MTR Rs1805087 Research Articles

Interactions between vitamin B2, the MTRR rs1801394 and MTR rs1805087 genetic polymorphisms, and colorectal cancer risk in a Korean population.

We explored whether the association between vitamin B2 and colorectal cancer (CRC) risk could be modified by the MTRR rs1801394 and MTR rs1805087 genetic polymorphisms and examined whether the interaction effects are sex-specific. We performed a case-control study involving 1,420 CRC patients and 2,840 controls from the Korea National Cancer Center. Dietary vitamin B2 intake was assessed using a semiquantitative food frequency questionnaire, and the association with CRC was evaluated. Genotyping was performed using an Illumina MEGA-Expanded Array. For gene-nutrient interaction analysis, pre-matched (1,081 patients and 2,025 controls) and matched (1,081 patients and 1,081 controls) subsets were included. Unconditional and conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). A higher intake of vitamin B2 was associated with a significantly lower CRC risk (OR, 0.65; 95% CI, 0.51 to 0.82; p<0.001). Carriers of at least 1 minor allele of MTRR rs1801394 showed a significantly higher CRC risk (OR, 1.43; 95% CI, 1.12 to 1.83). Males homozygous for the major allele (A) of MTRR rs1801394 and who had a higher intake of vitamin B2 had a significantly lower CRC risk (OR, 0.31; 95% CI, 0.18 to 0.54; p-interaction=0.02). In MTR rs1805087, males homozygous for the major allele (A) and who had a higher vitamin B2 intake had a significantly lower CRC risk (OR, 0.38; 95% CI, 0.25 to 0.60; p-interaction<0.001). The MTRR rs1801394 and MTR rs1805087 genetic polymorphisms may modify the association between vitamin B2 and CRC risk, particularly in males. However, further studies are warranted to confirm these interaction results.

The prevalence and linkage disequilibrium of 21 genetic variations related to thrombophilia, folate cycle, and hypertension in reproductive age women of Rostov region (Russia).

Several maternal genetic variations are known to play an important role during pregnancy since they can affect mother health and/or fetal growth. The frequency of these variants is variable among different populations. This study aimed to investigate thrombophilia, folate metabolism and hypertension genetic variants in reproductive age women of Rostov region (Russia) and then assess their linkage disequilibrium (LD) and heterogeneity among populations. A total of 3108 reproductive age women were included (33.75±5.13 years). Twenty-one genetic variants were detected with RT-PCR. LD was tested according to (D') coefficient and p value. The highest frequency of mutant allele in studied population was as follows: PAI-1 rs1799768, MTRR rs1801394, AGT rs699, and AGTR2 rs1403543. We showed a high possibility of coinheritance of MTHFR rs1801133 with rs1801131 and AGT rs699 with rs4762 (D'=0.992 and 0.999, respectively). In addition, comparative analysis showed F7 rs6046, FGB rs1800790, MTR rs1805087, and AGT rs699 significantly more frequent among Rostov females by 1.3-1.5 times than European. MTHFR rs1801133, ADD1 rs4961, AGTR2 rs1403543, NOS3 rs2070744, and rs1799983 were with higher frequencies in Europeans than those in the studied group. Our data could be used as a reference for further associative studies of targeted genetic variations in different pregnancy complications specifically in this population.

Association of Methionine Synthase rs1805087 Polymorphism With Arsenic-Related Skin Pigmentary Changes: A Population-Based Case-Control Study

