Martinez CA, Northrup H, Lin JI, Morrison AC, Fletcher JM, Tyerman GH, Au KS. (2009) Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida. American Journal of Obstetrics and Gynecology. 2009 Aug 14.
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, TX.
OBJECTIVE: We tested putative functional single nucleotide polymorphisms (SNPs) in genes that regulate the folate/homocysteine metabolism pathway for their contribution to spina bifida (SB) susceptibility.
STUDY DESIGN: The study consisted of 610 unrelated simplex SB patient families. Genotypes of 46 SNPs located in the coding sequence or promoter region of 11 genes were investigated. Associations between transmission of alleles and SB in the offspring were examined using the reconstruction combined transmission disequilibrium test.
RESULTS: Significant association of SNP rs5742905 in cystathionine-beta-synthase, rs1643649 in dihydrofolate reductase, rs2853533 in thymidylate synthetase, and rs3737965 in methylenetetrahydrofolate reductase was found (P = .015, .041, .021, and .007 respectively).
CONCLUSION: Transmission disequilibrium of SNP alleles in cystathionine-beta-synthase, dihydrofolate reductase, methylenetetrahydrofolate reductase, and thymidylate synthetase confers an increased susceptibility to SB.
PMID: 19683694
Showing posts with label homocysteine. Show all posts
Showing posts with label homocysteine. Show all posts
Wednesday, August 19, 2009
Monday, June 29, 2009
Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their
Ratan SK, Rattan KN, Pandey RM, Singhal S, Kharab S, Bala M, Singh V, Jhanwar A. (2008) Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls. Pediatric Surgery International. Jul;24(7):803-8.
Department of Pediatric Surgery, Pandit BD Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India. drjohnsimmi@yahoo.com
The aim of this study is to evaluate the folate, vitamin B12, fluoride and homocysteine levels in newborns with neural tube defect (NTD) and their parents. The study included 35 neonates with NTD and their parents, 31 neonates with congenital anomalies other than NTD formed control 1, 24 neonates with no anomalies, with the highest birth order and normal siblings formed control 2. These groups matched for socio-economic and nutritional status. Demographic, antenatal history, parental habits, folate (RBC, whole blood and serum), serum vitamin B12 and homocysteine levels were estimated using chemiluminescence technology. Chi-square test was used to assess association between factors and the outcome. One-way ANOVA was used to compare means in the three groups. To determine the risk factors for NTD, odds ratios (95% CI) was computed using bivariate and multivariate logistic regression analysis (STATA 9.0). No difference was found between NTD group and 'control 1' group. The fathers in NTD group had significantly lower folate and vitamin B12 and a higher homocysteine, in comparison to 'control 2' group (i.e. with normal babies). The babies with NTD had higher homocysteine while their mothers had significantly low folate levels in comparison to 'control 2' mothers. Low RBC folate, low serum vitamin B12 and high plasma homocysteine in both the parents had an association with NTD. Multivariate logistic regression revealed high homocysteine of father as the only independent significant risk factor [OR(95% CI):2.6(2.6, 226)] for NTD and also for other anomalies. NTD (and other congenital anomalies) may not only be due to nutritional deficiency in the mothers but also due to more intricate gene-nutrient interaction defects in the affected families, probably some abnormal folate-homocysteine metabolism. These defects seem to be affect the fathers more severely and in all likelihood, get transmitted to the babies from either or both the parents. The emergence of father's serum homocysteine levels as an independent risk factor for NTD and also other congenital anomalies calls for further studies to evaluate if this can be taken as a marker for congenital anomalies in the fetus during antenatal screening.
PMID: 18463884
Department of Pediatric Surgery, Pandit BD Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India. drjohnsimmi@yahoo.com
The aim of this study is to evaluate the folate, vitamin B12, fluoride and homocysteine levels in newborns with neural tube defect (NTD) and their parents. The study included 35 neonates with NTD and their parents, 31 neonates with congenital anomalies other than NTD formed control 1, 24 neonates with no anomalies, with the highest birth order and normal siblings formed control 2. These groups matched for socio-economic and nutritional status. Demographic, antenatal history, parental habits, folate (RBC, whole blood and serum), serum vitamin B12 and homocysteine levels were estimated using chemiluminescence technology. Chi-square test was used to assess association between factors and the outcome. One-way ANOVA was used to compare means in the three groups. To determine the risk factors for NTD, odds ratios (95% CI) was computed using bivariate and multivariate logistic regression analysis (STATA 9.0). No difference was found between NTD group and 'control 1' group. The fathers in NTD group had significantly lower folate and vitamin B12 and a higher homocysteine, in comparison to 'control 2' group (i.e. with normal babies). The babies with NTD had higher homocysteine while their mothers had significantly low folate levels in comparison to 'control 2' mothers. Low RBC folate, low serum vitamin B12 and high plasma homocysteine in both the parents had an association with NTD. Multivariate logistic regression revealed high homocysteine of father as the only independent significant risk factor [OR(95% CI):2.6(2.6, 226)] for NTD and also for other anomalies. NTD (and other congenital anomalies) may not only be due to nutritional deficiency in the mothers but also due to more intricate gene-nutrient interaction defects in the affected families, probably some abnormal folate-homocysteine metabolism. These defects seem to be affect the fathers more severely and in all likelihood, get transmitted to the babies from either or both the parents. The emergence of father's serum homocysteine levels as an independent risk factor for NTD and also other congenital anomalies calls for further studies to evaluate if this can be taken as a marker for congenital anomalies in the fetus during antenatal screening.
