Homocysteine Abstracts 1

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Elevated plasma total homocysteine and C677T mutation of the methylenetetrahydrofolate reductase gene in patients with spina bifida

            (Bjorke-Monsen, Ueland et al. 1997) Download

Total plasma homocysteine (tHcy) was significantly higher in 28 children with spina bifida (median 6.05 mumol/l) as compared with 76 controls (median 4.94 mumol/l). This difference was confined to a subgroup of patients (16/28) with one or two C677T-mutated alleles in the methylenetetrahydrofolate reductase gene. Since we found no significant difference between patients and controls in serum folate, erythrocyte folate, serum cobalamin or serum methylmalonic acid, which were within the normal range for both patients and controls, the elevated tHcy could not be attributed to vitamin deficiencies. Our findings point to an additional genetic defect involving folate-dependent enzymes in a subgroup of patients with neural-tube defects.

Association of blood lead and homocysteine levels among lead exposed subjects in Vietnam and Singapore

            (Chia, Ali et al. 2007) Download

OBJECTIVES: Lead and homocysteine are both linked to cardiovascular disease. With this in mind, the authors evaluated the relation between blood lead and homocysteine in people aged 19-66 years in two Asian populations. METHODS: This cross-sectional study comprised 183 workers from a lead stabiliser factory in Singapore and 323 workers from a battery factory in Vietnam. Workers were occupationally exposed to lead. Blood lead was analysed using atomic absorption spectrophotometry while plasma homocysteine was measured using high performance liquid chromatography. RESULTS: Chinese subjects had the lowest blood lead levels while the Indians had the highest. Controlling for age, sex and race, an increase of 1 microg/dl in blood lead was associated with an increase of 0.04 micromol/l of homocysteine on the log scale. Gender and ethnicity seemed to be strongly associated with the relation between lead and homocysteine. The positive relation between lead and homocysteine among the Vietnamese subjects was significant (Pearson's r = 0.254, p<0.01). When blood lead levels were divided by quartiles, the correlation coefficient between blood lead levels in the 4th quartile and homocysteine among the Vietnamese was higher (r = 0.405, p<0.01). Overall, an increase of 1 microg/dl in blood lead in all the Vietnamese subjects was associated with an increase of 0.05 micromol/l increase in homocysteine on the log scale. However, in the 4th quartile, the same increase was associated with an increase of 0.41 micromol/l of homocysteine on the log scale. CONCLUSIONS: Blood lead was found to be associated with homocysteine levels in this Asian sample. Although we cannot determine causality from cross-sectional data, it is sensible to consider the probability that this relation could explain one of the mechanisms of the impact of lead on the cardiovascular system. More studies would be needed to confirm this inference.

Total blood mercury, plasma homocysteine, methylmalonic acid and folate in US children aged 3-5 years, NHANES 1999-2004

            (Gallagher and Meliker 2011) Download

BACKGROUND: Mercury is a known neurotoxicant; however, the relationship between childhood exposures and neurodevelopmental outcomes is uncertain, and may be modified by nutrition-related susceptibilities. In vitro studies found that mercury inhibited methionine synthase, an enzyme that interacts with vitamin B-12 and folate to regenerate the amino acid methionine from homocysteine, and inhibition of methionine synthase diverted homocysteine to cysteine and glutathione synthesis. The relationships between mercury, homocysteine, B-12, and folate have not been examined in children. OBJECTIVE: This study aimed to evaluate associations between Hg and homocysteine in male and female children differentiated by higher and lower methylmalonic acid (MMA, an indicator of vitamin B-12 deficiency) and folate status. DESIGN: Cross-sectional data on total blood mercury (Hg), plasma homocysteine, MMA, and serum folate were obtained from the 1999-2004 National Health and Nutrition Examination Surveys for children aged 3-5 years (n=1005). We used multiple linear regression to evaluate relationships between homocysteine and Hg quartiles, stratified by sex, MMA >/= and folate < sample medians, adjusted for demographic, anthropometric, and environmental factors. RESULTS: In boys with higher MMA and lower folate (n=135), but not in other children, we observed inverse associations between homocysteine and Hg. Children with Hg >3.49 mumol/L showed 1.14 mumol/L lower homocysteine (p<0.001) relative to the lowest quartile (</= 0.70 mumol/L) (Gallagher and Meliker). Compared to other subsamples, this subsample had significantly higher homocysteine levels. CONCLUSION: Hg was inversely correlated with plasma homocysteine in young boys, but not girls, with higher MMA and lower folate. Additional studies are merited to evaluate Hg and amino acid metabolism in susceptible children.

Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism

            (Hustad, Ueland et al. 2000) Download

BACKGROUND: Plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. tHcy concentrations are partly determined by folate, cobalamin, and vitamin B(6) status, and methylenetetrahydrofolate reductase (MTHFR) and other flavoenzymes are important for the biotransformation of these vitamins. This motivates the investigation of the possible relationship between riboflavin status and tHcy. METHODS: The study had a cross-sectional design and included 423 healthy blood donors, ages 19-69 years. We determined plasma tHcy, serum folate, serum cobalamin, serum creatinine, and MTHFR C677T genotype. In addition, we measured riboflavin and its two coenzyme forms, flavin mononucleotide and flavin adenine dinucleotide, in EDTA plasma by capillary electrophoresis and laser-induced fluorescence detection. RESULTS: Riboflavin determined tHcy independently in a multiple linear regression model with adjustment for sex, age, folate, cobalamin, creatinine, and MTHFR genotype (P = 0.008). tHcy was 1.4 micromol/L higher in the lowest compared with the highest riboflavin quartile. The riboflavin-tHcy relationship was modified by genotype (P = 0.004) and was essentially confined to subjects with the C677T transition of the MTHFR gene. CONCLUSIONS: Plasma riboflavin is an independent determinant of plasma tHcy. Studies on deficient populations are needed to evaluate the utility of riboflavin supplementation in hyperhomocysteinemia.

Copper and homocysteine in cardiovascular diseases

         (Kang 2011) Download

High blood copper (Cu) and homocysteine (Hcy) concentrations have been independently reported as risk factors for cardiovascular diseases. When they are simultaneously measured, a concomitant increase in both parameters in association with vascular dysfunction has been observed. Cu chelator penicillamine can significantly diminish the inhibitory effect of Hcy on endothelial function, which has led to the interpretation that Cu mediates the deleterious effect of Hcy. However, Cu itself has been shown to be beneficial to the cardiovascular system. In particular, Cu promotion of angiogenesis has been well documented. Cu stimulates endothelial cell proliferation and differentiation and promotes microtubule formation in cultured saphenous veins. High levels of Hcy do not affect the process of microtubule formation, but the combination of Cu and Hcy leads to a significant inhibitory effect. Under other conditions, Cu does not affect, but Hcy inhibits, the endothelium-dependent relaxation of blood vessels and the combination of both augments the inhibition. Why does Cu produce adverse effects when it co-exists with Hcy? Cu forms complexes with Hcy and the Cu-Hcy complexes possess a deleterious potential due to their redox properties. Cu chelation can remove Cu from the Cu-Hcy complexes, but leaves behind high levels of Hcy and produces Cu deficiency. An alternative approach should focus on the reduction of Hcy, but maintenance of Cu, making detrimental Cu beneficial. A comprehensive understanding of Cu speciation and a development of selective modulation of Cu coordination to Cu-binding molecules to avoid Cu-Hcy complex formation would effectively improve the condition of cardiovascular disease.

MTHFR C677T and MTR A2756G Polymorphisms and the Homocysteine Lowering Efficacy of Different Doses of Folic Acid in Hypertensive Chinese Adults

            (Qin, Li et al. 2012) Download

ABSTRACT: BACKGROUND: This study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4mg/d and 0.8mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in hypertensive Chinese adults. METHODS: A total of 480 subjects with mild or moderate essential hypertension were randomly assigned to three treatment groups: 1) enalapril only (10mg, control group); 2) enalapril-FA tablet [10:0.4mg (10mg enalapril combined with 0.4mg of FA), low FA group]; and 3) enalapril-FA tablet (10:0.8mg, high FA group), once daily for 8 weeks. ResultsAfter 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However, compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects with CT or TT genotype in the low FA group (P<0.05 for either of these genotypes) and TT genotype in the high FA group (P<0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8: CC 10.8% vs. TT: 22.0%, P=0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P=0.989). CONCLUSIONS: This study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of FA supplementation.