Objective: Chronic arsenic exposure causes skin lesions including skin cancers, pigmentary changes, and keratosis. Genetic polymorphism in arsenic metabolism may increase susceptibility to the development of arsenic-related skin lesions. This study was performed to determine whether arsenic metabolism-related gene variants are associated with arsenic-related pigmentary changes. Methods: This case–control study involved 189 patients with arsenic-related pigmentary changes and 103 controls. Thirty-eight polymorphisms in 10 genes determined by mass spectrometry assay served as candidate drivers of arsenic-induced pigmentary changes. Urine and plasma arsenic levels were determined by inductively coupled plasma mass spectrometry. Hair arsenic concentrations were measured by nondispersive atomic fluorescence spectrometry. Arsenic metabolites in urine were determined using high-performance liquid chromatography with inductively coupled plasma mass spectrometry. Serum folate was measured using a folate radio assay kit. Analysis of variance, nonparametric test, or the chi-square test was selected according to the data distribution. Spearman correlation analysis was used to determine the correlation between two parameters. Logistic regression was used to estimate the effect of single-nucleotide polymorphisms. Results: The arsenic concentrations in urine, plasma, and hair and the urine arsenic species were not significantly different between patients and controls. Logistic regression revealed that among the polymorphisms, the methionine synthase (MTR) rs1805087 polymorphism showed a protective effect against arsenic-related pigmentary changes. In the codominant model, the adjusted odds ratio for age, sex, and ethnicity was 0.41 (95% confidence interval [CI], 0.21–0.80; P = 0.008) for the AG genotype and 0.11 (95% CI, 0.02–0.60; P = 0.012) for the GG genotype. Conclusion: MTR polymorphism showed a protective effect against arsenic-related pigmentary changes in the logistic regression model. The effect of MTR rs1805087 might be independent of arsenic metabolism and one-carbon metabolism. More studies are needed to clarify the biological function of MTR rs1805087 and its relationship with the etiology of arsenic-related pigmentary changes.

Association of MTR and MTRR genes and oral health-related quality of life in children with dental caries.

This study aimed to assess whether genetic polymorphisms in MTR and MTRR are potential biomarkers of oral health-related quality of life (OHRQoL) in children with caries. A cross-sectional study was designed wherein pairs of parents/caregivers and children (aged two-five years) were selected. Clinical examination was used to detect dental caries, which were classified as low-severity and high-severity caries. The Early Childhood Oral Health Impact Scale (ECOHIS) questionnaire was used to assess OHRQoL. Genomic DNA extracted from the saliva was used to analyze two missense genetic polymorphisms: MTR (rs1805087) and MTRR (rs1801394). Mann-Whitney non-parametric test was used to analyze candidate genes with OHRQoL scale and domain, with a significance level of p≤0.05. MTR (rs1805087) was found associated (p = 0.05) with children's OHRQoL subscale scores in the dominant model (GG + AG). Genetic polymorphisms in MTR may increase the risk of poor OHRQoL in children with caries. Further studies are needed to investigate genetics, molecular factors, and OHRQoL.

Role of intergenic interactions among folate cycle genes in the development of fetal growth retardation

Objective: Metabolic disturbances in the folate cycle in mothers can lead to fetal growth retardation (FGR). This study was to analyze the role of intergenic interactions among maternal folate cycle genes in the development of FGR. Methods: This case-control study recruited 365 women in the third trimester of pregnancy, including 122 FGR patients and 243 controls. The women were genotyped for 5 polymorphisms of the 4 folate cycle genes: MTR (rs1805087), MTRR (rs1801394), serine hydroxymethyl transferase (SHMT1; rs1979277), and TYMS (rs699517 and rs2790). The SNP × SNP interactions in the two-, three-, and four-locus models were analyzed using the multifactor dimensionality reduction method and a modification of it (the model-based multifactor dimensionality reduction method). Results: Four loci of maternal folate cycle genes (rs1805087 MTR, rs2790 TYMS, rs1801394 MTRR, and rs1979277 SHMT1) were associated with FGR in 3 significant models of single nucleotide polymorphism (SNP) × SNP interactions (two-, three-, and four-locus models) (P &lt;0.05). The highest contribution to FGR was made by polymorphic loci rs1979277 SHMT1 (1.70% of entropy), rs1805087 MTR (0.96%), and interactions between rs1979277 SHMT1 × rs1805087 MTR (-1.11%) and rs1801394 MTRR × rs1979277 SHMT1 (−0.64%). The four-locus maternal genotype combination AG rs1801394 MTRR × AA rs1805087 MTR × CT rs1979277 SHMT1 × AG rs2790 TYMS was associated with an increased risk of FGR (β = 2.69, P = 0.012). FGR-associated SNPs were correlated with the expression of 16 genes (MTR, MTRR, SHMT1, ALKBH5, CTD-2303H24.2, ENOSF1, FAM106A, FOXO3B, LGALS9C, LLGL1, MIEF2, NOS2P2, RP11-806L2.6, SMCR8, TOP3A, and USP32P2) in various tissues and organs related to FGR pathophysiology. Conclusion: SNP × SNP interactions of maternal folate cycle genes (MTR, MTRR, SHMT1, and TYMS) are associated with the development of FGR.

