scholarly journals Genetic polymorphisms in one-carbon metabolism increased the risk of persistence of pre-neoplastic cervical lesions

2019 ◽  
Author(s):  
Nayara Nascimento Toledo Silva ◽  
Ana Carolina Silva Santos ◽  
Verlândia Mendes Nogueira ◽  
Cláudia Martins Carneiro ◽  
Angelica Alves Lima
Keyword(s):  
Genetic Polymorphism ◽  
Carbon Metabolism ◽  
Mthfr C677t ◽  
Methionine Synthase ◽  
Cervical Carcinogenesis ◽  
Cervical Lesions ◽  
Neoplastic Lesion ◽  
One Carbon Metabolism ◽  
Ms A2756g

Abstract Background: Cervical cancer is caused by high-risk Human Papillomavirus (hr-HPV) infection associated with cofactors that has been analyzed as predictors of cytological abnormalities remission or persistence. These cofactors may be classified as environmental, epigenetic or genetic. Polymorphism in genes of enzymes that act on one-carbon metabolism alter their activity and may be associated with cervical carcinogenesis because they affect DNA synthesis and repair, and gene expression. Therefore, the objective of this study was to analyze the risk of persistence of pre-neoplastic cervical lesions according to genetic polymorphisms involved in one-carbon metabolism. Sample group was divided in Remission (n=60) - presence of pre-neoplastic lesion at first meeting (T1), and normal cytology after six months of follow-up (T2), and Persistence (n=46) - presence of pre-neoplastic lesion at T1 and T2. Cervical samples were obtained for cytological analysis (T1 and T2), HPV detection (T1), and evaluation of polymorphism C667T of Methylenetetrahydrofolate Reductase (MTHFR C677T), A2756G of Methionine Synthase (MS A2756G), A66G of Methionine Synthase Reductase (MTRR A66G), double or triple 28 bp tandem repeat in 5'-untranslated enhanced region of Thymidylate Synthase (TSER), and 6 bp deletion at nucleotide1494 in TS 3'-untranslated region (TS3'UTR). Genetic Risk Score (GRS) was calculated for analyze all genetic polymorphism simultaneously. Results: No differences were observed between Remission and Persistence groups of GRS, or genotypic and allelic distribution of MTHFR C677T and MS A2756G polymorphisms. However, higher risk of persistence was observed among women presenting heterozygote genotype - ins/del [OR (IC95%): 3.22 (1.19 – 8.69), p=0.021], or polymorphic genotype – del/del [OR (IC95%): 6.50 (1.71 – 24.70), p=0.006] of TS3’UTR. Conclusions: Presence of TS3’UTR polymorphism increased risk of persistence of cervical abnormalities. This genetic variant could be considered as potential marker of cervical carcinogenesis, assisting follow-up of women with persistent pre-neoplastic cervical lesions.

scholarly journals Genetic polymorphisms in one-carbon metabolism increased the risk of persistence of pre-neoplastic cervical lesions

2019 ◽  
Author(s):  
Nayara Nascimento Toledo Silva ◽  
Ana Carolina Silva Santos ◽  
Verlândia Mendes Nogueira ◽  
Cláudia Martins Carneiro ◽  
Angelica Alves Lima
Keyword(s):  
Genetic Polymorphism ◽  
Carbon Metabolism ◽  
Mthfr C677t ◽  
Methionine Synthase ◽  
Cervical Carcinogenesis ◽  
Cervical Lesions ◽  
Neoplastic Lesion ◽  
One Carbon Metabolism ◽  
Ms A2756g

