DNMT3B Rs2424913 Research Articles

DNMT3B rs2424913 as a Risk Factor for Congenital Heart Defects in Down Syndrome

Impairments of the genes that encode enzymes that are involved in one-carbon metabolism because of the presence of gene polymorphisms can affect the methylation pattern. The altered methylation profiles of the genes involved in cardiogenesis may result in congenital heart defects (CHDs). The aim of this study was to investigate the association between the MTHFR rs1801133, MTHFR rs1801131, MTRR rs1801394, DNMT1 rs2228611, DNMT3A rs1550117, DNMT3B rs1569686, and DNMT3B rs2424913 gene polymorphisms and congenital heart defects in Down syndrome (DS) individuals. The study was conducted on 350 participants, including 134 DS individuals with CHDs (DSCHD+), 124 DS individuals without CHDs (DSCHD-), and 92 individuals with non-syndromic CHD. The genotyping was performed using the PCR-RFLP method. A statistically significant higher frequency of the DNMT3B rs2424913 TT in the DSCHD+ individuals was observed. The DNMT3B rs2424913 TT genotype, as well as the T allele, had significantly higher frequencies in the individuals with DS and atrial septal defects (ASDs) in comparison with the individuals with DS and other CHDs. Furthermore, our results indicate a statistically significant effect of the DNMT3B rs1569686 TT genotype in individuals with non-syndromic CHDs. The results of the study suggest that the DNMT3B rs2424913 TT genotypes may be a possible predisposing factor for CHDs in DS individuals, and especially those with ASDs.

Association of the DNA Methyltransferase and Folate Cycle Enzymes' Gene Polymorphisms with Coronary Restenosis.

Background: In recent years, the interest in genetic predisposition studies for coronary artery disease and restenosis has increased. Studies show that polymorphisms of genes encoding folate cycle and homocysteine metabolism enzymes significantly contribute to atherogenesis and endothelial dysfunction. The purpose of this study was to examine some SNPs of genes coding for folate cycle enzymes and DNA methyltransferases as risk factors for in-stent restenosis. Methods: The study included 113 patients after stent implantation and 62 patients without signs of coronary artery disease at coronary angiography as the control group. Real-time PCR and RFLP-PCR were applied to genotype all participants for MTHFR rs1801133, MTHFR rs1801131, MTR rs1805087, MTRR rs1801394, DNMT1 rs8101626, DNMT3B rs1569686, and DNMT3B rs2424913 gene polymorphisms. Statistical data processing was carried out using the R language and the SPSS Statistics 20 software. Results: Statistically significant differences in the DNMT3B gene polymorphisms were found between patients with and without in-stent restenosis. An association of TT rs1569686 and TT rs2424913 genotypes with the development of restenosis was revealed. The TT rs1569686 genotype was more frequent in the patients under the age of 65 years and in the subgroup of patients with post-12-month restenosis, as was the minor GG genotype for MTR rs1805087. The homozygous TT genotype for MTHFR rs1801133 was significantly more frequent in the subgroup over 65 years old. The frequencies of the heterozygous genotype for the MTRR gene and the minor GG homozygotes for the DNMT1 gene were significantly higher in the subgroup with in-stent restenosis under 65 years old. Conclusions: The results of this study could be used for a comprehensive risk assessment of ISR development, determining the optimal tactics and an individual approach in the treatment of patients with coronary artery disease before or after percutaneous coronary interventions, including homocysteine-lowering treatment in patients with hyperhomocysteinemia and a high risk of in-stent restenosis.

Polymorphisms in GNMT and DNMT3b are associated with methotrexate treatment outcome in plaque psoriasis