Role of polymorphic loci &lt;i&gt;VDR&lt;/i&gt; rs10735810, &lt;i&gt;MTHFR&lt;/i&gt; rs1801131, &lt;i&gt;MTHFR&lt;/i&gt; rs1801133, &lt;i&gt;MTR&lt;/i&gt; rs1805087,&lt;i&gt; MTRR&lt;/i&gt; rs1801394 AND &lt;i&gt;VEGFA&lt;/i&gt; rs3025039 in missed abortion: A prospective cohort study

Background. Premature termination of pregnancy, including miscarriage, remains among the critical problems in modern obstetrics and gynaecology practices. In the context of early gestational failure and the notion that 80% of early miscarriages are triggered by genetic reset — some natural filter — an analysis of current knowledge of the genetic aspects of missed abortion (MA) appears relevant.Objectives. A study of the haplotype frequencies for VDR rs10735810, MTHFR rs1801131, MTHFR rs1801133, MTR rs1805087, MTRR rs1801394 and VEGFA rs3025039 polymorphic loci and their association with vitamin D deficiency in women with missed abortion.Methods. A total of 178 women aged 18 to 41 years were examined. The main cohort consisted of MA patients (n = 101) who were divided between cohort I (n = 58; patients with primary MA) and cohort II (n = 43; patients with recurrent MA). The control cohort (n = 77) consisted of women with a successful pregnancy (Z34.0) entailing a term and live birth. Genotyping of polymorphic loci VDR rs10735810, MTHFR rs1801131, MTHFR rs1801133, MTR rs1805087, MTRR rs1801394 and VEGFA rs3025039 was performed in 177 patients. Total serum 25(OH) D (n = 99) was determined by mass spectrometry. Statistical analysis was carried out using the Statistica v. 10 data analysis software (StatSoft, Russia; TIBCO, USA). Results. No differences were revealed for the frequencies of studied haplotypes between MA women and those who gave birth to healthy full-term newborns (p &gt;0.1). No association was found between first-trimester MA and the presence of polymorphic loci variants (p &gt;0.1). The GG haplotype of gene VDR is even less frequent in recurrent MA patients than in control (14.0% vs. 23.7%; OR = 2.29; 95% CI: 0.738–7.075). The GG haplotype of gene MTR has a 2-fold higher frequency in primary MA patients compared to control, albeit at no statistical significance (8.6 vs. 4.0%). Haplotype TT of the gene VEGF polymorphism occurs even less frequently in primary MA patients than in control (3.5 vs. 7.9%, respectively). Patients with first-trimester MA exhibited an association between vitamin D deficiency and the frequency of polymorphic variants VDR rs10735810 (p = 0.0304) and MTHFR rs1801133 (p = 0.0180). The other studied genes did not reveal such an association.Conclusion. The study demonstrates a pathogenetic association of polymorphic variants VDR rs10735810 and MTHFR rs1801133 with missed abortion and vitamin D deficiency.

Evidence of Association between MTRR and TNF-α Gene Polymorphisms and Oral Health-Related Quality of Life in Children with Anterior Open Bite.

To assess the impact of AOB on OHRQoL in children and to evaluate whether MTR (rs1805087), MTRR (rs1801394), TGFβ1 (rs1800469) and TNF-α (rs1799964, rs1799724 and rs1800629) genes are potential biomarkers for OHRQoL in children with AOB. A cross-sectional study was performed with 173 children aged between 2-6 years. The Brazilian version of Early Childhood Oral Health Impact Scale (ECOHIS) was applied. Genetic polymorphisms were analyzed using real-time PCR. Mann-Whitney U-test and Chi-square were used. The overall mean ECOHIS scores were 5.49 (SD= 5.72) and 3.45 (SD = 4.49) (p < 0.01) in the AOB and control groups, respectively. Children with the CC genotype of TNF-α (rs1799724) had a significantly higher psychological QoL level. The MTRR AA genotype group showed a lower QoL level in the child subscale (p = 0.006), function (p = 0.017), and psychological (p = 0.006) domains. There was no significant difference between OHRQoL and the genetic polymorphisms in MTR and TGFβ1. Genetic polymorphisms in TNF-α and MTRR are associated with the impact on the OHRQoL in children with AOB.

