Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study

We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to some extent explain why this polymorphism is associated with low BMD or fracture in some study populations and not in others. It would also indicate that fractures associated with the TT genotype could be preventable by vitamin B supplementation. We have, therefore, reviewed baseline food record data from our original study to determine if BMD and fracture associations with the MTHFR genotype depended on the intake of folate, riboflavin, or other members of the vitamin B complex, associated with homocysteine metabolism. We analyzed genotype, BMD, and dietary records from 1700 healthy postmenopausal women who participated in the DOPS study. For the assessment of fracture risk, we used longitudinal observations from 854 women in the control group who remained compliant with their initial allocation of no treatment. Riboflavin intake was significantly correlated with femoral neck (FN) BMD in women with the TT genotype (r = 0.24, P < 0.01). FN and lumbar spine (LS) BMD were only associated with the MTHFR genotype in the lowest quartile of riboflavin intake. At the FN, similar threshold effects were shown for folate, vitamin B12, and vitamin B6. Among these vitamin B complex members, stepwise regression analysis identified riboflavin as the only significant predictor of FN BMD in the TT genotype. In conclusion, we confirm reports that BMD in the MTHFR TT genotype is only significantly reduced in the lowest quartile of riboflavin, B12, B6, and folate intake, at least at the time of menopause. Vitamin B supplementation would only be expected to benefit BMD in about 2% of the population, i.e., those with the TT genotype and low vitamin B intake.     

Methylenetetrahydrofolate reductase polymorphism interacts with riboflavin intake to influence bone mineral density

Bone mineral density is a complex trait regulated by an interaction between genetic and environmental factors. Recent studies have identified a functional polymorphism affecting codon 677 of the methylenetetrahydrofolate reductase (MTHFR) gene that is associated with reduced bone mineral density (BMD) in Japanese and Danish postmenopausal women and increased risk of fracture in elderly Danish women. Since dietary B vitamins can influence circulating homocysteine (tHcy) levels, we examined the relationship among MTHFR genotype, B complex vitamins (folate, vitamin B12, vitamin B6 and riboflavin), BMD, and rate of change in BMD in a longitudinal study of 1241 Scottish women aged 45-54 years, at the time of initial study, who were followed up for a mean (SD) of 6.6 (0.7) years. There was no significant association between BMD and either MTHFR genotype or B complex vitamins when examined separately. However, we detected a significant interaction among quartile of energy-adjusted riboflavin intake, MTHFR 'TT' genotype, and BMD (P = 0.01 for baseline FN BMD, P = 0.02 for follow-up FN BMD). Increasing dietary riboflavin intake correlated with LS BMD and FN BMD in homozygotes for the MTHFR 'T' allele, which remained significant for FN after adjustment for confounders (r = 0.192, P = 0.036 for baseline; r = 0.186, P = 0.043 at follow-up) but not in the other genotypes. This raises the possibility that riboflavin intake and MTHFR genotype might interact to regulate BMD. Further work is required to determine if this association holds true for other populations and ethnic groups.     

Association of a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with bone phenotypes depends on plasma folate status.

A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes in 1632 individuals revealed that the genotype effect on BMD and quantitative ultrasound was dependent on the level of folate. Our findings support the hypothesis that the association between an MTHFR polymorphism and bone phenotypes depends on folate status. INTRODUCTION: Genome-wide screens using quantitative ultrasound (QUS) and BMD phenotypes have shown suggestive linkage on chromosome 1pter-1p36.3, a region containing the methylenetetrahydrofolate reductase (MTHFR) gene. Individuals homozygous (TT) for the MTHFR C677T polymorphism who have low plasma folate concentrations exhibit elevated plasma homocysteine (tHcy) concentrations that may compromise bone quality. We hypothesized that folate status might modify an association between the C677T polymorphism and bone, possibly by influencing homocysteine concentrations. MATERIALS AND METHODS: QUS (broadband ultrasound attenuation [BUA], speed of sound, and quantitative ultrasound index) of the heel and BMD of the hip and spine were measured in 1632 male and female members of the Framingham Offspring Study (1996-2001). Participants were assessed for plasma folate concentration and genotyped for the MTHFR C677T polymorphism. TT participants were compared with individuals in the CC + CT group using analysis of covariance. RESULTS: Adjusted mean QUS and BMD measures did not differ between C677T groups. Although all participants with plasma folate concentrations > or =4 ng/ml had approximately 2% higher QUS and BMD than those with folate <4 ng/ml, the association disappeared after controlling for tHcy. Suggestive interactions between folate status and the C677T group (CC + CT versus TT) were found for hip BMD (p < or = 0.05) and BUA (p = 0.11). Compared with CC + CT participants, TT individuals had lower mean BUA (p = 0.06) and Ward's area BMD (p = 0.08) within the folate <4 ng/ml group and significantly higher hip BMD (p < or = 0.05) within the folate > or =4 ng/ml group. For both folate groups, TT participants had higher age-adjusted mean plasma tHcy versus CC + CT participants. Controlling for tHcy in these models did not affect the statistical significance of the interaction effects. CONCLUSIONS: Our findings support the hypothesis that the association between the C677T MTHFR polymorphism and bone phenotypes depends on folate status. The mechanism mediating the association, however, remains unclear, but may be partially caused by homocysteine effects on bone.     

Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and bone mineral density in Chinese men and women

The relationship between MTHFR (C677T) genotypes of the methylenetetrahydrofolate reductase, bone mineral density (BMD), and vertebral fracture was studied in 657 Chinese men and women. No association between MTHFR (C677T) and BMD was found in postmenopausal women (aged 55–59 years, n = 178), elderly women (aged 70–79 years, n = 247), or elderly men (aged 70–79 years, n = 232) at the hip, spine, or total body (P > 0.05 by ANCOVA). In all study groups, there was no effect of an interaction between MTHFR (C677T) and daily dietary calcium intake on BMD (P > 0.05 for the interaction effects by two-way ANCOVA). No statistically significant association was observed between MTHFR (C677T) genotypes and vertebral fracture. The MTHFR (C677T) genotypes for CC, CT, and TT among elderly women with or without vertebral fracture were 5%, 33%, 62%; 6%, 37%, and 57%, respectively, and those for elderly men with and without vertebral fracture were 9%, 31%, 60%; 5%, 35%, and 60%, respectively. The prevalence of TT in our study group was 5% compared to 8% in the Danish or 18.6% in the Japanese. We found no association between MTHFR (C677T) and BMD of Chinese men or women. It would be interesting to study the interactions with folate, B12, and homocysteine.     

Effect of dietary B vitamins on BMD and risk of fracture in elderly men and women: the Rotterdam study

A mildly elevated homocysteine (Hcy) level is a novel and potentially modifiable risk factor for age-related osteoporotic fractures. Elevated Hcy levels can have a nutritional cause, such as inadequate intake of folate, riboflavin, pyridoxine or cobalamin, which serve as cofactors or substrates for the enzymes involved in the Hcy metabolism. We examined the association between intake of Hcy-related B vitamin (riboflavin, pyridoxine, folate and cobalamin) and femoral neck bone mineral density BMD (FN-BMD) and the risk of fracture in a large population-based cohort of elderly Caucasians.

We studied 5304 individuals aged 55 years and over from the Rotterdam Study. Dietary intake of nutrients was obtained from food frequency questionnaires. Incident non-vertebral fractures were recorded during a mean follow-up period of 7.4 years, and vertebral fractures were assessed by X-rays during a mean follow-up period of 6.4 years. We observed a small but significant positive association between dietary pyridoxine (β = 0.09, p = 1 × 10^− 8) and riboflavin intake (β = 0.06, p = 0.002) and baseline FN-BMD. In addition, after controlling for gender, age and BMI, pyridoxine intake was inversely correlated to fracture risk. As compared to the three lowest quartiles, individuals in the highest quartile of age- and energy-adjusted dietary pyridoxine intake had a decreased risk of non-vertebral fractures (HR = 0.77, 95% CI = 0.65–0.92, p = 0.005) and of fragility fractures (HR = 0.55, 95% CI = 0.40–0.77, p = 0.0004). Further adjustments for other dietary B vitamins (riboflavin, folate and cobalamin), dietary intake of calcium, vitamin D, vitamin A and vitamin K, protein and energy intake, smoking and BMD did not essentially modify these results.

We conclude that increased dietary riboflavin and pyridoxine intake was associated with higher FN-BMD. Furthermore, we found a reduction in risk of fracture in relation to dietary pyridoxine intake independent of BMD. These findings highlight the importance of considering nutritional factors in epidemiological studies of osteoporosis and fractures.     