PMID: 18463884
Sunday, October 21, 2007
The effect of C677T mutation of methylene tetrahydrofolate reductase gene and plasma folate level on hyperhomocysteinemia in patients with meningomyel
Lee BH, Cheong HI, Shin YS, Cho BK, Wang KC. The effect of C677T mutation of methylene tetrahydrofolate reductase gene and plasma folate level on hyperhomocysteinemia in patients with meningomyelocele. Child's Nervous System. 2000 Sep;16(9):559-63.
To evaluate the relationship between genotypes of methylene tetrahydrofolate reductase (MTHFR), and plasma folate and homocysteine (Hcy) levels in meningomyelocele, 21 Korean patients, 47 of their family members, and 43 healthy controls were recruited. The presence of C677T mutation in the MTHFR gene and plasma concentrations of folate/Hcy were investigated. The genotype frequency of C677T mutation was not higher in study groups (patients and family members). The plasma folate concentration showed no difference either between the study and the control groups or among MTHFR-genotypic groups. The plasma Hcy concentration in homozygotes in the study group was higher than that in the control group, and higher than that in heterozygotes when plasma folate levels were low (P=0.006). Although neither MTHFR genotype nor plasma folate/Hcy level plays a definite part on its own, they seem to have an additive effect on the occurrence of meningomyelocele. Our results support folate supplementation for the prevention of hyperhomocysteinemia and meningomyelocele.
PMID: 11048629
To evaluate the relationship between genotypes of methylene tetrahydrofolate reductase (MTHFR), and plasma folate and homocysteine (Hcy) levels in meningomyelocele, 21 Korean patients, 47 of their family members, and 43 healthy controls were recruited. The presence of C677T mutation in the MTHFR gene and plasma concentrations of folate/Hcy were investigated. The genotype frequency of C677T mutation was not higher in study groups (patients and family members). The plasma folate concentration showed no difference either between the study and the control groups or among MTHFR-genotypic groups. The plasma Hcy concentration in homozygotes in the study group was higher than that in the control group, and higher than that in heterozygotes when plasma folate levels were low (P=0.006). Although neither MTHFR genotype nor plasma folate/Hcy level plays a definite part on its own, they seem to have an additive effect on the occurrence of meningomyelocele. Our results support folate supplementation for the prevention of hyperhomocysteinemia and meningomyelocele.
PMID: 11048629
Homocysteine, folate, lipid profile and MTHFR genotype and disability in children with myelomeningocele
Rendeli C, Ausili E, Castorina M, Antuzzi D, Tabacco F, Caldarelli M. Homocysteine, folate, lipid profile and MTHFR genotype and disability in children with myelomeningocele. Child's Nervous System. 2006 Oct;22(10):1316-21. Epub 2006 Apr 7.
STUDY DESIGN: We performed a cross-sectional study in myelomeningocele children. OBJECTIVE: To investigate plasma total homocysteine, folate, lipid profile, 5,10- metylenetetrahydrofolate reductase genotype (MTHFR) and disability.
MATERIALS AND METHODS: Sixty patients aged between 2 and 14 years with myelomeningocele (18 ambulatory and 42 non-ambulatory) and 150 healthy children of same age, are investigated for lipid profile, homocysteine concentration and for the determination of MTHFR genotype.
RESULTS: Plasma homocysteine concentrations were significantly higher in myelomeningocele children than in the control group. In myelomeningocele female group, there were higher levels of total cholesterol and very-low-density lipoprotein cholesterol with respect to the control group. Myelomeningocele children walking with tutorial aid showed triglyceride levels significantly lower than those observed in myelomeningocele non-walking children.
CONCLUSION: Disability, insulin uptake, lipid, homocysteine, hormones plasma levels, and genetic factors such as allelic variants of MTHFR are possible for cardiovascular disease in myelomeningocele children. This study highlights the importance of a continuous surveillance of any changes in the lipid profile that should be corrected as soon as possible. Constant physical activity necessary to increase HDL levels should be planned in all susceptible children. Nonetheless, further investigations are necessary to identify new homocysteine susceptible genes for prevention of early atherosclerosis and consequent cardiovascular disease.