Homocysteine and heavy metal interactions in atrial fibrillation and ablation treatments

            (Ravasini, Mossop et al. 2008) Download

Unexpected inverse relationship between insulin resistance and serum homocysteine in healthy subjects

            (Rosolova, Simon et al. 2002) Download

Mild hyperhomocysteinemia has been established as a new independent risk factor for atherosclerosis and thrombosis. The metabolic syndrome of insulin resistance is associated with a high risk of coronary heart disease. Our objective was to determine if any relationship exists between the metabolic syndrome of insulin resistance in non-diabetic subjects and total serum homocysteine levels. Sixty-six healthy volunteers (33 males and 33 females) were selected from the population of Pilsen. Insulin resistance was measured by the Insulin Suppression Test using Octreotide. Steady-state plasma glucose concentrations at the end of the test period provided a quantitative measure of insulin resistance. Serum homocysteine level was estimated by high-pressure liquid chromatography. Serum folate and vitamin B12 were estimated using commercial kits on an Abbott IMx analyzer. All other laboratory tests were performed by standard methods in a routine biochemical laboratory. Subjects with the highest tertile of steady-state plasma glucose showed a significantly higher body mass index, blood pressure, fasting plasma triglyceride levels, plasminogen activator inhibitor-1 and lower HDL-cholesterol, i.e. an insulin resistance pattern. These subjects had significantly lower serum homocysteine levels compared with non-insulin resistant subjects. The negative association of insulin resistance and serum homocysteine was unexpected. The contribution of plasma folate levels to serum homocysteine levels and serum creatinine was significantly negative and positive, respectively.

Association of Plasma Homocysteine and Insulin Resistance in Coronary Artery Disease

         (Sainani and Karatela 2009) Download

Objectives: Although insulin resistance and hyperhomocysteinemia may both be associated with endothelial dysfunction and cardiovascular disease, associations between them in coronary artery disease (CAD) are not well characterized. We investigated association between insulin resistance and homocysteine in CAD.

Methods: One hundred thirty subjects were studied. Of these sixty-five were angiographically documented CAD patients and 65 subjects were without CAD as documented by normal stress test and 2D echo. Fasting levels of plasma homocysteine, serum vitamin B12, folic acid, insulin, insulin resistance (HOMA-IR), lipid parameters, along with BMI and blood pressure levels were estimated. The prevalence of hyperhomocysteinemia (>15 μmol//) and insulin resistance (HOMA-IR>4.65 or BMI>27.5 kg/m2 and HOMAI-IR>3.6) and reduced vitamin B12 (<147 pmol/l) and folic acid (<10 nmol/l) level were determined. Student’s t-test, Pearson’s correlation, multivariate and stepwise logistic regression analysis were performed.

Result: Significantly raised levels of insulin resistance, homocysteine, LDL cholesterol, triglycerides, insulin levels were observed among the cases compared to the controls. Among the CAD subjects, hyperhomocysteinemia was observed in 22 (33.3%) subjects, raised insulin resistance in 21 (32.31% subjects), and dyslipidemia in 34 (53.4%) subjects. We also observed reduced levels of vitamin B12 and folic acid in blood among 23 (35.1%) CAD patients. There was no significant difference in age and gender between the case and control groups. There was a significant difference in prevalence (case vs. controls) of smoking (32.8% vs 12.3%), hypertension (38.5% vs. 1.2 %) and diabetes (27.7% vs. 4.3 %). On comparing the insulin resistant CAD subjects with the insulin non-resistant CAD subjects, we observed significantly raised (p< 0.05) homocysteine levels among former group. Reduced levels of vitamin B12 and folic acid levels were observed among the insulin-resistant CAD compared to the insulin non- resistant CAD subjects. Plasma homocysteine was found correlated with insulin resistance among CAD subjects. Logistic regression analysis revealed insulin resistance [crude odds ratio: 3.35, 95%CI:1.9-6.03, adjusted odds ratio: 2.9, 95%CI:1.5-5.82] and homocysteine [crude odds ratio: 6.14, 95%CI:1.94-19.45 adjusted odds ratio: 6.71, 95%CI:1.32-34.18] as associated with CAD independent of several risk factors such as, age, gender, dyslipidemia and blood pressure levels.

Conclusion: We observed that both insulin resistance and homocysteine were significantly and independently associated with CAD risk. There was also a significant association between plasma homocysteine and insulin resistance in CAD subjects.