Abstract Background: Cervical cancer is caused by high-risk Human Papillomavirus (hr-HPV) infection associated with cofactors that has been analyzed as predictors of cytological abnormalities remission or persistence. These cofactors may be classified as environmental, epigenetic or genetic. Polymorphism in genes of enzymes that act on one-carbon metabolism alter their activity and may be associated with cervical carcinogenesis because they affect DNA synthesis and repair, and gene expression. Therefore, the objective of this study was to analyze the risk of persistence of pre-neoplastic cervical lesions according to genetic polymorphisms involved in one-carbon metabolism. Sample group was divided in Remission (n=60) - presence of pre-neoplastic lesion at first meeting (T1), and normal cytology after six months of follow-up (T2), and Persistence (n=46) - presence of pre-neoplastic lesion at T1 and T2. Cervical samples were obtained for cytological analysis (T1 and T2), HPV detection (T1), and evaluation of polymorphism C667T of Methylenetetrahydrofolate Reductase (MTHFR C677T), A2756G of Methionine Synthase (MS A2756G), A66G of Methionine Synthase Reductase (MTRR A66G), double or triple 28 bp tandem repeat in 5'-untranslated enhanced region of Thymidylate Synthase (TSER), and 6 bp deletion at nucleotide1494 in TS 3'-untranslated region (TS3'UTR). Genetic Risk Score (GRS) was calculated for analyze all genetic polymorphism simultaneously. Results: No differences were observed between Remission and Persistence groups of GRS, or genotypic and allelic distribution of MTHFR C677T and MS A2756G polymorphisms. However, higher risk of persistence was observed among women presenting heterozygote genotype - ins/del [OR (IC95%): 3.22 (1.19 – 8.69), p=0.021], or polymorphic genotype – del/del [OR (IC95%): 6.50 (1.71 – 24.70), p=0.006] of TS3’UTR. Conclusions: Presence of TS3’UTR polymorphism increased risk of persistence of cervical abnormalities. This genetic variant could be considered as potential marker of cervical carcinogenesis, assisting follow-up of women with persistent pre-neoplastic cervical lesions.

scholarly journals 3’UTR Polymorphism of Thymidylate Synthase gene increased the risk of persistence of pre-neoplastic cervical lesions

2020 ◽  
Author(s):  
Nayara Nascimento Toledo Silva ◽  
Ana Carolina Silva Santos ◽  
Verlândia Mendes Nogueira ◽  
Cláudia Martins Carneiro ◽  
Angelica Alves Lima
Keyword(s):  
Thymidylate Synthase ◽  
Carbon Metabolism ◽  
Mthfr C677t ◽  
Methionine Synthase ◽  
Cervical Carcinogenesis ◽  
Cervical Lesions ◽  
Neoplastic Lesions ◽  
One Carbon Metabolism ◽  
Ms A2756g

Abstract Background: Cervical cancer is caused by high-risk Human Papillomavirus (hr-HPV) infection associated with cofactors that has been analyzed as predictors of the remission or persistence of cytological abnormalities remission or persistence. These cofactors can be either environmental, epigenetic, or genetic. Polymorphism in genes of enzymes that act on one-carbon metabolism alter their activity and also may be associated with cervical carcinogenesis because they affect DNA synthesis and repair, and gene expression. Therefore, this study aimed to analyze the risk of persistence of pre-neoplastic cervical lesions according to genetic polymorphisms involved in one-carbon metabolism. Methods: Our sample consisted of 106 women, divided into two groups – Remission (n=60), i.e., with the presence of pre-neoplastic lesions at first meeting (T1) and normal cytology after six months of follow-up (T2), and Persistence (n=46), i.e., with the presence of pre-neoplastic lesions at T1 and T2. We obtained cervical samples for cytological analysis (T1 and T2), HPV detection (T1), and evaluation of polymorphism C667T of Methylenetetrahydrofolate Reductase (MTHFR C677T), A2756G of Methionine Synthase (MS A2756G), A66G of Methionine Synthase Reductase (MTRR A66G), double or triple 28 bp tandem repeat in 5’-untranslated enhanced region of Thymidylate Synthase (TSER), and 6 bp deletion at nucleotide1494 in TS 3’-untranslated region (TS3’UTR). To analyze all genetic polymorphisms simultaneously, we calculated the Genetic Risk Score (GRS). Results: We observed no differences between the Remission and Persistence groups regarding the GRS. Also, there were no differences in the genotypic and allelic distribution of MTHFR C677T and MS A2756G polymorphisms. However, the risk of persistence was higher among women with the heterozygote genotype - ins/del [OR (IC95%): 3.22 (1.19 – 8.69), p=0.021], or the polymorphic genotype – del/del [OR (IC95%): 6.50 (1.71 – 24.70), p=0.006] of TS3’UTR. Conclusions: The presence of the TS3’UTR polymorphism increased the risk of persistence of cervical abnormalities. This genetic variant could be a potential marker of cervical carcinogenesis and therefore assist the follow-up of women with persistent pre-neoplastic cervical lesions.

