular Disorders—Axis I,28 the tool 321
266 validated for the physical diagnosis of TMD and that al- STAGE 4—STATISTICAL METHODS 322
267 lows classification of participants into some of the Data processing and statistical analysis were per- 323
268 following diagnostic subgroups: no TMD (subgroup formed using STATA 12.0 (StataCorp, College Station, 324
269 0), painful muscle disorders (subgroup 1), joint disc TX). The sample included patients seeking care and 325
270 position changes (subgroup 2), and painful or degener- their companions at the Fluminense Federal University 326
271 ative TMJ conditions (subgroup 3). This classification during a 2-year period after applying the inclusion 327
272 is not mutually exclusive, allowing each participant criteria. Calculation of the sample size was designed 328
273 to belong to more than 1 diagnosis subgroup. to detect a risk factor that affected 40% of the sample 329
274 The joint diagnoses (subgroups 2 and 3) were com- (a, 5%; power, 90%). To verify the normal distribution 330
275 bined to form a single joint disorders group. Thus, 3 of the numerical variables, the Shapiro-Wilk test was 331
276 groups were formed: 1) control (no TMD diagnosed), used, followed by analysis of variance with the Student 332
277 2) muscle disorders, and 3) joint disorders. Partici- t test and Mann-Whitney test for normal and non- 333
278 pants who had muscle and joint TMDs were excluded. normal distributions, respectively. The c2 test was 334
279 This tool was administered to all participants by a sin- used to evaluate the relevance of nominal variables 335
280 gle trained examiner (L.L.B.). among groups. The parametric test with the Pearson 336

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 1.e4 ESTROGEN AND TEMPOROMANDIBULAR DISORDERS

337 Q9 linear correlation coefficient was used to evaluate the 393

1.4 (0.7-2.7)
Control and No TMD
and With Arthralgia
338 correlation between age and the number of joints 394

OR (CI)

—
339 with pain. 395
340 Differences in the frequency of genotypes and al- 396
341 P Value leles among groups were analyzed using the c2 test af- 397
342 ter fitting for Hardy-Weinberg equilibrium. P values 398
.27

.31

—
343 less than .05 were considered statistically significant, 399
344 and the risks associated with individual alleles and ge- 400
345 1.0 (0.3-3.2) notypes were calculated as odds ratio and 95% confi- 401
Control and Joint

OR (CI)

346 dence interval. ARLEQUIN 20 software (http:// 402

—

—
347 anthro.unige.ch/arlequin) was used to calculate link- 403

Abbreviations: —, undetermined; CI, confidence interval; OR, odds ratio; TMD, temporomandibular disorder; TMJ, temporomandibular joint.
348 age disequilibrium and haplotypes. 404
349 405
P Value

.52

.88

Results
—

350 406
351 407
CLINICAL FINDINGS: PREVALENCE OF TMD AND
352 408
1.5 (0.6-3.3)
Control and Muscle

OTHER ARTHRALGIA
OR (CI)

353 409
—

354 Of 337 volunteers evaluated during a 2-year period, 410

355 212 were included in the study. Of these, 58 (32 411
356 women [55.2%] and 26 men [44.8%]) had TMDs and 412
P Value

357 other arthralgia. Of the TMD subgroups, 42 (33%) 413

.32

.38

358 had only muscular disorders and 16 (12.5%) had only 414
359 joint disorders. The group without TMD but with 415
360 other chronic joint pain (n = 82) was composed of 416
Arthralgia (n = 82)
No TMD and With

361 52 women (63.4%) and 30 men (36.6%). The control 417

41.3  12.4

group was composed of 72 participants (39 women

2.1  1.4

2.2  1.3

362 418
[54.2%] and 33 men [45.8%]) without articular symp-
52
30

363 419
364 toms and other TMD diagnoses. 420
365 Based on results of the c2 test, there was no statisti- 421
366 cally relevant difference in the prevalence of reported 422
Quinelato et al. Estrogen and Temporomandibular Disorders. J Oral Maxillofac Surg 2017.

