title: Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder.
abstract: BACKGROUND
  Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD.
  
  
  METHODS
  A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated.
  
  
  RESULTS
  Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161).
  
  
  CONCLUSIONS
  Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome.
authors: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Málaga, Spain.
authors: Angel
authors: A
authors: Aneiros-Guerrero
authors: Ana M
authors: AM
authors: Lendinez
authors: Arturo R
authors: AR
authors: Palomares
authors: Beatriz
authors: B
authors: Perez-Nevot
authors: Lidia
authors: L
authors: Aguado
authors: Alvaro
authors: A
authors: Mayor-Olea
authors: Maximiliano
authors: M
authors: Ruiz-Galdon
authors: Armando
authors: A
authors: Reyes-Engel
references: Med Hypotheses. 2008 Oct;71(4):564-7
references: 18597950
references: Biopsychosoc Med. 2007 Jan 10;1:3
references: 17371573
references: Pain. 1999 Mar;80(1-2):15-22
references: 10204713
references: Int J Oral Maxillofac Surg. 2007 May;36(5):391-4
references: 17391927
references: J Biol Chem. 2002 Oct 11;277(41):38381-9
references: 12161434
references: Mol Psychiatry. 2000 Jan;5(1):96-100
references: 10673775
references: J Craniomandib Disord. 1992 Fall;6(4):301-55
references: 1298767
references: Am J Orthod Dentofacial Orthop. 2001 Sep;120(3):308-13
references: 11552131
references: J Hum Genet. 2006;51(2):98-103
references: 16315005
references: J Dent Res. 2004 Aug;83(8):619-24
references: 15271970
references: Biochemistry. 2002 Nov 12;41(45):13378-85
references: 12416982
references: Swed Dent J. 2010;34(3):139-47
references: 21121413
references: Mol Hum Reprod. 2007 Apr;13(4):213-22
references: 17277043
references: J Pain. 2009 May;10(5):527-33
references: 19411060
references: Proc (Bayl Univ Med Cent). 2008 Jul;21(3):243-7
references: 18628971
references: J Am Dent Assoc. 1990 Mar;120(3):253, 255, 257 passim
references: 2179355
references: Methods Mol Biol. 2010;617:375-93
references: 20336436
references: Genet Mol Res. 2005 Jun 30;4(2):115-25
references: 16110434
references: Pharmacogenet Genomics. 2010 Apr;20(4):239-48
references: 20216107
references: J Neurochem. 1996 Jun;66(6):2621-4
references: 8632190
references: Neurogenetics. 2003 Aug;4(4):207-12
references: 12687422
references: Redox Rep. 2004;9(6):331-6
references: 15720828
references: Biotechniques. 1998 Feb;24(2):238-9
references: 9494722
references: Lung Cancer. 2007 Aug;57(2):143-51
references: 17420066
references: Saudi Med J. 2008 Sep;29(9):1352-4
references: 18813430
references: J Oral Maxillofac Surg. 1998 Feb;56(2):214-23
references: 9461148
references: J Prosthodont. 2006 Jan-Feb;15(1):9-19
references: 16433646
references: Int J Vitam Nutr Res. 1988;58(4):436-41
references: 3072307
references: Br J Oral Maxillofac Surg. 2004 Oct;42(5):405-9
references: 15336765
references: Community Dent Oral Epidemiol. 1980 Dec;8(8):434-6
references: 6942960
references: Minerva Stomatol. 2004 Nov-Dec;53(11-12):651-60
references: 15894940
references: Int J Oral Maxillofac Surg. 2006 Feb;35(2):165-9
references: 16154319
references: J Am Dent Assoc. 2004 Apr;135(4):474-83
references: 15127871
references: Cells Tissues Organs. 2001;169(3):187-92
references: 11455113
references: Oral Maxillofac Surg Clin North Am. 2007 May;19(2):267-77, viii
references: 18088884
references: Carcinogenesis. 1991 Jan;12(1):25-8
references: 1988177
references: Oral Dis. 2004 Nov;10(6):349-52
references: 15533210
references: J Orofac Pain. 2006 Fall;20(4):271-87
references: 17190026
references: J Oral Maxillofac Surg. 2010 Dec;68(12):2975-9
references: 20656393
references: Semin Orthod. 2008 Jun;14(2):146-156
references: 18663384
references: Pain. 2009 Dec 15;147(1-3):187-93
references: 19796878