scholarly journals 3’UTR Polymorphism of Thymidylate Synthase gene increased the risk of persistence of pre-neoplastic cervical lesions

2020 ◽  
Author(s):  
Nayara Nascimento Toledo Silva ◽  
Ana Carolina Silva Santos ◽  
Verlândia Mendes Nogueira ◽  
Cláudia Martins Carneiro ◽  
Angelica Alves Lima
Keyword(s):  
Thymidylate Synthase ◽  
Carbon Metabolism ◽  
Mthfr C677t ◽  
Methionine Synthase ◽  
Cervical Carcinogenesis ◽  
Cervical Lesions ◽  
Neoplastic Lesions ◽  
One Carbon Metabolism ◽  
Ms A2756g

Abstract Background: Cervical cancer is caused by high-risk Human Papillomavirus (hr-HPV) infection associated with cofactors that has been analyzed as predictors of the remission or persistence of cytological abnormalities remission or persistence. These cofactors can be either environmental, epigenetic, or genetic. Polymorphism in genes of enzymes that act on one-carbon metabolism alter their activity and also may be associated with cervical carcinogenesis because they affect DNA synthesis and repair, and gene expression. Therefore, this study aimed to analyze the risk of persistence of pre-neoplastic cervical lesions according to genetic polymorphisms involved in one-carbon metabolism. Our sample consisted of 106 women, divided into two groups – Remission (n=60), i.e., with the presence of pre-neoplastic lesions at first meeting (T1) and normal cytology after six months of follow-up (T2), and Persistence (n=46), i.e., with the presence of pre-neoplastic lesions at T1 and T2. We obtained cervical samples for cytological analysis (T1 and T2), HPV detection (T1), and evaluation of polymorphism C667T of Methylenetetrahydrofolate Reductase (MTHFR C677T), A2756G of Methionine Synthase (MS A2756G), A66G of Methionine Synthase Reductase (MTRR A66G), double or triple 28 bp tandem repeat in 5’-untranslated enhanced region of Thymidylate Synthase (TSER), and 6 bp deletion at nucleotide1494 in TS 3’-untranslated region (TS3’UTR). To analyze all genetic polymorphisms simultaneously, we calculated the Genetic Risk Score (GRS). Results: We observed no differences between the Remission and Persistence groups regarding the GRS. Also, there were no differences in the genotypic and allelic distribution of MTHFR C677T and MS A2756G polymorphisms. However, the risk of persistence was higher among women with the heterozygote genotype - ins/del [OR (IC95%): 3.22 (1.19 – 8.69), p=0.021], or the polymorphic genotype – del/del [OR (IC95%): 6.50 (1.71 – 24.70), p=0.006] of TS3’UTR. Conclusions: The presence of the TS3’UTR polymorphism increased the risk of persistence of cervical abnormalities. This genetic variant could be a potential marker of cervical carcinogenesis and therefore assist the follow-up of women with persistent pre-neoplastic cervical lesions.

scholarly journals The Allele Frequencies of Three Polymorphisms in Genes Involved in Homocysteine Metabolism in a Group of Unrelated Healthy Singaporeans

2010 ◽  
Vol 29 (2) ◽  
pp. 111-119 ◽  
Author(s):  
Chuanfei Chen ◽  
Yik-Yuen Gan
Keyword(s):  
Genetic Risk ◽  
Total Population ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr C677t ◽  
Allele Frequencies ◽  
Methionine Synthase ◽  
Asian Populations ◽  
Insertion Allele ◽  
677T Allele ◽  
Ms A2756g

The cystathionineβ-synthase (CBS) 844ins68 polymorphism, methionine synthase (MS) A2756G SNP, and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T SNP are associated with homocysteine (Hcy) level in humans. Elevated Hcy level is considered a risk factor for atherosclerotic diseases among Asian populations. Therefore, the three polymorphisms may vary the risk for developing such diseases in Singaporeans. In this study, the three polymorphisms were determined in a group of unrelated healthy Singaporeans (273 Chinese, 127 Indians, and 156 Malays). Regarding allele frequencies, Indians had the highest frequencies of the CBS insertion allele (2.0%) and the MS 2756G allele (26.4%), while Chinese had the highestMTHFR677T allele frequency (27.5%). In addition, theMTHFR677T allele was found significantly lower in Chinese males than in their female counterparts. As the CBS insertion allele was suggested to be associated with lower Hcy level, whereas the MS 2756G allele and theMTHFRT/T genotype were related to higher Hcy level, the MS A/G or G/G genotype and theMTHFRT/T genotype were considered double genetic risk factors for elevated Hcy level. The frequency of such double genetic risk was 0.7% (4 subjects) in the total population consisting of 3 Chinese (1.1%) and 1 Malays (0.6%). NoMTHFRT/T genotype was found in Indians. Such results suggested that Chinese could have higher Hcy levels than Malays while the situation for Indians was complicated. Since human Hcy levels are also affected by environmental factors, further studies are required to better evaluate the association between these three polymorphisms and Hcy levels and/or disease susceptibilities in Singaporeans.