PMID: 16602021
STUDY DESIGN: We performed a cross-sectional study in myelomeningocele children. OBJECTIVE: To investigate plasma total homocysteine, folate, lipid profile, 5,10- metylenetetrahydrofolate reductase genotype (MTHFR) and disability.
MATERIALS AND METHODS: Sixty patients aged between 2 and 14 years with myelomeningocele (18 ambulatory and 42 non-ambulatory) and 150 healthy children of same age, are investigated for lipid profile, homocysteine concentration and for the determination of MTHFR genotype.
RESULTS: Plasma homocysteine concentrations were significantly higher in myelomeningocele children than in the control group. In myelomeningocele female group, there were higher levels of total cholesterol and very-low-density lipoprotein cholesterol with respect to the control group. Myelomeningocele children walking with tutorial aid showed triglyceride levels significantly lower than those observed in myelomeningocele non-walking children.
CONCLUSION: Disability, insulin uptake, lipid, homocysteine, hormones plasma levels, and genetic factors such as allelic variants of MTHFR are possible for cardiovascular disease in myelomeningocele children. This study highlights the importance of a continuous surveillance of any changes in the lipid profile that should be corrected as soon as possible. Constant physical activity necessary to increase HDL levels should be planned in all susceptible children. Nonetheless, further investigations are necessary to identify new homocysteine susceptible genes for prevention of early atherosclerosis and consequent cardiovascular disease.
PMID: 16602021
Wednesday, August 1, 2007
Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk
Morin I, Devlin AM, Leclerc D, Sabbaghian N, Halsted CH, Finnell R, Rozen R. Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Molecular Genetics & Metabolism 2003 Jul;79(3):197-200.
Genetic variants in folate metabolism have been reported to increase risk for neural tube defects (NTD). The first such sequence change was the 677C-->T substitution in methylenetetrahydrofolate reductase (MTHFR), but additional sequence changes have been identified in enzymes or transporters for folates. Two recently identified variants are the 1561C-->T (H475Y) mutation in glutamate carboxypeptidase II (GCPII) and the 80A-->G (H27R) change in the reduced folate carrier RFC-1. We examined a group of mothers of spina bifida offspring, and a group of control women, for the above polymorphisms to assess their impact on NTD risk as well as on homocysteine and nutrient (RBC folate, serum folate, and serum cobalamin) levels. The GCPII variant (in the heterozygous state) did not influence NTD risk or metabolite levels; homozygous mutant (YY) women were not observed in our study group. The homozygous mutant (RR) genotype for the RFC-1 gene was not associated with a significant difference in NTD risk (OR=1.39, 95% CI=0.55-3.54), but there was a borderline significant (p=0.065) decrease in RBC folate levels, compared with the HH genotype. However, the combination of the RR genotype for RFC-1 and low RBC folate was associated with a significant 4.6-fold increase in NTD risk (OR=4.6, 95% CI=1.47-14.37). Since this small study is the first to demonstrate increased risk for women with the RFC-1 variant for having a child with a NTD, additional larger studies are required to confirm this change as another potential genetic modifier for spina bifida risk.
PMID: 12855225
Genetic variants in folate metabolism have been reported to increase risk for neural tube defects (NTD). The first such sequence change was the 677C-->T substitution in methylenetetrahydrofolate reductase (MTHFR), but additional sequence changes have been identified in enzymes or transporters for folates. Two recently identified variants are the 1561C-->T (H475Y) mutation in glutamate carboxypeptidase II (GCPII) and the 80A-->G (H27R) change in the reduced folate carrier RFC-1. We examined a group of mothers of spina bifida offspring, and a group of control women, for the above polymorphisms to assess their impact on NTD risk as well as on homocysteine and nutrient (RBC folate, serum folate, and serum cobalamin) levels. The GCPII variant (in the heterozygous state) did not influence NTD risk or metabolite levels; homozygous mutant (YY) women were not observed in our study group. The homozygous mutant (RR) genotype for the RFC-1 gene was not associated with a significant difference in NTD risk (OR=1.39, 95% CI=0.55-3.54), but there was a borderline significant (p=0.065) decrease in RBC folate levels, compared with the HH genotype. However, the combination of the RR genotype for RFC-1 and low RBC folate was associated with a significant 4.6-fold increase in NTD risk (OR=4.6, 95% CI=1.47-14.37). Since this small study is the first to demonstrate increased risk for women with the RFC-1 variant for having a child with a NTD, additional larger studies are required to confirm this change as another potential genetic modifier for spina bifida risk.
PMID: 12855225
Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population.
Relton CL, Wilding CS, Pearce MS, Laffling AJ, Jonas PA, Lynch SA, Tawn EJ, Burn J. Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. Journal of Medical Genetics. 2004 Apr;41(4):256-60.