Effect of folate, vitamin B6, and vitamin B12 intake and MTHFR C677T polymorphism on homocysteine concentrations of renal transplant recipients

Plasma hyperhomocysteinemia (HHcy) is considered a risk factor for chronic allograft dysfunction (CAD), the main cause of functional loss in transplant recipients. Genetic polymorphisms that alter enzymes involved in homocysteine (Hcy) metabolism, such as methylenetetrahydrofolate reductase (MTHFR), and vitamin deficiency can result in HHcy. The objectives of this study were to investigate the relationship between HHcy and CAD development, and to evaluate the effect of intake of folate and vitamins B6 and B12 as well as MTHFR C677T polymorphism on Hcy concentrations. Ninety-eight renal transplant recipients including 48 showing CAD and 50 with normal renal function (NRF), were included in this cross-sectional study. Peripheral blood samples were collected for plasma Hcy quantification by liquid chromatography/sequential mass spectrometry (LC-MS/MS), and for MTHFR polymorphism analysis using polymerase chain reaction-restriction fragment length polymorphism. Dietary intake was evaluated using a nutritional questionnaire. HHcy (P=.002) and higher mean concentrations of Hcy (P=.029) were associated with CAD. An association was observed between HHcy and 677T variant allele in the CAD group (P=.0005). There was no correlation between Hcy concentration and folate, vitamin B6 or vitamin B12 intake in the CAD group. However, a negative correlation was observed between Hcy concentration and folate intake (P=.043), and also between Hcy concentration and vitamin B6 intake (P=.030) in the NRF group. According to our study, HHcy is associated with CAD development. In patients with CAD, MTHFR polymorphism seems to have a greater effect on the Hcy concentration than the vitamin intake. Increased folate and vitamin B6 intakes seem to reduce Hcy concentrations among transplant recipients with NRF, and could contribute to reducing the risk of CAD development.     

Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Is Associated With Spinal BMD in 9‐Year‐Old Children

The C677T MTHFR polymorphism has been associated with lumbar spine and hip BMD. In older adults, the genetic effect has been reported in women only. However, in younger adults, this influence may only be present in men. This study is the first to investigate associations between the C677T MTHFR polymorphism and bone phenotypes in children. Regression analyses were used to study the relationship between MTHFR genotype and bone phenotypes derived from total body DXA scans in children 9.9 yr of age from the Avon Longitudinal Study of Parents and Children (ALSPAC). A total of 5816 children had both genetic and DXA data for the total body less head region (TBLH) and 3196 for the spine. A strong association was observed between the C677T MTHFR genotype and spine BMD (p < 0.001; 0.10 SD decrease per T allele). There was some evidence that this genetic effect was stronger in boys compared with girls (p = 0.04 for sex interaction). In contrast, there was no association between the C677T MTHFR genotype and TBLH BMD. The association between MTHFR genotype and spine BMD was attenuated particularly in girls by high maternal dietary intakes of vitamin B₆ and folate during pregnancy but not by child dietary intakes at 7 yr. To the extent that these findings reflect known influences of C677T MTHFR genotype on plasma homocysteine levels, our results suggest that the latter is an important regulator of spinal BMD in childhood.     

Association of the methylenetetrahydrofolate reductase C677T polymorphism and fracture risk in Chinese postmenopausal women

Osteoporotic fractures are a leading cause of disability and, indirectly, of death in the elderly population. Previous studies have shown that homocysteine level and the C677T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) may be involved in the development of osteoporosis and its related fracture in European populations. The aim of this study was to verify the association of this polymorphism with bone mineral density (BMD) and fractures in our 1899 Chinese postmenopausal women. The C677T T allele frequency in this population was 39.2%. The distribution of the MTHFR genotypes followed the Hardy-Weinberg equilibrium. BMD at total body, total hip or femoral neck did not significantly vary with MTHFR C677T genotype. The T allele carrier tended to have higher risk of having osteoporosis or osteopenia, but the difference was statistically insignificant. However, Poisson regression analysis revealed that the T allele carriers had an increased risk of fractures (RR=1.7, 95% CI=1.1-2.7, p=0.01) which occurred before or after menopause. As far as fracture incidence after menopause was concerned, the CT or TT genotype had more than twice the risk of the CC genotype (RR=2.5, 95% CI=1.2-4.9, p=0.009). This association was independent of age, physical activity, occupation, passive smoking, height, weight, years since menopause, and total hip BMD. Our data show that the MTHFR C677T polymorphism is an independent predictor of fracture risk, although it only had a weak effect on BMD. Further study on the mechanistic role that this polymorphism plays in the development of fractures may lead to better understanding of the etiology of osteoporotic fracture.     

