Genetic polymorphisms in folate and homocysteine metabolism as risk factors for DNA damage

Botto, Nicoletta; Andreassi, Maria Grazia; Manfredi, Samantha; Masetti, Serena; Cocci, Franca; Colombo, Maria Giovanna; Storti, Simona; Rizza, Antonio; Biagini, Andrea

doi:10.1038/sj.ejhg.5201024

Cited by 74 publications

(52 citation statements)

References 44 publications

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“…† P value for both codominant and dominant model. been reported to be associated with higher plasma Hcy concentrations (Botto et al, 2003;Vaughn et al, 2004). Our finding, demonstrating that the 66G/524C haplotype was associated with higher osteocalcin concentrations, further supports that hyperhomocysteinemia is associated with higher osteocalcin levels (Dhonukshe-Rutten et al, 2005).…”

Section: Nssupporting

confidence: 86%

“…Indeed, a genetic defect in MTRR has been detected in patients with homocystinuria, Methionine synthase reductase polymorphisms are associated with serum osteocalcin levels in postmenopausal women an inherited disorder of Hcy metabolism characterized by severe hyperhomocysteinemia and early onset of atherosclerosis and osteoporosis (Leclerc et al, 1998). Although the A66G and C524T genetic polymorphisms of MTRR have been reported to be associated with enzyme activity (Olteanu et al, 2002) and plasma Hcy concentration (Botto et al, 2003;Vaughn et al, 2004), the association of these polymorphisms with bone metabolism has not been determined. We therefore investigated the relationships between the A66G and C524T polymorphisms of MTRR gene and bone mineral density and serum osteocalcin levels in postmenopausal women.…”

Section: Introductionmentioning

confidence: 99%

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Methionine synthase reductase polymorphisms are associated with serum osteocalcin levels in postmenopausal women

Kim

Park²,

Koh³

et al. 2006

Exp Mol Med

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Homocysteine (Hcy) is thought to play an important role in the development of osteoporosis and fracture. Methionine synthase reductase (MTRR) is an enzyme involved in the conversion of Hcy to methionine. We hypothesized that certain genetic polymorphisms of MTRR leading to reduced enzyme activity may cause hyperhomocysteinemia and affect bone metabolism. We therefore examined the associations of the A66G and C524T polymorphisms of the MTRR gene with bone mineral density (BMD) and serum osteocalcin levels in postmenopausal women. Although we did not detect any significant associations between MTRR polymorphisms and BMD or serum osteocalcin levels, we found that the 66G/524C haplotype, which has reduced enzyme activity, was significantly associated with serum osteocalcin levels in a gene-dose dependent manner (P = 0.002). That is, the highest osteocalcin levels (34.5 ± 16.8 ng/ml) were observed in subjects bearing two copies, intermediate osteocalcin levels (32.6 ± 14.4 ng/ml) were observed in subjects bearing one copy, and the lowest levels of osteocalcin (28.8 ± 10.9 ng/ml) were observed in subjects bearing no copies. These results suggest that the 66G/524C haplotype of the MTRR gene affect bone turn over rate.

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Section: Nssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Methionine synthase reductase polymorphisms are associated with serum osteocalcin levels in postmenopausal women

Kim

Park²,

Koh³

et al. 2006

Exp Mol Med

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“…MTHFR catalyzes irreversible reduction of 5,10-methylentetrahydrofolate to 5-methyltetrahydrofolate. The most significant polymorphic variants of the MTHFR gene are, probably, C677T and A1298C, which are suggested to modulate the risk to develop different multifactorial diseases including some cancers [14,15,34,35]. The MTRR enzyme participates in transferring of methyl group from 5-tetrahydrophosphate to homocysteine.…”

Section: Discussionmentioning

confidence: 99%

“…The MTRR enzyme participates in transferring of methyl group from 5-tetrahydrophosphate to homocysteine. The most significant and well-studied polymorphic variant of the MTRR gene is A66G, the change of A to G leads to decrease of catalytic activity of the enzyme, that in turn hampers homocysteine re-methylation and may cause different genetic defects [34,35].…”