Methotrexate is used as first-line treatment of moderate to severe psoriasis. Despite the marked variability in treatment outcomes, no pharmacogenetic markers are currently used for personalised management of therapy. In this retrospective study, we investigated the effects of genetic predisposition on efficacy and toxicity of low-dose methotrexate in a cohort of 137 patients with moderate to severe plaque psoriasis. We genotyped 16 polymorphisms in genes for enzymes involved in the folate–methionine pathway and in methotrexate transport, and analysed their association with treatment efficacy and toxicity using classification and regression tree analysis and logistic regression. The most pronounced effect observed in this study was for GNMT rs10948059, which was identified as a risk factor for inadequate efficacy leading to treatment discontinuation. Patients carrying at least one variant allele had ~7-fold increased risk of treatment failure compared to patients with the wild-type genotype, as shown by the classification and regression tree analysis and logistic regression (odds ratio [OR], 6.94; p = 0.0004). Another risk factor associated with insufficient treatment responses was DNMT3b rs2424913, where patients carrying at least one variant allele had a 4-fold increased risk of treatment failure compared to patients with the wild-type genotype (OR, 4.10; p = 0.005). Using classification and regression tree analysis, we show that DNMT3b rs2424913 has a more pronounced role in patients with the variant GNMT genotype, and hence we suggest an interaction between these two genes. Further, we show that patients with the BHMT rs3733890 variant allele had increased risk of hepatotoxicity (OR, 3.17; p = 0.022), which is the most prominent reason for methotrexate discontinuation. We also show that variants in the genes for methotrexate transporters OATP1B1 (rs2306283/rs4149056 SLCO1B1 haplotypes) and ABCC2 (rs717620) are associated with increased risk of treatment failure. The associations identified have not been reported previously. These data suggest that polymorphisms in genes for enzymes of the methionine cycle (which affect cell methylation potential) might have significant roles in treatment responses to methotrexate of patients with psoriasis. Further studies are warranted to validate the potential of the pharmacogenetic markers identified.

Association of СОМТ, DRD2/ANKK1, MTHFR, MIR 137, DNMT3B polymorphisms with the clinical features of schizophrenia patients in acute stage and remission

Updated view of genetic features of schizophrenia based on rare SNPs/CNVs with a huge influence on a disease and common SNPs with a small effect of each allele is presented. Altogether these genetic factors are acting to create neuropathophysiological disturbances observed in schizophrenia. Association of five polymorphisms MIR137 rs1625579, DRD2/ANKK1 rs1800497, MTHFR rs1801133, DNMT3B rs2424913, СОМТ rs4680 with the risk of schizophrenia in the Belarusian population, the level of symptoms of schizophrenia patients assessed by PANSS in the acute stage and remission, cognitive impairments, and treatment trajectory of schizophrenia patients during antipsychotic treatment were analyzed. The A/A-genotype of СОМТ rs4680 (р = 0.008) and the С/С-genotype of MTHFR rs1801133 (р = 0.02) are associated with the risk of schizophrenia among Belarusians. The T-allele of MTHFR rs1801133 is a risk factor of positive symptoms (р = 0.02). Combining the C/C-genotype (DNMT3B rs2424913) and the G-allele (COMT rs4680) is associated with a significant difference in negative symptoms level between men and women. The polymorphism of СОМТ rs4680 (р < 0.05) and the combination of СОМТ rs4680 + DRD2/ANKK1 rs1800497 (р = 0.005) as well as MTHFR rs1801133 + DNMT3B rs2424913 (р = 0.006) are related to the cognitive parameters measured by the WCST and Stroop test respectively. Schizophrenia patients who are the G-allele carriers of MIR137 rs1625579 demonstrated a more favorable negative symptom trajectory in comparison to Т/Тhomozygotes (F = 2.2, p = 0.03). The trajectory of negative symptoms (F = 2.2, p = 0.03) and general psychopathological symptoms (F = 4.3, p = 0.0001) is different between men and women under antipsychotic treatment. These differences are associated with a minor amount of alleles of MIR137 rs1625579, DRD2/ANKK1 rs1800497, MTHFR rs1801133 polymorphic sites.