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD

Osteoporosis is a common disease with a strong genetic component. Linkage studies have suggested linkage between BMD and loci on chromosome 1. The MTHFR gene is located on chromosome 1. MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which is used for homocysteine methylation to methionine. The rare genotype (TT) of the C677T polymorphism has previously been demonstrated to be associated with increased plasma homocysteine levels in individuals with inadequate plasma folate levels. Recently, the TT genotype has been found to be associated with reduced bone mass. We therefore examined if the C677T polymorphism in the MTHFR gene is associated with changes in bone mass and risk of osteoporotic fractures in 388 osteoporotic patients and 336 normal individuals. The distributions of the genotypes CC, CT and TT in women with osteoporotic vertebral fractures and normal controls were 43.5%, 42.2% and 14.3% and 52.0%, 42.0% and 8.0%, respectively, ²=5.62, P=0.06. Since studies of the functionality of this polymorphism have revealed that only the TT genotype is associated with biochemical changes, we also compared the prevalence of the TT genotype versus the CT- and CC genotypes in patients and controls and found that the TT genotype is significantly more common in women with vertebral fractures (14.3%) compared with normal controls (8.0%), ²=4.31, P<0.05. Logistic regression analysis demonstrated that vertebral fractures were significantly associated with BMD (lumbar spine) and height but only marginally with the MTHFR genotype (P=0.06). Multiple linear regression analysis revealed that weight, age and the MTHFR polymorphism were predictors of lumbar spine BMD in women. However, age- and gender-corrected BMD of the lumbar spine and the hip was not significantly different between MTHFR genotypes. Furthermore, individuals with the TT genotype did not have BMD significantly lower than the combined group of individuals with the CT- or CC genotypes. In conclusion, we have demonstrated that the rare TT genotype of the C677T polymorphism in the MTHFR gene is associated with increased risk of osteoporotic fractures in women and a weak predictor of lumbar spine BMD.     

Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients

BACKGROUND: Hyperhomocysteinemia is an established, independent risk factor for vascular disease morbidity and mortality. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T has been shown to result in increased total homocysteine concentrations on the basis of low folate levels caused by a decreased enzyme activity. The effect of this polymorphism on total homocysteine and folate plasma levels in renal transplant patients is unknown. METHODS: We screened 636 kidney graft recipients for the presence of the MTHFR C677T gene polymorphism. The major determinants of total homocysteine and folate plasma concentrations of 63 patients, who were identified to be homozygous for this gene polymorphism compared with heterozygotes (N = 63), and patients with wild-type alleles (N = 63), who were matched for sex, age, glomerular filtration rate (GFR), and body mass index, were identified by analysis of covariance. The variables included sex, age, GFR, body mass index, time since transplantation, folate and vitamin B12 levels, the use of azathioprine, and the MTHFR genotype. To investigate the impact of the kidney donor MTHFR genotype on total homocysteine and folate plasma concentrations, a similar model was applied in 111 kidney graft recipients with stable graft function, in whom the kidney donor C677T MTHFR gene polymorphism was determined. RESULTS: The allele frequency of the C677T polymorphism in the MTHFR gene was 0.313 in the whole study population [wild-type (CC), 301; heterozygous (CT), 272; and homozygous mutant (TT), 63 patients, respectively] and showed no difference in the patient subgroups with various renal diseases. The MTHFR C677T gene polymorphism significantly influenced total homocysteine and folate plasma concentrations in renal transplant recipients (P = 0.0009 and P = 0.0002, respectively). Furthermore, a significant influence of the GFR (P = 0.0001), folate levels (P = 0.0001), age (P = 0.0001), body mass index (P = 0.0001), gender (P = 0.0005), and vitamin B12 levels (P = 0.004) on total homocysteine concentrations was observed. The donor MTHFR gene polymorphism had no influence on total homocysteine and folate levels. Geometric mean total homocysteine levels in patients homozygous for the mutant MTHFR allele were 18.6 micromol/liter compared with 14.6 micromol/liter and 14.9 micromol/liter in patients heterozygous for the MTHFR gene polymorphism and those with wild-type alleles (P < 0.05 for TT vs. CT and CC). Geometric mean folate levels were lower in CT and TT patients (11.2 and 10.2 nmol/liter) compared with CC patients (13.6 nmol/liter, P < 0.05 vs. CT and TT). CONCLUSIONS: This study demonstrates that homozygosity for the C677T polymorphism in the MTHFR gene significantly increases total homocysteine concentrations and lowers folate levels in kidney graft recipients, even in patients with excellent renal function (GFR more than median). These findings have important implications for risk evaluation and vitamin intervention therapy in these patients who carry an increased risk for the development of cardiovascular disease.     