Homocysteine to hydrogen sulfide or hypertension

            (Sen, Mishra et al. 2010) Download

Hyperhomocysteinemia, an increased level of plasma homocysteine, is an independent risk factor for the development of premature arterial fibrosis with peripheral and cerebro-vascular, neurogenic and hypertensive heart disease, coronary occlusion and myocardial infarction, as well as venous thromboembolism. It is reported that hyperhomocysteinemia causes vascular dysfunction by two major routes: (1) increasing blood pressure and, (2) impairing the vasorelaxation activity of endothelial-derived nitric oxide. The homocysteine activates metalloproteinases and induces collagen synthesis and causes imbalances of elastin/collagen ratio which compromise vascular elastance. The metabolites from hyperhomocysteinemic endothelium could modify components of the underlying muscle cells, leading to vascular dysfunction and hypertension. Homocysteine metabolizes in the body to produce H(2)S, which is a strong antioxidant and vasorelaxation factor. At an elevated level, homocysteine inactivates proteins by homocysteinylation including its endogenous metabolizing enzyme, cystathionine gamma-lyase. Thus, reduced production of H(2)S during hyperhomocysteinemia exemplifies hypertension and vascular diseases. In light of the present information, this review focuses on the mechanism of hyperhomocysteinemia-associated hypertension and highlights the novel modulatory role of H(2)S to ameliorate hypertension.

Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida

            (Shaw, Rozen et al. 1998) Download

Maternal periconceptional use of vitamin supplements containing folic acid substantially reduces the risk of neural tube defects (NTDs) in the offspring. The mechanism underlying this reduction in risk is unknown. Several recent studies have reported an association between homozygosity for a variant form (the C677T genotype) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and risk for NTDs in individuals. It has been hypothesized that maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme. Using data from two California case-control interview studies (1987-1991 birth cohorts), the authors investigated whether an interaction for spina bifida risk existed between infant MTHFR C677T genotype and maternal use of supplements containing folic acid. The authors genotyped the allelic variants of MTHFR in 214 liveborn case infants with spina bifida and 503 control infants for whom information on maternal periconceptional vitamin use was available. The percentage of all case infants with the C677T MTHFR mutation, for both homozygous (TT) and heterozygous (TC) genotypes, was slightly higher than that of controls. The C677T genotype was substantially more frequent among both case and control Hispanic infants than among non-Hispanic infants. Among all infants whose mothers did not periconceptionally use vitamins containing folic acid, the risk of spina bifida, as measured by the odds ratio, was 1.6 (95% confidence interval (CI) 0.8-3.1) for all infants with the TT genotype and 2.0 (95% CI 0.5-7.4) for non-Hispanic white infants with the TT genotype, as compared with infants with the CC genotype. This result indicates a modestly increased risk associated with the C677T genotype. A lower risk estimate (odds ratio=1.2, 95% CI 0.4-4.0) was observed among infants whose mothers periconceptionally used vitamin supplements containing folic acid. This population-based California study found a modestly increased risk of spina bifida among infants who were homozygous for the C677T genotype, but only minimal evidence of an interaction between the C677T genotype and maternal folic acid intake in the occurrence of spina bifida. If this mutant MTHFR genotype plays a role in the association between maternal vitamin use and NTD risk, it may be a small role, or it may be conditional on maternal genotype.

The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother

            (Shields, Kirke et al. 1999) Download

Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n=271) and families (n=218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P=.02) but no evidence of a maternal TT genotypic effect (P=. 83). The log-linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype.

Copper deficiency decreases plasma homocysteine in rats

         (Uthus, Reeves et al. 2007) Download

The purpose of this study was to determine the effects of copper deficiency on key aspects of homocysteine metabolism that involve methionine recycling and transsulfuration. Male weanling Sprague-Dawley rats were fed AIN-93G-based diets containing <1 or approximately 6 mg Cu/kg. After 6 wk (Expt. 1) and 4 wk (Expt. 2) we found that plasma homocysteine was significantly decreased, and plasma glutathione significantly increased, in rats fed the low-Cu diet. Real-time RT-PCR was used to determine the expression of the subunits of glutamate-cysteine ligase (Gcl) in liver that catalyzes the rate-limiting step in glutathione biosynthesis. The expression of Gclc, the catalytic subunit of Gcl, was upregulated by Cu deficiency; Gclm, the modifier subunit, was not affected. Hepatic betaine-homocysteine methyltransferase (Bhmt), which catalyzes one of the two ways that homocysteine can be remethylated to methionine, was downregulated by Cu deficiency. Because Cu deficiency results in upregulation of Gclc and an increase in the biosynthesis of glutathione, it is plausible that the net flux of homocysteine through the transsulfuration pathway is increased. Furthermore, if Bhmt is downregulated, less homocysteine is available for remethylation (methionine recycling) and more is then available to irreversibly enter the transsulfuration pathway where it is lost. The net effect of increased Gclc and decreased Bhmt would be a decrease in homocysteine as a result of Cu deficiency.