Section: Discussionmentioning

confidence: 99%

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Polymorphisms in xenobiotic‐metabolizing genes and the risk of chronic lymphocytic leukemia and non‐Hodgkin's lymphoma in adult Russian patients

et al. 2007

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Polymorphisms in genes coding xenobiotic-metabolizing enzymes are considered as risk factors modifying susceptibility to cancer. We developed a biochip for the analysis of 18 mutations in 10 genes of metabolizing system: CYP1A1, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, CYP2C9, CYP2C19, and NAT2. Using allele-specific hybridization on the biochip 76 T-cell non-Hodgkin's lymphoma (NHL) patients, 83 B-cell chronic lymphocytic leukemia (B-CLL) patients, and 177 healthy donors were tested. Polymorphic CYP1A1 alleles were more frequent in B-CLL patients relative to normal controls, for example, a combination of polymorphic variants 4887C > A, 4889A > G, and 6235T > C (OR 5 1.76, 95% CI 5 1.0-3.1). The GSTM1 null genotype was more frequent in NHL patients relative to controls (OR 5 1.82, 95% CI 5 1.1-3.1). The combination of unfavorable polymorphic CYP1A1 variants and GSTM1 null genotype was found more frequently in B-CLL patients relative to controls (OR 5 2.52, 95% CI 5 1.3-4.9). In addition, male B-CLL patients demonstrated a significantly increased occurrence of heterozygous and homozygous allele *2 of CYP2C9 gene (OR 5 2.38, 95% CI 5 1.1-5.2) as well as a combination of alleles *2 and *3 of the gene (OR 5 2.09, 95% CI 5 1.1-3.9). Thus, our findings show the association between polymorphic alleles of CYP1A1, GSTM1, and CYP2C9 genes and the risk to develop NHL or B-CLL. The developed biochip can be considered as a convenient analytical tool for research studies and predictive analysis in oncohematology. Am. J. Hematol. 83:279-287, 2008. V

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Maternal polymorphisms 677C‐T and 1298A‐C of MTHFR, and 66A‐G MTRR genes: Is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome?

Martínez‐Frías

Pérez

Desviat

et al. 2006

American J of Med Genetics Pt A

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This study was aimed at analyzing the effect of mutations in three non-synonymous SNP genes (677C > T and 1298A > C of the methylenetetrahydrofolate reductase (MTHFR) gene, and 66A > G in the MTRR gene) on total plasmatic homocysteine (Hcy), in 91 mothers of Down syndrome (DS) infants and 90 control mothers. The comparison of both groups of mothers is a new way to determine if those mutations and their interactions increase the risk for DS. Material came from the case-control network of the Spanish Collaborative Study of Congenital Malformations (ECEMC). Using a general lineal model in a backwards step, we performed the analyses including the different mutations, maternal age, the fact that each mother had a DS or a control infant, and all possible interactions of these variables, in the models, being maternal Hcy the continuous dependent variable. In another model, maternal folic acid intake during the third trimester of pregnancy was added. The results from both models were essentially the same: Hcy levels variability differs from case mothers to control ones, the presence of the MTHFR1298A > C polymorphism also affects significantly the Hcy variance, as it does the statistical interaction between the mutations MTRR66A > G and MTHFR1298A > C in the mother. In this sense, the interaction between different polymorphisms may totally modify their individual effects, and some of those effects are different in mothers of DS children and in controls' mothers. For instance, only two mutations in MTRR66 (GGAA) in mothers of control infants increase the reference maternal Hcy level in 4.66 units, and the individual effect of the genotype with only two mutations in the MTHFR1298 gene (AACC) increases the reference Hcy level in 12.74 units. However, the presence of the four mutations (GGCC) interacts giving a statistically significant decrease in 6.00 units in the level of Hcy in control mothers. On the contrary, in mothers of DS infants, the sole presence of two mutations in one of these two genes decreases the levels of Hcy (-2.31 units for GGAA genotype, and -3.43 units for AACC genotype), while the presence of the four mutations (GGCC) increases Hcy in 9.53 units. Taking into consideration that in the one-carbon metabolism cystathionine beta-synthase (CBS) catalyzes Hcy in an irreversible way, and that CBS gene is located in chromosome 21, fetuses and infants with DS have functional folate deficiency due to overexpression of CBS. This fact, as well as others influencing Hcy levels (such as nutrients interactions and lifestyle), together with the fetal genotype, suggest that their relationship with DS could be through an effect on fetal survival up to birth. Three possible mechanisms are considered by evaluating the results in the light of the present knowledge on cytology and molecular biology.

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Genetic polymorphisms in folate and homocysteine metabolism as risk factors for DNA damage

Cited by 74 publications

References 44 publications

Methionine synthase reductase polymorphisms are associated with serum osteocalcin levels in postmenopausal women

Methionine synthase reductase polymorphisms are associated with serum osteocalcin levels in postmenopausal women

Polymorphisms in xenobiotic‐metabolizing genes and the risk of chronic lymphocytic leukemia and non‐Hodgkin's lymphoma in adult Russian patients

Maternal polymorphisms 677C‐T and 1298A‐C of MTHFR, and 66A‐G MTRR genes: Is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome?

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