Interplay between methylenetetrahydrofolate reductase gene polymorphism 677C→T and serum folate levels in determining hyperhomocysteinemia in heart transplant recipients

BACKGROUND: Homocysteine metabolism is often impaired in heart transplant recipients, and increased total homocysteine plasma levels may constitute a risk factor for the development of heart allograft vascular disease. Although 677C-->T transition in methylenetetrahydrofolate reductase (MTHFR) is associated with increased homocysteine levels in the general population, it is unclear whether MTHFR polymorphism influences homocysteine metabolism after heart transplant. METHODS: Homocysteine, serum folate, renal function, concentrations of cyclosporine and its metabolites, and MTHFR genotype were determined in 57 heart transplant recipients (age, 55 +/- 11 yr; 21% women; time from transplant, 48 +/- 42 months). RESULTS: Forty nine percent of the study population presented with hyperhomocysteinemia. Homocysteine was 17.1 +/- 5.9 micromol/liter, 19.4 +/- 4.9 micromol/liter, and 26.3 +/- 14.2 micromol/liter for genotypes CC, CT, and TT, respectively (p = 0.028, Kruskal-Wallis test). At multivariate analysis, MTHFR genotype was independently associated with homocysteine (p = 0.005). When the study population was divided into 2 groups accordingly to serum folate levels (above/below the median value of 6.1 ng/ml), MTHFR genotype remained a significant predictor of homocysteine only in patients with low serum folate (p = 0.048). CONCLUSIONS: This study demonstrates that hyperhomocysteinemia is frequent in heart transplant recipients and that the 677C-->T transition in the MTHFR gene independently and unfavorably influences homocysteine metabolism in this group of patients. Adequate folate intake may overcome genetic predisposition to hyperhomocysteinemia.     

亚甲基四氢叶酸还原酶基因多态性及同型半胱氨酸水平与冠心病关系的研究

目的：探讨亚甲基四氢叶酸还原酶（MTHFR）C677T基因多态性、血清同型半胱氨酸（Hcy）水平与冠心病发生的关系。方法：收集解放军总医院第一附属医院收治的冠心病患者172例和健康体检者（正常对照组）160例的空腹静脉血,应用基因芯片技术联合检测MTHFR基因C677T多态性位点,并比较冠心病患者和健康体检者的MTHFR基因型及不同MTHFR基因型冠心病患者中血清Hcy水平的变化。结果：①冠心病组与正常对照组MTHFR基因C677T分布频率分别为CC型20.3%比32.5%（P〈0.05）、CT型44.8%比43.1%（P〉0.05）和TT型34.9%比24.3%（P〈0.05）;②冠心病组血清Hcy水平与正常对照组水平之间存在明显差异（P〈0.05）;③冠心病的TT基因型组的Hcy水平明显高于CC基因型组和CT基因型组,差异具有统计学意义（P〈0.05）。结论：冠心病组MTHFR C677T基因TT型分布频率及Hcy水平均高于正常对照组,MFHFR基因C677T TT型与冠心病的发生有关。     

Effects of the C677T and A1298C polymorphisms of the MTHFR gene on the genetic predisposition for diabetic nephropathy.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is a regulatory enzyme of homocysteine metabolism. The C677T polymorphism of the MTHFR gene has been reported to be associated with elevated plasma homocysteine in patients with low folic acid intake. A recently reported second common polymorphism, A1298C, may increase homocysteine, but only in individuals carrying the T677 allele. This study aimed to investigate the influence of the C677T and A1298C polymorphisms of the MTHFR gene on the development of diabetic nephropathy in Caucasian patients with type 2 diabetes. METHODS: We genotyped 429 type 2 diabetic patients for the C677T and A1298C polymorphisms using standard PCR-based protocols, and divided them into three groups based on renal status: 159 patients with normoalbuminuria, 149 with microalbuminuria, and 121 with persistent proteinuria and chronic renal failure (CRF). The C677T and A1298C genotype frequencies were compared among the three groups. RESULTS: Although the frequencies of the CT and TT genotypes of the C677T polymorphism tended to increase with each stage of diabetic nephropathy (53, 56 and 63% in normoalbuminuria, microalbuminuria and proteinuria/CRF, respectively), these differences were not significant. When male and female patients were analysed separately, the effect was seen only in males. The CT + TT genotype was present in 46% of male patients with normoalbuminuria, in 57% with microalbuminuria and in 68% with proteinuria/CRF (OR = 2.46; 95% CI 1.13-5.38). There were no differ-ences in the A1298C polymorphism among the three groups. CONCLUSIONS: These findings indicate that the C677T polymorphism is a risk factor for diabetic nephrop-athy in male patients with type 2 diabetes.     