Polymorphisms in One-Carbon Metabolism Genes and Overall Survival in Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1568-1568
Author(s):  
James R. Cerhan ◽  
Matthew J. Maurer ◽  
Patricia Hartge ◽  
Stephen J. Chanock ◽  
Thomas M. Habermann ◽  
...  
Keyword(s):  
Overall Survival ◽  
Genetic Variation ◽  
Risk Score ◽  
Carbon Metabolism ◽  
B Cell Lymphoma ◽  
Clinical Variables ◽  
Carbon Transfer ◽  
One Carbon Metabolism ◽  
The Impact

Abstract Background. Intracellular one-carbon transfer reactions are essential for nucleotide synthesis and methylation of biologic compounds including DNA. Previous studies have linked genetic variants in one-carbon metabolism genes with risk of developing NHL, but little is known regarding the impact of these variants on disease outcome. We evaluated the hypothesis that inherited genetic variation in genes involved in one-carbon metabolism is associated with overall survival in DLBCL. Methods. We genotyped 30 single nucleotide polymorphisms (SNPs) from 18 candidate one-carbon metabolism genes in 215 DLBCL patients who participated in a population-based case-control study conducted from 1998–2000 using the SEER (Surveillance, Epidemiology and End Results) cancer registries in the Detroit, Iowa, Los Angeles and Seattle. Stage, B-symptoms, first course of therapy, date of last follow-up and vital status through early 2005 were obtained from cancer registry files. Cox proportional hazards analysis was used to estimate hazard ratios (HR) and corresponding 95% confidence intervals for the association between individual SNPs and overall survival, adjusting for age, demographic and clinical factors. We also used parallel modeling strategies to identify the best summary multi-SNP risk score to predict survival. Results. The median age at diagnosis was 57 years (range, 20–74), and 50 (23%) of the patients died during follow-up, with a median follow-up of 57 months (range, 31–78 months) for surviving patients. After adjusting for demographic and clinical variables, SNPs in SHMT1 (rs1979276; HRCT/TT=2.47, 1.31–4.67), BHMT (rs585800; HRAT/TT=2.02, 1.16–3.54), and TCN1 (rs526934; HRTT=1.86, 1.04–3.33) were the strongest and most robust predictors of survival. A summary score of the number of deleterious genotypes (0–3) from these three genes was strongly associated with survival (p=7.9 x 10−5) after accounting for demographic and clinical variables (HR=2.58 per deleterious genotype, 95% CI 1.75–3.80). A risk score combining the three SNPs with clinical and demographic variables (score of 0 to 5) was even more strongly associated with survival (p=1.4 x 10−13); the Kaplan Meier survival curves are shown in the Figure. In a time-dependent ROC analysis, the combined risk score had a concordance index of 0.75 at 5 years of follow-up (95% CI 0.69–0.81). Conclusion: Host genetic variation in the one-carbon metabolism genes SHMT1, BHMT, and TCN1, individually and particularly in combination, was associated with overall DLBCL survival after accounting for clinical and demographic factors, supporting a role for this pathway in disease progression. Future work should evaluate interactions of genes from this pathway with dietary nutrients and therapeutic agents in DLBCL prognosis. Figure Figure

scholarly journals The Effects of Polymorphisms in One-carbon Metabolism Genes on Manifestation of Ichthyosis Vulgaris

2021 ◽  
Vol 9 (A) ◽  
pp. 291-297
Author(s):  
Olena Fedota ◽  
Iurii Sadovnychenko ◽  
Lilia Chorna ◽  
Larysa Roshcheniuk ◽  
Vitalii Vorontsov ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Mthfr C677t ◽  
Healthy Controls ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Mthfr A1298c ◽  
Ichthyosis Vulgaris ◽  
Mtrr A66g ◽  
Pcr Rflp ◽  
One Carbon Metabolism