DNMT3B rs1569686 and rs2424913 gene polymorphisms are associated with positive family history of preterm birth and smoking status

AimTo evaluate the association between spontaneous preterm birth (SPTB) and DNA methyltransferase (DNMT)1, 3A, 3B, and 3L gene polymorphisms, and their contribution to the clinical characteristics of women with SPTB and their newborns.MethodsThis case-control study, conducted in 2018, enrolled 162 women with SPTB and 162 women with term delivery. DNMT1 rs2228611, DNMT3A rs1550117, DNMT3B rs1569686, DNMT3B rs2424913, and DNMT3L rs2070565 single nucleotide polymorphisms were genotyped using polymerase chain reaction and restriction fragment length polymorphism methods. The clinical characteristics included in the analysis were family history of preterm birth, maternal smoking, maternal age, gestational week at delivery, and fetal birth weight.ResultsDNMT gene polymorphisms were not significantly associated with SPTB. DNMT3B rs1569686 and rs2424913 minor alleles (T) were significantly more frequent in women with familial PTB than in women with non-familial PTB, increasing the odds for familial PTB 3.30 and 3.54 times under dominant genetic models. They were also significantly more frequent in women with SPTB who smoked before pregnancy, reaching the most significant association under additive genetic models (odds ratio 6.86, 95% confidence interval 2.25-20.86, P < 0.001; odds ratio 3.77, 95% confidence interval 1.36-10.52, P = 0.011, respectively).ConclusionsDNMT3B rs1569686 and rs2424913 gene polymorphisms might be associated with positive family history of PTB and smoking status.

Prevalence of Some Gene Polymorphisms Related to Early Pregnancy Loss among Russian Women

Background. A variety of biological processes regulated by differential gene expression are required to maintain a normal gestation and accordingly, the mutations and polymorphisms in such genes may cause miscellaneous biological disorders that eventually result in early pregnancy loss. Many studies reported that aberrant fetal DNA methylation as well as embryonic chromosome abnormalities may lead to impairment of fetal early growth and development. Therefore, we have aimed to genotype several gene polymorphisms might be involved in the above-mentioned biological disorders to screen their prevalence in Russian population. Materials and methods. 81 Russian women without previous history of normal pregnancy or early abortion were recruited into this population study to determine the genotype and allele frequencies through genotyping using RFLP-PCR method for DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248, and DNMT3L rs2070565, allele-specific PCR for SYCP3 T657C, and real-time PCR for MTHFR rs1801133, MTHFR rs1801131, MTR rs1805087, and MTRR rs1801394. Results. Minor homozygous genotypes and minor alleles of the polymorphisms DNMT3B rs2424913 (TT: 11.1%, T: 37.05%), DNMT1 rs2228611 (GG: 18.5%, G: 40.75%), and DNMT1 rs8101626 (GG: 16.0%, G: 40.1%) were quite prevalent in Russian women and as frequent as those of the well-studied polymorphisms: MTRR rs1801394 (GG: 27.2%, G: 50.65%), MTHFR rs1801131 (CC: 17.3%, C: 40.15%), and MTHFR rs1801133 (TT: 11.1%, T: 29.0%).The heterozygous genotype of SYCP3 T657C (CT: 12.3%, T: 6.15%) was also quite frequent. Conclusion. Based on our study and literature data, we suggest that DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626, and SYCP3 T657C polymorphisms along with the common folate cycle gene polymorphisms can be potential genetic predictors for early pregnancy loss in Russian women.

Association of DNMT3B and DNMN3L Gene Polymorphisms with Early Pregnancy Loss.

A total of 100 women with early pregnancy loss were recruited and further classified into two subgroups: sporadic pregnancy loss and recurrent pregnancy loss; each subgroup consisted of 50 women. The control group included 56 women with normal pregnancies. Genotyping was performed by PCR with restriction fragment length polymorphism analysis. A statistically significant increase in the frequencies of TT genotype and T allele for DNMT3B rs2424913 polymorphism was found in the total patient group and in both patient subgroups in comparison with the control. Moreover, homozygous TT genotype was associated with increased risk of early pregnancy loss (both sporadic and recurrent). DNMT3B rs2424913 gene polymorphism in women can be used a marker of predisposition to early pregnancy loss and recurrent pregnancy loss.

SA101 - ARE COMT, MIR137, MTHFR AND DNMT3B POLYMORPHIC ALLELES ASSOCIATED WITH SCHIZOPHRENIA SYMPTOMS SEVERITY IN MEN AND WOMEN?

