Biomedical subjects

Martin den Heijer

Publications and source records attributed to Martin den Heijer.

At least 19 recordsLinked to original sources

PubMed2007

No interaction between factor V Leiden and hyperhomocysteinemia or MTHFR 677TT genotype in venous thrombosis. Results of a meta-analysis of published studies and a large case-only study.

Homocysteine may have a thrombogenic effect through inhibition of inactivation of factor Va by activated protein C. Because factor V Leiden also leads to resistance of factor V to activated protein C, it would be possible that both factors show interaction for the risk of venous thrombosis. This has been reported in some studies, but not in others. We performed a metaanalysis to investigate a possible interaction between factor V Leiden and hyperhomocysteinemia, including 825 subjects with venous thrombosis and 2,109 controls, for the risk of venous thrombosis. In addition, we assessed a possible interaction between factor V Leiden and MTHFR 677TT genotype (the most common genetic determinant of homocysteine levels), including 2,547 subjects with venous thrombosis and 4,327 controls. We also investigated the interaction effect of factor V Leiden and hyperhomocysteinemia in a large case-only study using data of the VITRO study, including 2,077 subjects with first-time venous thrombosis. The meta-analysis yielded no evidence for additive or multiplicative interaction between factor V Leiden and hyperhomocysteinemia [relative excess risk due to interaction (RERI) -1.77 (95%CI -8.61 to 5.08) and multiplicative interaction term 0.86 (95%CI 0.35 to 2.14)]. The case-only study also showed no interaction effect [0.58 (95%CI 0.29 to 1.16)]. Also the metaanalysis on factor V Leiden and MTHFR 677TT yielded no evidence of interaction; RERI 0.13 (95%CI -3.60 to 3.86) and multiplicative interaction term 1.23 (95%CI 0.72 to 2.11). Both the meta-analyses of published studies and a large case-only study did not show evidence for interaction between factor V Leiden and hyperhomocysteinemia for risk of venous thrombosis.

Factor V↗

PubMed2006

Accurate, high-throughput typing of copy number variation using paralogue ratios from dispersed repeats.

Recent work has demonstrated an unexpected prevalence of copy number variation in the human genome, and has highlighted the part this variation may play in predisposition to common phenotypes. Some important genes vary in number over a high range (e.g. DEFB4, which commonly varies between two and seven copies), and have posed formidable technical challenges for accurate copy number typing, so that there are no simple, cheap, high-throughput approaches suitable for large-scale screening. We have developed a simple comparative PCR method based on dispersed repeat sequences, using a single pair of precisely designed primers to amplify products simultaneously from both test and reference loci, which are subsequently distinguished and quantified via internal sequence differences. We have validated the method for the measurement of copy number at DEFB4 by comparison of results from >800 DNA samples with copy number measurements by MAPH/REDVR, MLPA and array-CGH. The new Paralogue Ratio Test (PRT) method can require as little as 10 ng genomic DNA, appears to be comparable in accuracy to the other methods, and for the first time provides a rapid, simple and inexpensive method for copy number analysis, suitable for application to typing thousands of samples in large case-control association studies.

DNA↗

PubMed2006

The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida.

The methionine synthase reductase (MTRR) enzyme restores methionine synthase (MTR) enzyme activity and therefore plays an essential role in homocysteine remethylation. In some studies, the 66A>G polymorphism in the MTRR gene was associated with increased neural tube defect (NTD) risk. Using a case-control design, we studied the association between the MTRR 66A>G polymorphism and spina bifida risk in 121 mothers, 109 spina bifida patients, 292 control women, and 234 pediatric controls. Possible interactions between the MTRR 66A>G variant and the MTR 2756A>G polymorphism, the MTHFR 677C>T variant, plasma vitamin B12, and plasma methylmalonic acid (MMA) levels were examined in the 121 mothers and 292 control women. Meta-analyses were conducted to set the results of the case-control study in the context of eligible literature on the relation between the MTRR 66A>G variant and NTD risk. Finally, a transmission disequilibrium test was performed for 82 complete mother-father-child triads to test for preferential transmission of the MTRR risk allele. In our case-control study, the MTRR 66A>G polymorphism had no influence on spina bifida risk in children [odds ratio (OR) 0.6, 95% confidence interval (CI) 0.4-1.1]. The MTRR 66GG genotype increased maternal spina bifida risk by 2.1-fold (OR 2.1, 95% CI 1.3-3.3). This risk became more pronounced in combination with the MTHFR 677TT genotype (OR 4.0, 95% CI 1.3-12.5). Moreover, we demonstrate a possible interaction between the MTRR 66GG genotype and high plasma MMA levels (OR 5.5, 95% CI 2.2-13.5). The meta-analyses demonstrated that the maternal MTRR 66GG genotype was associated with an overall 55% (95% CI 1.04-2.30) increase in NTD risk and that the MTRR 66GG genotype did not increase NTD risk in children (OR 0.96, 95% CI 0.46-2.01). These data show that the MTRR 66GG genotype is a maternal risk factor for spina bifida especially when intracellular vitamin B12 status is low.