BACKGROUND: Ichthyosis vulgaris is the most common type of Mendelian disorders of cornification, caused by loss-of-function mutations in the gene encoding epidermal protein filaggrin (FLG), namely R501X and 2282del4. FLG 2282del4 mutation in heterozygotes is incompletely penetrant. Polymorphisms in one-carbon metabolism genes could be associated with clinical manifestation of ichthyosis vulgaris. AIM: The purpose of the present study was to analyze the effects of MTHFR, MTR and MTRR polymorphisms in patients with ichthyosis vulgaris. METHODS: 31 patients with ichthyosis vulgaris, 7 their FLG heterozygous relatives without symptoms of disorder, and 150 healthy controls were enrolled in study. FLG null mutations —R501X (rs61816761) and 2282del4 (rs558269137) — and one-carbon metabolism gene polymorphisms — MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), MTR A2756G (rs1805087) and MTRR A66G (rs1801394) — were analyzed by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: Among patients with ichthyosis, heterozygous for FLG 2282del4 mutation, the distributions of genotypes for folate metabolism genes were: MTHFR C677T CC:CT:TT —29.4%:70.6%:0.0%; MTHFR A1298C AA:AC:CC — 52.9%:47.1%:0.0%; MTR A2756G AA:AG:GG — 70.3%:23.5%:5.9%; MTRR A66G AA:AG:GG — 23.4%:52.9%:23.5%. The frequencies of MTR 2756AA and MTRR 66GG genotypes were 1.4–1.6 times higher in affected individuals heterozygous for 2282del4 than in patients with other FLG genotypes. In affected 2282del4 heterozygotes, the frequency of MTR 2756AA genotype was 1.6 times greater than in healthy controls (p<0.01). The strongest association was found between MTHFR 677CT/MTHFR 1298AA/MTR 2756AA/MTRR 66AG genotype and ichthyosis — OR=11.23 (95% CI 2.51−50.21, p=0.002). CONCLUSIONS: Various genotypes of one-carbon metabolism genes increase the risk of ichthyosis in heterozygotes for the FLG 2282del4 mutation (OR 2.799‑11.231). The most probable predisposing genotype is 677CT/1298AA/2756AA+AG/66AG.

scholarly journals Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

2012 ◽  
Vol 302 (1) ◽  
pp. E61-E67 ◽  
Author(s):  
Simon G. Lamarre ◽  
Anne M. Molloy ◽  
Stacey N. Reinke ◽  
Brian D. Sykes ◽  
Margaret E. Brosnan ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Folate Metabolism ◽  
Methionine Synthase ◽  
Vitamin B ◽  
Metabolomic Analysis ◽  
Elevated Plasma ◽  
H Nmr ◽  
Transsulfuration Pathway ◽  
One Carbon Metabolism ◽  
The One

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration. Am J Physiol Endocrinol Metab 301: E000–E000, 2011. First published September 20, 2011; 10.1152/ajpendo.00345.2011.—We carried out a1H-NMR metabolomic analysis of sera from vitamin B12-deficient rats. In addition to the expected increases in methylmalonate and homocysteine (Hcy), we observed an approximately sevenfold increase in formate levels, from 64 μM in control rats to 402 μM in vitamin B12-deficient rats. Urinary formate was also elevated. This elevation of formate could be attributed to impaired one-carbon metabolism since formate is assimilated into the one-carbon pool by incorporation into 10-formyl-THF via the enzyme 10-formyl-THF synthase. Both plasma and urinary formate were also increased in folate-deficient rats. Hcy was elevated in both the vitamin B12- and folate-deficient rats. Although plasma Hcy was also elevated, plasma formate was unaffected in vitamin B6-deficient rats (impaired transsulfuration pathway). These results were in accord with a mathematical model of folate metabolism, which predicted that reduction in methionine synthase activity would cause increased formate levels, whereas reduced cystathionine β-synthase activity would not. Our data indicate that formate provides a novel window into cellular folate metabolism, that elevated formate can be a useful indicator of deranged one-carbon metabolism and can be used to discriminate between the hyperhomocysteinemia caused by defects in the remethylation and transsulfuration pathways.

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