Background The mechanisms that determine the development of schizophrenia, progress notes or clinical manifestation can be different in males and females. The aim of the study was to analyze the association of some key genes with symptoms severity in men and women suffering from schizophrenia. Methods 150 Belarusian schizophrenia patients were genotyped using RFLP and TaqMan assays. PANSS was used to evaluate the symptom severity. Patient inclusion criteria were: ICD-10 schizophrenia diagnosis, age 24–65 (46,8±9,44) years. Results There was an association of COMT rs4680 with total score of negative items in combined sample with the effect much stronger for males than for females. Patients with G-allele had a higher degree of negative symptoms. For MIR137 rs1625579 a significant impact on the negative symptomsis observed only for females. COMT rs4680 and MIR137 rs1625579 were associated with total score of general psychopathology symptoms in combined sample, but the effect of COMT was stronger for males, and MIR137 - for females. Moreover, DNMT3b rs2424913 has a significant influence on such symptoms only for females. Carriers of MIR137 TT-genotype, COMT G-allele and DNMT3b T-allele demonstrated higher level of the symptoms. MTHFR rs1801133and MIR137 rs1625579 were associated with total score of positive symptoms in combined sample, but this association in females and males separately doesn’t reach statistically proved level.The highest degree of the symptoms had patients with MTHFR T- and MIR137 TT-alleles. Discussion These results indicate that genes investigated have gender-specific impacts on symptoms and confirm the different mechanisms of schizophrenia pathogenesis between males and females.

DNA (cytosine-5)-methyltransferase 3B (DNMT 3B) polymorphism and risk of Down syndrome offspring.

Down syndrome (DS) is the most common form of human genetic mental retardation. Several polymorphisms in genes coding folic acid cycle enzymes have been associated to the risk of bearing a DS child; however, the results are controversial. S-adenosyl-l-methionine (SAM) is an important intermediate of folic acid pathway and acts as methyl donor and substrate for DNA (cytosine-5)-methyltransferase 3B (DNMT3B – EC 2.1.1.37) de novo methylation processes during embryogenesis. Recent studies suggest that a functional polymorphism of DNMT 3B in maternal genotype may be associated with a decreased risk of having a DS child. We herein investigate the association of this polymorphism with the occurrence of DS in a Brazilian population. We have genotyped 111 mothers of DS infants (MDS) and 212 control mothers (CM) through PCR-RFLP. The observed genotypic frequencies were CC = 0.22; CT = 0.49 and TT = 0.29 in CM, and CC = 0.30; CT = 0.52 and TT = 0.18 in MDS. Allelic frequencies were C = 0.47 and T = 0.53 in CM and C = 0.56 and T = 0.44 in MDS. No deviation of HWE was observed, and both DNMT 3B rs2424913 genotype (χ2 = 4.53; DF = 1; P = 0.03) and allelic (χ2 = 4.90; DF = 1; P = 0.03) frequencies show significant differences between MDS and CM. The presence of the mutant DNMT 3B T allele decreases 30% the risk of bearing a DS child (OR = 0.69; 95% CI: 0.50–0.96; P = 0.03), and the risk is diminished up to 45% in association with the homozygous genotype (OR = 0.54; 95% CI: 0.31–0.96; P = 0.04). Our results suggest that women harboring the single nucleotide polymorphism DNMT 3B rs2424913 have a decreased risk of a DS pregnancy, and further studies are necessary to confirm this protective effect.

Association between DNA methyltransferase gene polymorphism and Parkinson’s disease

Parkinson’s disease (PD) is a common and complex neurodegenerative disorder, the second most prevalent, only behind Alzheimer’s disease. Recent studies suggest that environmental factors may contribute for neurodegeneration through induction of epigenetic modifications, such as DNA methylation, that is carried out by enzymes, such as DNMT1 and DNMT3B.This present study targeted to investigate the association among DNMT1 and DNMT3B polymorphisms with PD.Five hundred and twenty-two participants (214 PD patients following UK Brain Bank criteria and 308 healthy individuals) were evaluated. DNA was obtained from whole blood and genotypes were detected by an allelic discrimination assay using TaqMan® MGB probes on a real-time PCR system. The polymorphisms studied were rs2162560 and rs759920 (DNMT1) and rs2424913, rs998382 and rs2424932 (DNMT3B).Was found association between DNMT3B rs2424913 in T allele carriers with PD. The presence of the T allele was associated with PD (OR=1.80, 95% CI 1.16–2.81, p=0.009). No significant difference was observed for others DNMT3B SNPs. Also, no association between PD and the control group were observed for DNMT1 polymorphisms.This is the first study addressing an association between DNMT3B polymorphism and PD. The polymorphism may play a role in the pathogenesis of PD.