Folate metabolism abnormalities in infertile patients with endometriosis.

Background: Homocysteine levels can be impacted by enzymes variations. Aim: To correlate MTHFR, MTR and MTRR variants with homocysteine levels in the blood and follicular fluid and assisted reproduction results. Material & methods:MTHFR (rs2274976, rs1801131, rs1801133), MTR (rs1805087) and MTRR (rs1801394) genotyping was performed by TaqMan assays and compared with homocysteine levels, measured by ELISA, to oocytes retrieved and to the pregnancy status of women with endometriosis and controls. Results: The MTR G allele and GG genotype were more common in patients with endometriosis. They also showed lower levels of homocysteine and more clinical gestations. Epistasis analysis showed a model associated with gestational results, composed of MTHFR+MTR variants (CC+AG). Conclusion: The summation effect of variants in genes participating in folate metabolism was associated with pregnancy status in Brazilian women. MTR variants were more observed in endometriosis patients, as well as lower follicular Hcy levels and increased clinical pregnancy results.

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.

Association Between SNPs in the One-Carbon Metabolism Pathway and the Risk of Female Breast Cancer in a Chinese Population.

ObjectiveThe aim of this study is to assess the relationship between the single-nucleotide polymorphism (SNP) in the one-carbon metabolism pathway (MTR rs1805087; MTHFR rs1801133; ALDH1L1 rs2002287, rs2276731; DNMT1 rs16999593, rs2228611; DNMT3B rs2424908) and the risk of female breast cancer (BC) in a Chinese population.MethodsA population-based case–control study was conducted, involving a total of 439 BC patients and 439 age-matched healthy controls. We adopted Sequence MASSarray to identify genotyping, and used immunohistochemistry (IHC) to test the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) in tumor tissue.ResultsWe found that rs16999593 (TC/CC vs TT: adjusted OR=1.38, 95% CI: 1.03–1.84, p=0.030) was associated with an increased risk of BC, while rs2228611 was related to a decreased BC risk (GA/AA vs GG: adjusted OR=0.74, 95% CI: 0.56–0.97, p=0.030). In addition, stratified analysis revealed that DNMT1 rs16999593, rs2228611 and ALDH1L1 rs2002287 contributed to the risk of BC, with associations with ER, PR and HER-2 expression.ConclusionIn summary, this study revealed that DNMT1 rs16999593 and rs2228611 were associated with BC risk.

Features of the immune profile and polymorphism of candidate genes in children population of an industrially developed region with excessive contamination of the biological medium with mercury