Dietary selenium (Se) and copper (Cu) interact to affect homocysteine metabolism in rats

         (Uthus and Ross 2009) Download

Previously, we reported that both Se deficiency and Cu deficiency decreased plasma homocysteine (pHcys) and increased plasma glutathione (pGSH) in rats. We also showed that the catalytic subunit of glutamate-cysteine ligase (Gclc), which catalyzes the rate-limiting step in glutathione biosynthesis, was upregulated in Se and Cu deficiencies. We suggested that in both deficiencies, Hcys was being shunted through the trans-sulfuration pathway as a result of this up-regulation. Because both Se and Cu deficiencies have similar effects, we hypothesized that a combined deficiency would exacerbate the decrease in pHcys and the increase in pGSH by further up-regulating Gclc. In a 2 x 2 experiment, male weanling Sprague-Dawley rats (n = 8-20/group) were fed an amino-acid-based diet containing either 0 or 0.2 microg Se (as selenite)/g and <1 or 6 microg Cu (as Cu carbonate)/g for 5 weeks. Our findings show that a combined deficiency of both Se and Cu results in lower pHcys and significantly elevated pGSH. However, the up-regulation of liver Gclc alone cannot explain why rats fed with the doubly deficient diet have the lowest pHcys and the highest pGSH.

Impact of MTHFR C677T gene polymorphism and vitamins intake on homocysteine concentration in the Polish adult population

            (Waskiewicz, Piotrowski et al. 2011) Download

Background: Homocysteine (Hcy) levels are modulated by nutritional and genetic factors, among which is the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Aim: To determine the effects of the MTHTR C677T polymorphism, as well as the intake of folate, vitamins B(6) and B(12) on serum Hcy concentration in the Polish population. Methods: Within the framework of the National Multicentre Health Survey (WOBASZ), a representative sample of the whole Polish population aged 20-74 was screened in 2003-2005. Vitamins intake, Hcy level and known MTHTR C677T genotype were available for 1,561 men and 1,712 women. Results: In the Polish population, T/T, C/T and C/C genotype frequencies were 10%, 43% and 47%, respectively in men, and 9%, 42% and 49%, respectively in women. The T/T genotype was associated with increased levels of Hcy (13.14 mumol/L in men, and 9.77 mmol/L in women) compared to the C/C and C/T genotypes (10.18 and 8.77, respectively), after adjustment for age, methionine, coffee and alcohol intake, smoking and drugs used. In a multivariable linear regression model, among subjects with the T/T genotype, the only factor influencing Hcy was age in women. In the case of the other groups (C/C and C/T), there was a relationship between Hcy and age, alcohol consumption, drugs used, folate and vitamin B(6) in men, and age, smoking, coffee consumption, drugs used, folate and vitamin B(12) in women. Conclusions: The T/T genotype is associated with higher levels of Hcy (29% in men, and 11% in women) compared to other genotypes. Nutritional factors affect Hcy levels only in the C/C and C/T MTHFR genotypes. Kardiol Pol 2011; 69, 12: 1259-1264.

Association of blood lead (Pb) and plasma homocysteine: a cross sectional survey in Karachi, Pakistan