367 pain by gender or age (Table 1). 423

Control (n = 72) Muscle (n = 42) Joint (n = 16)

368 424
33.6  14.6

GENETIC ASSOCIATION ANALYSIS

2.3  1.2

2.5  0.8

369 425
9
7

370 The characteristics of the 8 polymorphisms studied 426

371 in the ESR1 (rs12154178, rs1884051, rs2273206, 427
372 rs7774230) and ESRRB (rs1676303, rs4903399, 428
Table 1. CLINICAL PARAMETERS OF STUDY POPULATION

373 rs10132091, rs7151924) genes are presented 429

37.7  17.1

3.1  1.6

3.7  0.3

374 in Table 2. 430

27
15

375 Frequencies of genotypes and alleles were adjusted 431

376 for age (Table 3). Alleles are homologous segments of 432
377 DNA with alternate forms of the same gene that affect 433
378 the same characteristic differently. The prevalence of 434
379 each genotype and alleles was compared among the 435
42.2  13.9

380 evaluated groups using the c2 test. 436

39
33
0

381 Relevant differences in the ESR1 and ESRRB genes 437

382 were observed compared with the control group. 438
383 The TT genotype for the ESR1 (rs2273206) gene was 439
384 strongly associated with the risk of developing 440
Mean pain duration (yr)

385 muscular TMDs and temporomandibular arthralgia 441

Number of joints with
pain (except TMJ)

386 (P = .04). 442

387 For the ESRRB (rs1676303) gene, an association 443
388 was observed between the CC genotype and the pres- 444
389 ence of articular TMDs associated with other chronic 445
Women
Variables

Age (yr)
Gender

390 arthralgia (P = .02). These results were confirmed by 446

Men

391 the increased risk of developing articular TMDs associ- 447

392 ated with the C allele (P = .04). 448

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449 Table 2. CHARACTERISTICS OF POLYMORPHISMS STUDIED IN ESR1 AND ESRRB GENES

505
450 506
451 Base 507
452 Changey 508
453 509
Gene Symbol Gene Name SNP Chromosome Base Pair Position* SNP Type Major Minor MAFz
454 510
455 511
ESR1 Estrogen receptor-1 (a) rs12154178 151929945 Intragenic A C 0.47
456 512
rs1884051 151962144 Intragenic A G 0.49
457 rs2273206 6 152061176 Intragenic G T 0.27 513
458 rs7774230 151843104 Intragenic C T 0.44 514
459 ESRRB Estrogen-related receptor-b rs1676303 76525821 Intragenic C T 0.21 515
460 rs4903399 76308859 Intergenic C T 0.16 516
461 rs10132091 14 76404475 Intragenic C T 0.47 517
462 rs7151924 76311726 Intergenic C T 0.29 518
463 Abbreviations: MAF, minor allele frequency; SNP, single-nucleotide polymorphism.
519
464 * ---. Q10 520
465 y According to Applied Biosystems (Thermo Scientific, Wilmington, DE). 521
466 z According to GenBank (National Center for Biotechnology Information, US National Library of Medicine, Bethesda, MD). 522
467 Quinelato et al. Estrogen and Temporomandibular Disorders. J Oral Maxillofac Surg 2017. 523
468 524
469 525
470 Not all allelic and genotypic frequencies of the SNPs and the joint capsule,34 raising interest in how this hor- 526
471 were within Hardy-Weinberg equilibrium. Neverthe- mone might influence the development of other types 527
472 less, the data were analyzed because the evaluated of joint disorders. The present study provides unprec- 528
473 genes had no description, until the present study, in edented preliminary evidence that polymorphisms in 529
474 the Brazilian population. genes related to the a (ESR1) and b (ESRRB) receptors 530
475 are associated with the risk of developing muscle and 531
476 ANALYSIS OF HAPLOTYPES IN ESR1 AND ESRRB joint TMDs, respectively, in individuals with chronic 532
477 GENES joint pain. 533
478 Because alterations in the ESR1 and ESRRB genes ER-a and ER-b are encoded by different genes in the 534
479 might have been related to the presence of chronic 6q25.1 and 14q23.2 human chromosomes, respec- 535
480 joint pain in participants with TMDs, haplotype anal- tively. After the hormone binds to these receptors, 536
481 ysis was performed by comparing the groups that complexes of hormone and receptor bind to specific 537
482 had joint pain with the control group and adjusting DNA sequences or interact with other transcription 538
483 for age (Table 4). Haplotype corresponds to a combina- factors,35 possibly activating approximately 137 genes 539
484 tion of adjacent loci alleles, which are part of the same under their control and making the effect of these re- 540
485 chromosome, usually inherited as a unit. However, ceptors highly complex.36 Gene regulation occurs by 541
486 there were no relevant associations between genes recruiting different transcription coregulators that 542
487 when analyzed as haplotypes. play a central role in the activation (or repression) of 543
488 genes. Fewer than 50% of these coregulators are com- 544
489 mon to the a and b types, thus contributing to the 545
Discussion
490 distinct functions of the 2 receptor subtypes.37 In addi- 546
491 The function of estrogen in the development and tion, although the 2 subtypes might be expressed in 547
492 perpetuation of chronic pain based on genomic mech- the same tissue, they cannot be expressed in the 548
493 anisms (determined by their interaction with nuclear same cell type. When present in cells that have the 2 549
494 ER-a and ER-b) and non-genomic mechanisms receptor subtypes, ER-b is responsible for antago- 550
495 (involving G protein-coupled receptors)4 has been nizing the actions of ER-a.38 551
496 extensively explored. However, the high prevalence ER-a and ER-b are expressed by chondrocytes, sub- 552
497 of osteoarthritis in postmenopausal women raised in- chondral bone cells, synoviocytes, ligament fibro- 553
498 terest in how such receptors might act not only in blasts, and myoblasts in humans and other species, 554
499 the perception and processing of painful stimuli33 suggesting the interaction between these receptor re- 555
500 but also in the homeostasis of articular tissues.34 gions.38 In bone tissue, ER-a is expressed by osteo- 556
501 Although much attention has concentrated on the ef- blasts and pre-osteoclasts, and osteoclast maturation 557
502 fects of estrogen on articular cartilage, estrogen defi- and bone resorption are associated with the loss of 558
503 ciency also clearly affects other joint tissues, such as expression of this receptor.39 In human skeletal mus- 559
504 periarticular bone, synovial lining, muscles, ligaments, cle, the expression of mRNA of the gene related to 560