Introduction. Analyzing the negative impact of technogenic chemicals on the health of the children’s population of industrially developed regions is an urgent problem of preventive medicine. Excessive accumulation of mercury in the human body causes disadaptation changes in the immune regulation of physiological processes. Therefore, the analysis of the features of the immune profile associated with polymorphic variants of candidate genes as markers of early disorders of the child population’s health status is relevant in preserving the health of the population of industrialized regions. Materials and methods. A clinical and laboratory examination of the biological environment of 215 children aged 4-6 years was carried out. The observation group consisted of 133 people living in an industrially developed region. The comparison group consisted of 82 people living in a relatively clean territory. The level of contamination of the biological medium with mercury was determined by inductively coupled plasma mass spectrometry. Identification of CD3+CD4+ -, CD3+CD8+- and CD19+ - lymphocytes was performed by flow cytofluorometry. The study of the phagocytic activity of leukocytes was carried out using formalized ram erythrocytes. The level of IgG production was determined using radial immunodiffusion by Mancini, specific IgG to mercury was carried out using allergosorbent testing with an enzyme label. Identification of single-nucleotide polymorphic variants (SNP) of the GSTA4 (rs3756980), FOXP3 (rs3761547), MTR (rs1805087), TERT (rs10054203) genes was carried out by real-time PCR. Results. Children living near the territory of the chemical industry enterprise in conditions of mercury exposure at a level not exceeding hygienic standards are characterized by an increased level of mercury contamination of urine, exceeding the reference level and the level of the comparison group by 1.8 times (p&lt;0.05). The immune profile of children in the observation group is characterized by a decrease in the CD4+/CD8+ immunoregulatory index due to the decline of CD3+CD4+ helpers and hyperproduction of CD3+CD8+ cytotoxic lymphocytes, inhibition of the phagocytic activity of leukocytes (percentage of phagocytosis, phagocytic number, phagocytic index) against the background of an increase in CD19+ lymphocytes, serum IgG and a marker of specific sensitization - IgG to mercury (p&lt;0.05). Changes in the immune profile of children with an increased level of mercury contamination are associated with the C-allele and TC-heterozygous and CC-homozygous genotypes of the GSTA4 gene (rs3756980), the C-allele and CC-genotype of the FOXP3 gene (rs3761547), the A-allele and AA-genotype of the MTR gene (rs1805087) (OR&gt;1, p&lt;0.05), the G-allele and GG-genotype of the TERT gene (rs10054203) (p&lt;0.05). These genes are responsible for the features of detoxification processes, immunoregulation and longevity programs. Conclusion. The established features of cellular (decrease in CD4+/CD8+ due to CD3+CD4+ deficiency with simultaneous increase in CD3+CD8+, inhibition of phagocytosis) and humoral (hyperproduction of IgG, specific IgG to mercury, CD19+) immunity associated with polymorphic variants of the glutathione S-transferase GSTA4 (rs3756980), transcription factor FOXP3 (rs3761547), MTR (rs1805087), TERT telomerase (rs10054203) in children with excessive contamination of the biological medium with mercury, a complex of immune and genetic markers of the effect and sensitivity of mercury exposure is formed.

Folate metabolizing gene polymorphisms and genetic vulnerability to preterm birth in Korean women.

The folate metabolism that converts homocysteine to methionine is closely related to the accumulation of homocysteine. Increased homocysteine levels lead to an impaired antithrombotic function of the vascular endothelium and uterine-placental circulation, resulting in abnormal pregnancy outcomes. Previous studies have reported that gene polymorphisms in folate metabolism are associated with the development of preterm birth (PTB) in various populations. we performed a case-control study to evaluate the association between five polymorphisms in folate metabolic genes (MTHFR, MTR, MTRR, TCN2) and PTB. In this study, a total of 254 subjects were analyzed (111 patients with PTB and 143 women at ≥ 38weeks of gestation). Genotype and allele frequency differences between patients and control groups and the Hardy-Weinberg equilibrium were assessed using a Chi-square test. For evaluation indicators, odds ratios (ORs) of 95% confidence intervals (CI) were estimated. In addition, we analyzed the combined genotype frequencies of SNPs of folate-metabolizing genes to measure gene-gene interactions for PTB. Our results showed that the MTR rs1805087 GG (p = 0.031), and TCN2 rs1801198 CG genotype (OR 0.53, 95% CI 0.288-0.980, p = 0.042) were significantly associated with PTB. The MTHFR rs4846049 AA showed a marginal trend toward significance (OR 0.15, 95% CI 0.018-1.205, p = 0.041). In particular, the combined genotypes, including MTHFR rs1537514 CC-MTRR rs1801394 GG, MTHFR rs1537514 CC-TCN2 rs1801198 CG, and MTR rs1805087 AA-TCN2 rs1801198 CG, have significant interactions with PTB (OR 0.49, 95% CI 0.248-0.992, p < 0.05). The polymorphisms of folate metabolic genes may have a genetic association with the development of PTB in Korean women. A larger sample set and functional studies are required to further elucidate our findings.