Association of plasma folate, plasma total homocysteine, but not methylenetetrahydrofolate reductase C667T polymorphism, with bone mineral density in postmenopausal Iranian women: a cross-sectional study

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have been well documented to cause hyperhomocysteinemia, and recent studies suggest an association of C677T mutation of methylenetetrahydrofolate reductase with low bone mineral density (BMD). In this study, the association of plasma total homocysteine (Hcy), plasma folate, and vitamin B12 as well as methylenetetrahydrofolate reductase C667T polymorphism with bone mineral density at neck of femur and lumbar spine in 271 postmenopausal Iranian women was investigated. Bone mineral density was measured by dual-energy X-ray absorptiometry. Restriction fragment length polymorphism was used for genotyping the methylenetetrahydrofolate reductase polymorphism. Plasma total homocysteine, plasma folate, and vitamin B12 were also determined. The bone mineral densities at the neck of femur and lumbar spine together with other clinical characteristics among methylenetetrahydrofolate reductase genotypes (CC, CT, and TT) were examined. Bone mineral densities at both neck of femur (r = -0.18, P = 0.003) and lumbar spine (r = -0.16, P = 0.01) were significantly and negatively correlated with the logarithm of plasma total homocysteine. Bone mineral density at the lumbar spine was also significantly and positively associated with plasma folate (r = 0.14, P = 0.02). However, no correlation between methylenetetrahydrofolate reductase polymorphism with bone mineral density at neck of femur (r = -0.01, P = 0.81) and lumbar spine (r = -0.04, P = 0.51) was observed. The negative association of plasma total homocysteine with bone mineral density was no longer significant when adjusted for folate and vitamin B12. Plasma folate and age were the main predictors of plasma total homocysteine explaining 15.3% and 5.2% of the variance of plasma total homocysteine, respectively. Methylenetetrahydrofolate reductase polymorphism, however, was not associated with plasma folate (r = 0.086, P = 0.17) or vitamin B12 (r = 0.05, P = 0.4). Plasma folate was one of the main predictors explaining 3.0% and 1.7% of variance of the bone mineral density at femoral neck and lumbar spine, respectively. Results from this study suggest hyperhomocysteinemia as a result of folate deficiency, but not methylenetetrahydrofolate reductase polymorphism, is independently associated with low bone mineral density and may contribute to the pathogenicity of osteoporosis in postmenopausal Iranian women.     

The effects of homocysteine and MTHFR genotype on hip bone loss and fracture risk in elderly women

Summary  Few studies have evaluated the effects of homocysteine and methylenetetrahydrofolate reductase (MTHFR) genotype on age-related bone loss. In our 5-year cohort study with 1,213 women aged 70–85 years, high homocysteine is associated with greater hip bone loss but not fracture risk. The effect of MTHFR genotype on bone density and fracture is weak. Introduction  Previous studies on the effects of homocysteine and MTHFR genotype on bone mineral density (BMD) and osteoporotic fracture risk have shown inconsistent results. Few studies have evaluated their effects on age-related bone loss. We evaluated the effects of homocysteine and MTHFR genotype variation on hip BMD and fracture risk over 5 years in a cohort of 1,213 community-dwelling women aged 70–85 years. Methods  Nutritional intake and prevalent fracture status were assessed at baseline, plasma homocysteine was measured at year 1, and hip dual-energy X-ray absorptiometry (DXA) BMD was measured at years 1 and 5. Clinical incident osteoporotic fractures confirmed by radiographic report were collected throughout the study and the MTHFR gene C677T and A1298C polymorphisms genotyped. Data were analyzed using analysis of covariance and Cox proportional hazard regression. Results  The highest tertile of homocysteine was associated with a greater hip BMD loss over 4 years (−2.8%) compared to the middle (−1.6%) and lowest tertiles (−1.2%) (P < 0.001). This effect remained after adjustment for covariates. There was no effect of homocysteine on fracture prevalence or incidence. MTHFR gene variation was only weakly related to one of the bone outcome measures. Conclusion  In this study population, high homocysteine is associated with greater hip bone loss but not fracture risk.     