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 616
615
614
613
612
611
610
609
608
607
606
605
604
603
602
601
600
599
598
597
596
595
594
593
592
591
590
589
588
587
586
585
584
583
582
581
580
579
578
577
576
575
574
573
572
571
570
569
568
567
566
565
564
563
562
561
Table 3. DISTRIBUTION OF GENOTYPES AND ALLELES OF ESR1 AND ESRRB GENES, ADJUSTED FOR AGE

1.e6
Q11

Control and No TMD

No TMD and Control and Muscle Control and Joint and With Arthralgia
Control Muscle Joint With Arthralgia
Gene SNP Genotypes (n = 72) (n = 42) (n = 16) (n = 82) P Value* ORy (CI) P Value* ORy (CI) P Value* ORy (CI)

ESR1 rs12154178 AA-AC-CC 20-46-4 11-26-5 6-7-3 20-52-7 .5 .09 .72

AC + CC 50 31 10 59 1 1.1 (0.4-2.6) .33 0.6 (0.2-2.0) .7 1.1 (0.5-2.4)
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A 86 48 19 92 .62 0.8 (0.4-1.45) 1 0.9 (0.4-2.0) .6 0.8 (0.5-1.3)

C 54 36 13 66
rs1884051 AA-AG-GG 17-41-7 12-24-3 6-6-4 22-44-11 .85 .26 .73
AG + GG 48 27 10 55 .77 0.7 (0.3-1.9) .27 0.59 (0.18-1.87) .8 0.8 (0.4-1.8)
A 75 48 18 88 .68 1.1 (0.6-2.0) 1 0.9 (0.4-2.0) 1 0.9 (0.9-1.5)
G 55 30 14 66
rs2273206 GG-GT-TT 51-17-0 29-8-2 12-4-0 49-23-10 .04 .77 .36
GT + TT 17 12 4 33 .79 1.2 (0.5-2.9) .63 1 (0.2-3.5) .07 2.0 (0.9-4.0)
G 119 68 28 121 .46 0.6 (0.3-1.4) .59 1 (0.3-3.2) .5 0.7 (0.3-1.4)
T 17 14 4 23
rs7774230 CC-CT-TT 17-40-9 6-21-12 3-7-4 14-54-7 .35 .3 .36
CT-TT 49 33 11 61 .3 1.9 (0.6-5.3) .5 1.2 (0.3-5.1) .41 1.5 (0.6-3.3)
C 74 33 13 82 .07 0.5 (0.3-1.0) .47 0.67 (0.2-1.5) .9 0.9 (0.5-1.5)
T 58 45 15 68
ESRRB rs1676303 CC-CT-TT 21-10-27 10-4-20 9-0-4 22-18-33 .45 .02 .54
CT-TT 37 24 4 51 .6 1.3 (0.5-3.3) .06 0.2 (0.0-0.9) .58 1.3 (0.6-2.7)