OBJECTIVE: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD).
DESIGN: Case-control association study.
SUBJECTS: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK.
MAIN OUTCOME MEASURES: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C-->T, MTHFR 1298A-->C, MTRR 66A-->G, SHMT 1420C-->T, CbetaS 844ins68, GCPII 1561C-->T, RFC-1 80G-->A). The impact of each polymorphism and the effect of gene-gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis.
RESULTS: The MTHFR 677C-->T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A-->G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CbetaS; MTHFR 677/MTRR) and one combination in case mothers (CbetaS/RFC-1) were shown to elevate NTD risk. Maternal-fetal interaction was also detected when offspring carried the MTHFR 677C-->T variant and mothers carried the MTRR 66A-->G variant, resulting in a significantly elevated risk of NTD.
CONCLUSION: Both independent genetic effects and gene-gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD.
PMID: 15060097
Full Text Online
OBJECTIVE: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD).
DESIGN: Case-control association study.
SUBJECTS: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK.
MAIN OUTCOME MEASURES: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C-->T, MTHFR 1298A-->C, MTRR 66A-->G, SHMT 1420C-->T, CbetaS 844ins68, GCPII 1561C-->T, RFC-1 80G-->A). The impact of each polymorphism and the effect of gene-gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis.
RESULTS: The MTHFR 677C-->T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A-->G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CbetaS; MTHFR 677/MTRR) and one combination in case mothers (CbetaS/RFC-1) were shown to elevate NTD risk. Maternal-fetal interaction was also detected when offspring carried the MTHFR 677C-->T variant and mothers carried the MTRR 66A-->G variant, resulting in a significantly elevated risk of NTD.
CONCLUSION: Both independent genetic effects and gene-gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD.
PMID: 15060097
Full Text Online
Thursday, July 19, 2007
The 894G>T variant in the endothelial nitric oxide synthase gene and spina bifida risk
van der Linden IJ, Heil SG, den Heijer M, Blom HJ. The 894G>T variant in the endothelial nitric oxide synthase gene and spina bifida risk.
Journal of Human Genetics. 2007;52(6):516-20. Epub 2007 May 4.
The 894G>T single nucleotide polymorphism (SNP) in the endothelial NOS (NOS3) gene, has recently been associated with embryonic spina bifida risk. In this study, a possible association between the NOS3 894G>T SNP and spina bifida risk in both mothers and children in a Dutch population was examined using both a case-control design and a transmission disequilibrium test (TDT). Possible interactions between the NOS3 894G>T SNP and the MTHFR 677C>T SNP, elevated plasma homocysteine, and decreased plasma folate concentrations were also studied. The NOS3 894TT genotype did not increase spina bifida risk in mothers or children (OR 1.50, 95%CI 0.71-3.19 and OR 1.78, 95%CI 0.75-4.25, respectively). The TDT demonstrated no preferential transmission of the NOS3 894T allele (Chi2=0.06, P=0.81). In combination with the MTHFR 677TT genotype or elevated plasma homocysteine concentrations, the NOS3 894GT/TT genotype increased maternal spina bifida risk (OR 4.52, 95%CI 1.55-13.22 and OR 3.38, 95%CI 1.46-7.84, respectively). In our study population, the NOS3 894GT/TT genotype might be a risk factor for having a spina bifida affected child in mothers who already have an impaired homocysteine metabolism.
PMID: 17479212
Free Full Text Article
Journal of Human Genetics. 2007;52(6):516-20. Epub 2007 May 4.
The 894G>T single nucleotide polymorphism (SNP) in the endothelial NOS (NOS3) gene, has recently been associated with embryonic spina bifida risk. In this study, a possible association between the NOS3 894G>T SNP and spina bifida risk in both mothers and children in a Dutch population was examined using both a case-control design and a transmission disequilibrium test (TDT). Possible interactions between the NOS3 894G>T SNP and the MTHFR 677C>T SNP, elevated plasma homocysteine, and decreased plasma folate concentrations were also studied. The NOS3 894TT genotype did not increase spina bifida risk in mothers or children (OR 1.50, 95%CI 0.71-3.19 and OR 1.78, 95%CI 0.75-4.25, respectively). The TDT demonstrated no preferential transmission of the NOS3 894T allele (Chi2=0.06, P=0.81). In combination with the MTHFR 677TT genotype or elevated plasma homocysteine concentrations, the NOS3 894GT/TT genotype increased maternal spina bifida risk (OR 4.52, 95%CI 1.55-13.22 and OR 3.38, 95%CI 1.46-7.84, respectively). In our study population, the NOS3 894GT/TT genotype might be a risk factor for having a spina bifida affected child in mothers who already have an impaired homocysteine metabolism.
PMID: 17479212
Free Full Text Article
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