Association of a common allelic polymorphism (C677T) in the methylene tetrahydrofolate reductase gene with a reduced risk of osteoporotic fractures. A case control study in Danish postmenopausal women

Twin studies indicate a substantial genetic component in the development of osteoporosis. One of the latest studied candidate genes is the one coding for methylene tetrahydrofolate reductase (MTHFR) (C677T) in which a point mutation gives rise to a thermolabile variant of MTHFR. The aim of this study was to investigate the influence of this mutation on peripheral measures of bone density and on the odds ratios (OR) for hip and lower forearm fracture in a case control study of Danish postmenopausal women. A total of 74 women with lower forearm fracture, 41 women with hip fracture, and 207 age-matched controls were included. All had broadband ultrasound attenuation (BUA) and speed of sound (SOS) measured at the heel as well as bone mineral density (BMD) measured by dual X-ray absorptiometry at the distal forearm. The MTHFR (C677T) genotypes were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Only 2 of 21 individuals with the TT genotype had sustained a fracture as opposed to 46 of 142 with the CT genotype and 67 of 159 with the CC genotype (P = 0.007). Using logistic regression, the following odds ratios were found when comparing the individuals homozygotic for the C-allele with those homozygotic for the T-allele: lower forearm fracture OR = 3.93 (1.25; 12.40, P = 0.02), hip fracture OR = 6.99 (l.35; 36.92, P = 0.02) and the fractures combined OR = 4.33 (1.73; 10.81, P = 0.002). In this study, the MTHFR (C677T) genotypes were not significantly associated with BMD at the lower forearm or with ultrasound parameters measured at the calcaneus. However, a significant increase in the odds ratio of fracture was found for the wild-type C-allele.     

Plasma homocysteine, folate, and vitamin B 12 and the risk of hip fracture: the hordaland homocysteine study.

Homocysteine and related factors were evaluated as risk factors for subsequent hip fractures among 4766 elderly men and women. High levels of homocysteine and low levels of folate predicted fracture, whereas vitamin B12 and genotypes were not related to fracture risk. High homocysteine may be a modifiable risk factor for hip fracture. INTRODUCTION: Elevated plasma total homocysteine (tHcy) and deficiencies of folate and vitamin B12 are associated with risk of osteoporosis and fracture. We examined whether plasma levels of tHcy, folate, and vitamin B12 and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298C-->T polymorphisms predicted hip fracture. MATERIALS AND METHODS: This was a population-based prospective study of 2639 women and 2127 men who were 65-67 yr at enrollment in 1992-1993. Information on hip fracture was obtained from computerized records of discharge diagnoses from all hospitalizations in the region in the period between enrollment and November 30, 2005. Cox proportional hazard regression was used to estimate fracture risk according to levels of plasma tHcy, folate, and vitamin B12 and for different genotypes. RESULTS: Over a median follow-up period of 12.6 yr, hip fracture was recorded in 184 (7.0%) women and 90 (4.2%) men. The adjusted hazard ratio (95% CI) for fracture in subjects with high (>or=15 microM) compared with low levels (<9.0 microM) of tHcy was 2.42 (1.43-4.09) among women and 1.37 (0.63-2.98) among men. Dose-response analyses indicated a positive association between plasma tHcy and risk of fracture in both sexes and a negative association between plasma folate and risk of fracture among women only. Plasma vitamin B12 level or MTHFR genotype was not significantly related to risk of fracture after adjustments for confounding factors. The association between tHcy and risk of hip fracture was only slightly weakened by adjustments for plasma levels of vitamin B12 and folate. CONCLUSIONS: tHcy seems to be a predictor for hip fracture among elderly men and women. Folate was a predictor among women only, whereas vitamin B12 and MTHFR genotype did not predict hip fracture. Our data corroborate the hypothesis that homocysteine may play a role in the pathogenesis of osteoporotic fractures.     