ESTROGEN AND TEMPOROMANDIBULAR DISORDERS

C 52 24 18 62 .2 0.6 (0.3-1.2) .04 2.7 (1.1-6.8) .7 0.9 (0.5-1.4)
T 64 44 8 84
rs4903399 CC-CT-TT 44-8-2 19-6-1 11-2-0 39-16-0 .62 .55 .06
CT-TT 10 7 2 16 .57 1.62 (0.5-4.8) .57 0.8 (0.1-4.1) .2 1.8 (0.7-4.4)
C 96 44 24 94 .61 0.6 (0.2-1.8) .4 1.5 (0.3-7.1) .5 0.7 (0.3-1.6)
T 12 8 2 16
rs10132091 CC-CT-TT 7-42-18 2-23-11 0-6-4 9-54-13 .41 .16 .37
CT-TT 60 34 10 67 .32 1.9 (0.3-10.0) .36 — 1 0.8 (0.3-2.4)
C 56 27 6 72 .65 0.8 (0.4-1.5) .44 0.5 (0.2-1.6) .4 1.2 (0.7-2.0)
T 78 45 14 80
rs7151924 CC-CT-TT 3-22-14 0-13-5 0-7-3 4-26-17 .15 .41 .99
CT-TT 36 18 10 43 .31 — .49 — .6 0.8 (0.1-4.2)
C 28 13 7 34 .84 1.0 (0.4-2.2) .86 0.9 (0.3-2.6) .9 1.0 (0.5-1.8)
T 50 23 13 60
Abbreviations: —, undetermined; CI, confidence interval; OR, odds ratio; SNP, single-nucleotide polymorphism; TMD, temporomandibular disorder.
* Compared with control group.
y Adjusted for age.
Quinelato et al. Estrogen and Temporomandibular Disorders. J Oral Maxillofac Surg 2017.
672
671
670
669
668
667
666
665
664
663
662
661
660
659
658
657
656
655
654
653
652
651
650
649
648
647
646
645
644
643
642
641
640
639
638
637
636
635
634
633
632
631
630
629
628
627
626
625
624
623
622
621
620
619
618
617
 728
727
726
725
724
723
722
721
720
719
718
717
716
715
714
713
712
711
710
709
708
707
706
705
704
703
702
701
700
699
698
697
696
695
694
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692
691
690
689
688
687
686
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684
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682
681
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679
678
677
676
675
674
673

QUINELATO ET AL
Table 4. ANALYSIS OF HAPLOTYPES
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Frequency P Value* (Adjusted for Age)

Control Muscle Joint No TMD and With Control and No TMD

Gene Haplotype (n = 72) (n = 42) (n = 16) Arthralgia (n = 82) Control and Muscle Control and Joint and With Arthralgia

ESR1—Ch6 AAGC 0.17 0.19 0.13 0.28 — .45 —

(rs12154178;
rs1884051; rs2273206;
rs7774230)
AAGT 0.29 0.13 0.33 0.16 .97 — .38
CGGC 0.19 0.068 0.26 0.11 .98 .83 .5
AGGT — 0.06 — 0.04 .23 — 1
CGGT 0.05 0.19 0.04 0.11 .63 .33 .97
AATT 0.02 0.10 — 0 .52 — .78
CAGC 0.05 0.07 — 0.06 .62 — .64
AGGC — — 0.02 0.03 — .73 .06
ESRRB—Ch14 TCTT 0.17 0.26 0.16 0.08 .05 1 .8
(rs1676303;
rs4903399;
rs10132091;
rs7151924)
CCCT 0.08 0.03 0.04 0.15 .8 — 1
TCTC 0.05 0.08 0.001 0.16 .11 — .57

Abbreviations: —, undetermined; TMD, temporomandibular disorder.

* Compared with control group.
Quinelato et al. Estrogen and Temporomandibular Disorders. J Oral Maxillofac Surg 2017.