Association of DNA methyltransferase polymorphisms with susceptibility to primary gouty arthritis.

Gouty arthritis is the most common type of inflammatory and immune disease, and the prevalence and incidence of gout increases annually. Genetic variations in the DNA methyltransferases (DNMTs) gene have not, to the best of our knowledge, been reported to influence gene expression and to participate in the pathogenesis of gout. The aim of the present study was to investigate whether the DNMT1, DNMT3A and DNMT3B polymorphisms contribute to gout susceptibility. These polymorphisms were screened for in 336 gout patients and 306 healthy control subjects (from a South China population) for association with gout. The distribution frequencies of DNMT1 rs2228611 AA genotype (P=0.007) and A allele (P=0.002; odds ratio=1.508, 95% confidence interval=1.158-1.964) were found to be significantly increased in the gout patients when compared with those in the healthy control subjects. The rs1550117 in DNMT3A and rs2424913 in DNMT3B exhibited no significant associations with gout susceptibility between the patients and control subjects. These results demonstrated that the DNMT1 rs2228611 polymorphism may be involved in the pathogenesis of gout, while DNMT3A rs1550117 and DNMT3B rs2424913 did not show any obvious significance in the current study; thus, may not be used as risk factors to predict the susceptibility to gout. However, further studies are required to investigate the functions and regulatory mechanism of the polymorphisms of DNMTs in gout.

Low-level environmental cadmium exposure is associated with DNA hypomethylation in Argentinean women.

Background: Cadmium, a common food pollutant, alters DNA methylation in vitro. Epigenetic effects might therefore partly explain cadmium’s toxicity, including its carcinogenicity; however, human data on epigenetic effects are lacking.Objective: We evaluated the effects of dietary cadmium exposure on DNA methylation, considering other environmental exposures, genetic predisposition, and gene expression.Methods: Concentrations of cadmium, arsenic, selenium, and zinc in blood and urine of nonsmoking women (n = 202) from the northern Argentinean Andes were measured by inductively coupled mass spectrometry. Methylation in CpG islands of LINE-1 (long interspersed nuclear element-1; a proxy for global DNA methylation) and promoter regions of p16 [cyclin-dependent kinase inhibitor 2A (CDKN2A)] and MLH1 (mutL homolog 1) in peripheral blood were measured by bisulfite polymerase chain reaction pyrosequencing. Genotyping (n = 172) for the DNA (cytosine-5-)-methyltransferase 1 gene (DNMT1 rs10854076 and rs2228611) and DNA (cytosine-5-)-methyltransferase 3 beta gene (DNMT3B rs2424913 and rs2424932) was performed with Sequenom iPLEX GOLD SNP genotyping; and gene expression (n = 90), with DirectHyb HumanHT-12 (version 3.0).Results: Cadmium exposure was low: median concentrations in blood and urine were 0.36 and 0.23 µg/L, respectively. Urinary cadmium (natural log transformed) was inversely associated with LINE-1 methylation (β = –0.50, p = 0.0070; β = –0.44, p = 0.026, adjusted for age and coca chewing) but not with p16 or MLH1 methylation. Both DNMT1 rs10854076 and DNMT1 rs2228611 polymorphisms modified associations between urinary cadmium and LINE-1 (p-values for interaction in adjusted models were 0.045 and 0.064, respectively). The rare genotypes demonstrated stronger hypomethylation with increasing urinary cadmium concentrations. Cadmium was inversely associated with DNMT3B (rS = –0.28, p = 0.0086) but not with DNMT1 expression (rS = –0.075, p = 0.48).Conclusion: Environmental cadmium exposure was associated with DNA hypomethylation in peripheral blood, and DNMT1 genotypes modified this association. The role of epigenetic modifications in cadmium-associated diseases needs clarification.