Abstract PO-161: Racial differences in the association of one-carbon metabolism polymorphisms and prostate cancer aggressiveness

Abstract Introduction: Prostate Cancer (PCa) disproportionately affects African Americans, as AA men are more commonly diagnosed with aggressive PCa and twice as likely to have mortality from the disease compared to European Americans (EA). The one- carbon metabolism pathway has been extensively studied for cancer development, yet little research has been reported on its association with aggressiveness of cancer at diagnosis. The purpose of our study is to determine whether there is difference by race for the impact of a DHFR 19bp polymorphism together with multiple single nucleotide polymorphisms (SNPs) in one-carbon metabolism genes on a cohort of men diagnosed with either low-aggressive or high-aggressive PCa. Methods: DNA samples from a population-based study of 1,498 PCa subjects in the North Carolina- Louisiana Prostate Cancer Project were analyzed. The DHFR 19bp polymorphism was targeted by utilizing two TaqMan TAMRA probes, one with a FAM fluorescent probe to identify the insertion allele and one with a VIC fluorescent probe to identify the deletion allele. Six SNPs were genotyped via TaqMan SNP genotyping assays by Applied Biosystems. Chi-Square analyses were performed to examine differences in genotype between race. A multivariable logistic regression model adjusted for confounders was utilized to estimate the association of the 19bp DHFR polymorphism and one-carbon metabolism SNPs with PCa aggressiveness. Results: A total of 152 participants were excluded due to insufficient DNA samples, resulting in a sample of 1,346 participants. The analysis consisted of 993 low-aggressive and 345 high aggressive PCa cases. Chi-square analyses revealed significant frequency differences between AAs and EAs for the 19bp DHFR deletion polymorphism (31.2% vs 17.6%), as well as MTHFR rs1801131, MTHFR rs1801133, MTR rs1805087, MTHFD1 rs2236225, and MTHFD2 rs7587117 (P values &amp;lt; 0.0001). After adjusting for confounders, the cohort was stratified based on DHFR polymorphism status. Among subjects with the 19bp DHFR double deletion, individuals with heterozygous MTR rs1805087 (AG) were significantly less likely to have aggressive PCa (OR = 0.27 [0.10, 0.74]) when compared to individuals with the GG genotype. Among the group that had at least one copy of wild-type DHFR, heterozygous individuals (GA) at MTHFD1 rs2236225 had a significantly lower chance of aggressive PCa diagnosis (OR = 0.60 [0.38, 0.95]) compared to individuals with the AA genotype. Conclusion: Substantial differences exist between AAs and EAs in regard to polymorphisms within the one-carbon metabolism pathway. There appears to be significant interaction among genes involved that can be attributable to the racial distribution of genetic polymorphisms. Studies examining the association between folate metabolism and PCa should consider the modulation effect of gene-gene interaction when analyzing the polymorphisms collectively. Citation Format: C. Tyler Ratliff, Lora J. Rogers, L. Joseph Su. Racial differences in the association of one-carbon metabolism polymorphisms and prostate cancer aggressiveness [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-161.

Association of genetic polymorphisms on methotrexate toxicity in patients with rheumatoid arthritis

IntroductionMethotrexate (MTX) is the treatment of choice for patients with rheumatoid arthritis (RA). However, it has been found to produce toxicity in some patients. Different polymorphisms can play a part in inter-individual differences in toxicity. Our aim is therefore to determine the influence of gene polymorphisms in the MTX metabolic pathway, such as MTHFR (rs1801133 and rs1801131), MTHFD1 (rs2236225), MTR (rs1805087), and ABCC2 (rs4148396), on toxicity in MTX treatment among Caucasian patients diagnosed with RA.Material and methodsReal-time polymnerase chain reaction (PCR) analysis with TaqMan probes was performed on these polymorphisms in 200 patients in a retrospective study.ResultsPatients with TT genotype and C allele for MTHFR rs1801133 gene polymorphism presented a higher risk of anaemia (p = 0.0304; OR = 3.70; 95% CI: 1.10–12.34) and dizziness (p = 0.0438; OR = 8.15; 95% CI: 1.61– 148.68). Patients with MTHFR rs1801131-C allele or CC genotype presented a higher risk of mucositis (p = 0.0188; OR = 3.02; 95% CI: 1.22–7.91), acneiform rash (p = 0.0322; OR = 5.74; 95% CI: 1.34–39.21), and alopecia (p = 0.0072; OR = 5.11; 95% CI: 1.37–17.70). Patients with MTR rs1805087- CC genotype presented a higher risk of anosmia (p = 0.0038; OR = 98.00; 95% CI: 3.16–infinite); patients with the TT genotype or T allele for MTHFD1 rs2236225 presented a higher risk of liver failure (p = 0.00229; OR = 2.34; 95% CI: 1.14–4.96) and alopecia (p = 0.0248; OR = 3.83; 95% CI: 1.10–13.30), and patients with the TT genotype for ABCC2 rs4148396 polymorphism (p = 0.0466; OR = 2.67; 95% CI: 0.98–6.94) presented a higher risk of headaches.ConclusionsPharmacogenomic analysis of these polymorphisms may facilitate decision-making in relation to MTX treatment toxicity among RA patients.

