Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder.

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.

Human genetic selection on the MTHFR 677C>T polymorphism.

BACKGROUND: The prevalence of genotypes of the 677C>T polymorphism for the MTHFR gene varies among humans. In previous studies, we found changes in the genotypic frequencies of this polymorphism in populations of different ages, suggesting that this could be caused by an increase in the intake of folate and multivitamins by women during the periconceptional period. The aim was to analyze changes in the allelic frequencies of this polymorphism in a Spanish population, including samples from spontaneous abortions (SA). METHODS: A total of 1305 subjects born in the 20th century were genotyped for the 677C>T polymorphism using allele specific real-time PCR with Taqman probes. A section of our population (n = 276) born in 1980-1989 was compared with fetal samples (n = 344) from SA of unknown etiology from the same period. RESULTS: An increase in the frequency of the T allele (0.38 vs 0.47; p < 0.001) and of the TT genotype (0.14 vs 0.24; p < 0.001) in subjects born in the last quarter of the century was observed. In the 1980-1989 period, the results show that the frequency of the wild type genotype (CC) is about tenfold lower in the SA samples than in the controls (0.03 vs 0.33; p < 0.001) and that the frequency of the TT genotype increases in the controls (0.19 to 0.27) and in the SA samples (0.20 to 0.33 (p < 0.01)); r = 0.98. CONCLUSION: Selection in favor of the T allele has been detected. This selection could be due to the increased fetal viability in early stages of embryonic development, as is deduced by the increase of mutants in both living and SA populations.

Influence of gender and genetic variability on plasma angiotensin peptides.

INTRODUCTION: We analysed the influence of three polymorphisms of the renin-angiotensin system (RAS) (I/D from angiotensin-converting enzyme [ACE], M235T from angiotensinogen gene [ATG] and A1166C from AT1 receptors) on plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)]. MATERIALS AND METHODS: The study population consisted of a homogeneous group of 93 healthy subjects (43 men and 50 women, mean age: 20.67+/-2.75 years). The mean blood pressure (BP) was 126+/-7/76+/-5 (SD) mmHg and the mean body mass index (BMI) was 22.4+/-2.5 kg/m2. Angiotensin peptides were separated by high performance liquid chromatography (HPLC) and quantified by radio immuno assay (RIA). Genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme analysis. RESULTS: Mean peptide levels were 92.48+/-102.12 pg/ml for Ang I, 22.35+/-10 pg/ml for Ang II, and 31.65+/-27.46 pg/ml for Ang-(1-7). Men had significantly higher levels of Ang-(1-7) (37.76+/-36.47 pg/ml) than women (26.04+/-13.98 pg/ml) (p<0.05). Among genotypes of each polymorphism, men with the T allele showed higher Ang- (1-7) levels compared with those with the MM genotype (p<0.05). Genotype analysis in women showed that higher Ang I levels were related with the DD genotype. When both genders were compared according to genotype, higher values of Ang-(1-7) levels and its molar ratios were found in men, and there was significantly greater Ang I levels in DD genotypes in women than men (136.72+/-112.43 vs . 65.36+/-46.83 pg/mL). CONCLUSIONS: Significant correlations were found between Ang I and Ang II as well as between Ang II and Ang-(1-7) in the different study group distributions. No correlation was found between levels of Ang I and Ang-(1-7). Certain genotypes exert an influence on angiotensin peptide plasma levels which can only be seen when the population is divided according to gender.