1.e7
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783
782
781
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769
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766
765
764
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761
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757
756
755
754
753
752
751
750
749
748
747
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743
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741
740
739
738
737
736
735
734
733
732
731
730
729
 1.e8 ESTROGEN AND TEMPOROMANDIBULAR DISORDERS

785 ER-a was 180 times higher than that of ER-b.40 Thus, it degenerative joint changes.44 Polymorphisms in the 841
786 is believed that alterations in only 1 of the genes rs1676303 region were associated in previous studies 842
787 related to ERs can cause alterations in the function of with joint rotator cuff lesions.44,45 In the present 843
788 the 2 receptors, thereby influencing various physio- study, the TT genotype was associated with 844
789 logic functions, among which are increased pain pro- increased risk of developing joint disease. The 845
790 cessing and the development and metabolism of the influence of polymorphisms in the ESRRB gene 846
791 TMJ and associated structures.2-9 related to the development of TMDs has been 847
792 In support of this notion, in the present study, the investigated in only 1 study, conducted by the 848
793 TT genotype polymorphism rs2273206 in the ESR1 authors’ group, with the GG genotype in the 849
794 gene was strongly associated with the risk of devel- rs6574293 region being associated with increased 850
795 oping muscular TMDs. In a study of 100 women, risk of developing the disorder.20 851
796 Q6 Kang et al (2007) observed the association between Although there are different concentrations and ER 852
797 polymorphisms in the ESR1 gene and susceptibility locations in body tissues, their identification has 853
798 to pain in women with osteoarthritis of the TMJ. Smith occurred mainly in the articular cartilage, growth 854
799 et al22 evaluated 398 women with TMD and observed plate, and TMJ.46 Thus, because the presence of poly- 855
800 the presence of epistatic interactions (when $2 genes morphisms in the ESR1 and ESRRB genes was not 856
801 determine the production of enzymes that catalyze observed in the group without TMD but with joint 857
802 different steps of a single biosynthetic pathway) pain, the influence of mutations in the genes and 858
803 between polymorphisms in the COMT (catechol-O- changes in the metabolism of the TMJ is re- 859
804 methyltransferase) and ESR1 genes. This finding em- emphasized. 860
805 phasizes the influence of estrogen on the metabolism In this study, for ethical reasons, the acquisition of 861
806 and development of TMJ structures and its relation tomographic images from all participants was not 862
807 to pain modulation and processing.41 It is believed possible, which represents a major limitation. Howev- 863
808 that the COMT gene has great influence on the devel- er, this work is important for pioneering the study of 864
809 opment of chronic pain when polymorphisms in this the genetic basis of TMDs and chronic arthralgia. It is 865
810 gene coexist with other SNPs, such as the ESR1 believed that alterations in estrogen-related hormone 866
811 gene, thereby affecting the stability of the proteins receptors act through the modulation of pain process- 867
812 produced and influencing their translation process.42 ing and in the metabolism of structures related to the 868
813 Approximately 2,334 SNPs in the ESR1 gene have TMJ. Other types of genetic studies should be carried 869
814 been identified to date that are related not only to out, including the analysis of specific miRNAs and 870
815 reproductive tract diseases but also to osteoporosis, the levels of gene expression and tissue proteins after 871
816 cardiovascular disease, CNS disorders, and malig- TMJ surgery, to elucidate the pathophysiologic mecha- 872
817 nancies, such as breast cancer.43 The most-studied nism of TMDs. However, because of the restricted sam- 873
818 SNPs related to ESR1 are the microsatellite (TA)n and ple size in the present study, future studies should 874
819 the PvuII and XbaI SNPs. These polymorphisms are include larger samples and other genetic evaluations. 875
820 located in noncoding regions and can interfere with In the sample studied, polymorphisms in the ESR1 876
821 the modulation of gene transcription, because in the gene were associated with the presence of myogenic 877
822 first intron of the gene, where the PvuII and XbaI TMDs associated with chronic arthralgia. In this 878
823 SNPs are located, and in the promoter region, where same group of participants, alterations in the ESRRB 879
824 the (TA)n and (GT)n repeats are located, they usually gene were associated with the presence of artic- 880
825 contain a large number of regulatory sequences.43 ular TMDs. Q7 881
826 In relation to the ESRRB gene, and corresponding 882
827 with the literature cited earlier, an association was 883
828 observed between the CC genotype and the presence References 884
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999
944 1000
945 1001
946 1002
947 1003
948 1004
949 1005
950 1006
951 1007
952 1008

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