            (Yakub and Iqbal 2010) Download

BACKGROUND: High blood lead (Pb) and hyperhomocysteinemia have been found to be associated with cardiovascular disease (CVD). Mean blood Pb and mean plasma homocysteine levels have been reported to be high in Pakistani population. The objective of the present study was to assess the relationship of blood Pb to the risk of hyperhomocysteinemia in a low income urban population of Karachi, Pakistan. METHODOLOGY/PRINCIPAL FINDINGS: In a cross sectional survey, 872 healthy adults (355 males, 517 females; age 18-60 years) were recruited from a low income urban population of Karachi. Fasting venous blood was obtained and assessed for blood Pb and plasma/serum homocysteine, folate, pyridoxal phosphate (PLP, a coenzymic form of vitamin B6) and vitamin B12. The study population had median (IQR) blood Pb of 10.82 microg/dL (8.29-13.60). Prevalence of high blood Pb (levels>10 microg/dL) was higher in males compared to females (62.5% males vs 56% females; p value=0.05). Mean+/-SD/median (IQR) value of plasma homocysteine was significantly higher in the highest quartile of blood Pb compared to the lowest quartile 16.13+/-11.2 micromol/L vs 13.28+/-9.7micromol/L/13.15 (10.33-17.81) micromol/L vs 11.09 (8.65 14.31) micromol/L (p value<0.001). Daily consumption of fruit juice had a positive influence on both levels of plasma homocysteine and blood Pb. Compared with the lowest quartile of blood Pb, the OR for hyperhomocysteinemia was 1.69 (95% CI, 1.00 to 2.85) for the fourth quartile when the model was adjusted for age, gender, folate and vitamin B12. CONCLUSIONS/SIGNIFICANCE: This study showed a relationship between blood Pb and hyperhomocysteinemia in a general population of Karachi, Pakistan. The harmful effect of Pb on cardiovascular system could be due to its association with hyperhomocysteinemia.


Bjorke-Monsen, A. L., P. M. Ueland, et al. (1997). "Elevated plasma total homocysteine and C677T mutation of the methylenetetrahydrofolate reductase gene in patients with spina bifida." QJM 90(9): 593-6.

Chia, S. E., S. M. Ali, et al. (2007). "Association of blood lead and homocysteine levels among lead exposed subjects in Vietnam and Singapore." Occup Environ Med 64(10): 688-93.

Gallagher, C. M. and J. R. Meliker (2011). "Total blood mercury, plasma homocysteine, methylmalonic acid and folate in US children aged 3-5 years, NHANES 1999-2004." Sci Total Environ 409(8): 1399-405.

Hustad, S., P. M. Ueland, et al. (2000). "Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism." Clin Chem 46(8 Pt 1): 1065-71.

Kang, Y. J. (2011). "Copper and homocysteine in cardiovascular diseases." Pharmacol Ther 129(3): 321-31.

Qin, X., J. Li, et al. (2012). "MTHFR C677T and MTR A2756G Polymorphisms and the Homocysteine Lowering Efficacy of Different Doses of Folic Acid in Hypertensive Chinese Adults." Nutr J 11(1): 2.

Ravasini, J. A., P. Mossop, et al. (2008). "Homocysteine and heavy metal interactions in atrial fibrillation and ablation treatments." Europace 10(12): 1458; author reply 1458-7.

Rosolova, H., J. Simon, et al. (2002). "Unexpected inverse relationship between insulin resistance and serum homocysteine in healthy subjects." Physiol Res 51(1): 93-8.

Sainani, G. S. and R. A. Karatela (2009). "Association of Plasma Homocysteine and Insulin Resistance in Coronary Artery Disease." J Assoc Physicians of India 57.

Sen, U., P. K. Mishra, et al. (2010). "Homocysteine to hydrogen sulfide or hypertension." Cell Biochem Biophys 57(2-3): 49-58.

Shaw, G. M., R. Rozen, et al. (1998). "Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida." Am J Epidemiol 148(1): 30-7.

Shields, D. C., P. N. Kirke, et al. (1999). "The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother." Am J Hum Genet 64(4): 1045-55.

Uthus, E. O., P. G. Reeves, et al. (2007). "Copper deficiency decreases plasma homocysteine in rats." J Nutr 137(6): 1370-4.

Uthus, E. O. and S. Ross (2009). "Dietary selenium (Se) and copper (Cu) interact to affect homocysteine metabolism in rats." Biol Trace Elem Res 129(1-3): 213-20.

Waskiewicz, A., W. Piotrowski, et al. (2011). "Impact of MTHFR C677T gene polymorphism and vitamins intake on homocysteine concentration in the Polish adult population." Kardiol Pol 69(12): 1259-64.

Yakub, M. and M. P. Iqbal (2010). "Association of blood lead (Pb) and plasma homocysteine: a cross sectional survey in Karachi, Pakistan." PLoS One 5(7): e11706.