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.

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels.

DNA methyltransferase 1 (DNMT1) is responsible for the maintenance of DNA methylation patterns during cell division. Several human diseases are characterized by impaired DNMT1 gene methylation, but less is known about the factors that regulate DNMT1 promoter methylation levels. Dietary folates and related B-vitamins are essential micronutrients for DNA methylation processes, and we performed the present study to investigate the contribution of circulating folate, vitamin B12, homocysteine, and common polymorphisms in folate pathway genes to the DNMT1 gene methylation levels. We investigated DNMT1 gene methylation levels in peripheral blood DNA samples from 215 healthy individuals. All the DNA samples were genotyped for MTHFR 677C > T (rs1801133) and 1298A > C (rs1801131), MTRR 66A > G (rs1801394), MTR 2756A > G (rs1805087), SLC19A1 (RFC1) 80G > A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp insertion/deletion (indel) (rs34489327), DNMT3A -448A > G (rs1550117), and DNMT3B -149C > T (rs2424913) polymorphisms. Circulating homocysteine, folate, and vitamin B12 levels were available from 158 of the recruited individuals. We observed an inverse correlation between plasma homocysteine and DNMT1 methylation levels. Furthermore, both MTR rs1805087 and TYMS rs34743033 polymorphisms showed a statistically significant effect on DNMT1 methylation levels. The present study revealed several correlations between the folate metabolic pathway and DNMT1 promoter methylation that could be of relevance for those disorders characterized by altered DNA methylation.

Associations between folate metabolism enzyme polymorphisms and breast cancer: A meta-analysis.

We performed this meta-analysis to explore associations between folate metabolism enzyme polymorphisms and breast cancer (BC) in a larger pooled population. Systematic literature research was performed to identify eligible studies for pooled analyses. Totally 92 genetic association studies were included for analyses. The pooled analyses revealed significant findings for MTRR rs1801394 polymorphism in South Asians, for MTR rs1805087 polymorphism in Caucasians and East Asians, and for MTHFR rs1801133 polymorphism in East Asians. In conclusion, the present meta-analysis indicated that MTRR rs1801394, MTR rs1805087, and MTHFR rs1801133 polymorphisms could be used to identify individuals at high risk of developing BC.

Pharmacogenetics of platinum-based chemotherapy: impact of DNA repair and folate metabolism gene polymorphisms on prognosis of non-small cell lung cancer patients.

Chemotherapy based on platinum compounds is the standard treatment for NSCLC patients with EGFR wild type, and is also used as second line in mutated EGFR patients. Nevertheless, this therapy presents poor clinical outcomes. ERCC1, ERCC2, XRCC1, MDM2, MTHFR, MTR, and SLC19A1 gene polymorphisms may contribute to individual variation in response and survival to platinum-based chemotherapy. The aim of this study was to investigate the influence of these polymorphisms on response and survival of NSCLC patients treated with platinum-based chemotherapy. A retrospective-prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR real-time with Taqman® probes. Patients with ERCC1 rs3212986-GG (p = 0.0268; OR = 2.50; CI95% = 1.12-5.69) and XRCC1 rs25487-GG (p = 0.0161; OR = 2.99; CI95% = 1.26-7.62) genotype showed significantly better ORR. Cox survival analysis revealed that patients carrying the MDM2 rs1690924-GG genotype (p = 0.0345; HR = 1.99; CI95% = 1.05-3.80) presented higher risk of death. Furthermore, carriers of MTR rs1805087-A alleles (p = 0.0060; HR = 8.91; CI95% = 1.87-42.42) and SLC19A1 rs1051266-AA genotype (p = 0.0130; HR = 1.74; CI95% = 1.12-2.68) showed greater risk of progression. No influence of ERCC1 rs11615, ERCC2 rs13181, ERCC2 rs1799793, XRCC1 rs1799782, MDM2 rs1470383, MTHFR rs1801131, and MTHFR rs1801133 on platinum-based chemotherapy clinical outcomes was found. In conclusion, our results suggest that ERCC1 rs3212986, XRCC1 rs25487, MDM2 rs1690924, MTR rs1805087, and SLC19A1 rs1051266 gene polymorphisms may significantly act as predictive factors in NSCLC patients treated with platinum-based chemotherapy.