MTHFR C677T genotype as a risk factor for epilepsy including post-traumatic epilepsy in a representative military cohort

The well-studied C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme is a biologically plausible genetic risk factor for seizures or epilepsy. First, plasma/serum levels of homocysteine, a pro-convulsant, are moderately elevated in individuals with the homozygote TT genotype. Furthermore, the TT genotype has been previously linked with migraine with aura-a comorbid condition-and with alcohol withdrawal seizures. Finally, several small studies have suggested that the TT genotype may be overrepresented in epilepsy patients. In this study, we consider whether the MTHFR C677T or A1298C variants are associated with risk of epilepsy including post-traumatic epilepsy (PTE) in a representative military cohort. Study subjects were selected from the cohort of military personnel on active duty during the years 2003 through 2007 who had archived serum samples at the DoD Serum Repository, essentially all active duty personnel during this time frame. We randomly selected 800 epilepsy patients and 800 matched controls based on ICD-9-CM diagnostic codes. We were able to isolate sufficient genetic material from the archived sera to genotype approximately 85% of our study subjects. The odds of epilepsy were increased in subjects with the TT versus CC genotype (crude OR=1.52 [1.04-2.22], p=0.031; adjusted OR=1.57 [1.07-2.32], p=0.023). In our sensitivity analysis, risk was most evident for patients with repeated rather than single medical encounters for epilepsy (crude OR=1.85 [1.14-2.97], p=0.011, adjusted OR=1.95 [1.19-3.19], p=0.008), and particularly for PTE (crude OR=3.14 [1.41-6.99], p=0.005; adjusted OR=2.55 [1.12-5.80], p=0.026). Our early results suggest a role for the common MTHFR C677T variant as a predisposing factors for epilepsy including PTE. Further exploration of baseline homocysteine and folate levels as predictors of seizure risk following traumatic brain injury is warranted.     

Methylenetetrahydrofolate reductase gene C677T polymorphism,plasma homocysteine and folate in end-stage renal disease dialysis and non-dialysis patients

BACKGROUND: It has been recently suggested that the presence of the methylenetetrahydrofolate reductase gene 677TT genotype is associated with younger age at initiation of dialysis, thus raising a hypothesis that younger renal patients carrying the TT genotype are at higher risk to develop end-stage renal disease. The aim of this study was to test the association between the C677T polymorphism and the presence of end-stage renal disease using a family-based study design. MATERIAL AND METHOD: C677T polymorphism was genotyped in a group of 247 family trios (offspring affected with end-stage renal disease, dialysed or conservatively treated, and both parents). Transmission/disequilibrium test (TDT) was used to evaluate allele transmission from heterozygous parents to affected offspring. RESULTS: The TDT analysis revealed no significant deviation in the transmission of the MTHFR C677T alleles to CRF patients (51 vs. 49% for the C allele and T allele transmission, respectively). We observed a significant relationship between MTHFR genotypes and total plasma homocysteine (tHcy), as well as folate concentration. Also, plasma tHcy and folate were negatively correlated. CONCLUSION: Our results did not show any association between the MTHFR reductase C677T polymorphism and the increased risk of the development of end-stage renal disease. Whether this polymorphism contributes to the faster rate of decline of renal function in renal patients, must be evaluated further.     

MTHFR c.677C>T polymorphism as an independent predictor of peak bone mass in Danish men--results from the Odense Androgen Study

The MTHFR c.677C>T polymorphism has been shown to have significant effects on skeletal health in middle-aged to elderly women and men. Despite an accumulating amount of data on MTHFR genetics and the association between homocysteine levels and fracture, it remains unknown if MTHFR c.677C>T genotype affects bone mineral accretion in youth or bone loss in adulthood. The purpose of this cross-sectional study was to examine the effects of this common allelic polymorphism on peak bone mass and bone turnover. We performed MTHFR genotyping in 780 healthy Danish men, aged 20 to 29 years, participating in the Odense Androgen Study. BMD at the spine, hip and whole-body was measured using a Hologic QDR-4500 densitometer. Genotype frequencies were compatible with Hardy-Weinberg equilibrium. Spine BMD was significantly associated with genotype, with a decrease in BMD of 0.20 SD for each copy of the T-allele. Effects were independent of age, BMI, smoking and serum levels of vitamin D and IGF-I. Associations with BMD of the hip and whole body were short of statistical significance. MTHFR genotype showed no association with the bone turnover markers 1-CTP, bone specific alkaline phosphatase or osteocalcin. In conclusion, significant skeletal effects of this common polymorphism were present at the lumbar spine in men at the age of 25 years.