Genetic variants of the folate metabolic system and mild hyperhomocysteinemia may affect ADHD associated behavioral problems

An etiologically complex disorder, Attention Deficit Hyperactivity Disorder (ADHD), is often associated with various levels of cognitive deficit. Folate/vitamin B9 is crucial for numerous biochemical pathways including neural stem cell proliferation and differentiation, regulation of gene expression, neurotransmitter synthesis, myelin synthesis and repair, etc. and a scarcity has often been linked to cognitive deficit. Our pilot study in the field revealed significant association of few genetic variants with ADHD. Mild hyperhomocysteinemia and vitamin B12 deficiency was also noticed in the probands. In the present study additional genetic variants, folate and vitamin B6, which may affect folate-homocysteine metabolic pathway, were investigated in 866 individuals including nuclear families with ADHD probands (N=221) and ethnically matched controls (N=286) to find out whether ADHD associated traits are affected by these factors. Population based analysis revealed significant over representation of MTRR rs1801394 “G” allele and “GG” genotype in all as well as male probands. Stratified analysis showed significantly higher frequency of RFC1 rs1051266 and BHMT rs3733890 “AG” genotypes in full term and prematurely delivered ADHD probands respectively. Probands with rs1801394 “GG” genotype and BHMT rs3733890 “G” allele showed association with hyperhomocysteinemia. MTHFR rs1801131, MTR rs1805087 and BHMT rs3733890 also showed association with ADHD index. While rs1051266, rs1801131, and rs1805087 showed association with behavioral problems, rs3733890 was associated with ODD score. Conduct problem exhibited association with RFC1 rs1051266, MTHFR rs1801133 and MTRR rs1801394. Gene-gene interaction analysis revealed positive synergistic interactions between rs1051266, rs1801131 and rs1801394 in the probands as compared to the controls. It can be inferred from the data obtained that folate system genetic variants and mild hyperhomocysteimenia may affect ADHD associated traits by attenuating folate metabolism.

Relationship Between Polymorphisms in Methotrexate Pathway Genes and Outcome of Methotrexate Treatment in a Cohort of 119 Patients with Juvenile Idiopathic Arthritis.

To identify clinical and pharmacogenetic determinants of efficacy and toxicity of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) over time. A cohort of 119 consecutive patients with JIA treated with MTX was reviewed. The Juvenile Arthritis Disease Activity Score including 71 joints was used to measure disease activity. Nonresponders were patients who did not reach a minimum of 30% improvement after 6 months of treatment or were switched to biologic drugs in the first 6 months because of inefficacy. All adverse events (AE) were noted. Genotyping of single-nucleotide polymorphisms (SNP) in the genes coding for MTX transporters, folate pathway, and adenosine pathway was performed using real-time PCR methods. Univariate and multivariable penalized logistic and Cox regression were used to analyze data. Thirty patients (25.8%) were defined as nonresponders and 55 (47.2%) were switched to biologics during the followup. Sixty-five patients (54.5%) reported AE in a total of 405 patient-years, and 10 patients (8.4%) discontinued MTX because of AE. AMPD1 rs17602729 and MTHFD1 rs2236225 were associated with gastrointestinal AE while the latter together with MTRR rs1801394 also demonstrated associations with developing hepatoxicity. MTHFR rs1801131, ABCG2 rs2231137, wild-type of MTR rs1805087, and wild-type of ABCC2 rs2273697 were identified as potential markers for discontinuing MTX treatment because of AE. MTHFR rs1801133, MTRR rs1801394, and ABCC2 rs2273697 were associated with switching to biologics. SNP in different MTX metabolic pathways influence treatment with MTX. Genetic variability is a better marker for toxicity than efficacy.