Adolescent↗

PubMed2006

Molecular genetic analysis of the human dihydrofolate reductase gene: relation with plasma total homocysteine, serum and red blood cell folate levels.

Disturbances in folate metabolism may increase the risk of certain malignancies, congenital defects and cardiovascular diseases. The gene dihydrofolate reductase (DHFR) is primarily involved in the reduction of dihydrofolate, generated during thymidylate synthesis, to tetrahydrofolate in order to maintain adequate amounts of folate for DNA synthesis and homocysteine remethylation. In order to reveal possible variation that may affect plasma total homocysteine (tHcy), serum folate and red blood cell (RBC) folate levels, we sequenced the DHFR coding region as well as the intron-exon boundaries and DHFR flanking regions from 20 Caucasian individuals. We identified a 9-bp repeat in the 5'-upstream region that partially overlapped with the 5'-untranslated region, and several single-nucleotide polymorphisms, all in non-coding regions. We screened subjects for the 9-bp repeat (n=417), as well as the recently reported 19-bp deletion in intron 1 (n=330), and assessed their associations with plasma tHcy, serum and RBC folate levels. The 19-bp del/del genotype was associated with a lower plasma tHcy (-14.4% [95% confidence interval: -23.5 to -4.5], P=0.006) compared with the wild-type genotype. This may suggest that intracellular folate levels are affected.

5' Flanking Region↗

PubMed2006

Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: A randomized, placebo-controlled, double-blind trial.

The Vitamins and Thrombosis (VITRO) study investigated the effect of homocysteine lowering by daily supplementation of B vitamins on the risk reduction of deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients between 20 to 80 years old with a first objectively confirmed proximal DVT or PE in the absence of major risk factors and a homocysteine concentration above the 75th percentile of a reference group were asked to participate (hyperhomocysteinemic group). A similar study was conducted in a random sample of patients with a homocysteine below the 75th percentile of the reference group (normohomocysteinemic group). After informed consent was obtained, patients were randomized to daily multivitamin supplementation (5 mg folic acid, 50 mg pyridoxine, and 0.4 mg cyanocobalamin) or placebo and were followed for 2.5 years. End points were objectively diagnosed recurrent DVT or PE. A total of 701 patients were enrolled (360 in the hyperhomocysteinemic and 341 in the normohomocysteinemic group). The number of recurrent events of venous thrombosis was 43 of 353 in the vitamin group (54/1000 py) and 50 of 348 in the placebo group (64/1000 py). The hazard ratio associated with vitamin treatment was 0.84 (95% CI, 0.56-1.26): 1.14 (95% CI, 0.65-1.98) in the hyperhomocysteinemic group and 0.58 (95% CI, 0.31-1.07) in the normohomocysteinemic group. The results of our study do not show that homocysteine lowering by B vitamin supplementation prevents recurrent venous thrombosis.

Adolescent↗

PubMed2006

Polymorphisms in the E-cadherin (CDH1) gene promoter and the risk of bladder cancer.

AIM: E-cadherin plays a role in carcinogenesis. For two genetic polymorphisms in the gene (CDH1) promoter, a reduced transcription has been reported: a C/A single nucleotide polymorphism (SNP) and a G/GA SNP at -160 bp and -347 bp, respectively, upstream of the transcriptional start site. We studied the association between both polymorphisms and the risk of bladder cancer. METHODS: One hundred and ninety-seven patients with bladder cancer and 344 population controls were genotyped and haplotyped for both SNPs. RESULTS: A borderline significantly increased risk for bladder cancer was found for A allele carriers (OR 1.36; 95% CI: 0.96-1.94). We did not find any association between the -347 G/GA SNP and bladder cancer. Haplotype analyses did not yield much stronger associations with bladder cancer than the -160 C/A genotype analyses. CONCLUSION: This study supports earlier suggestions that the -160 C/A SNP in the CDH1 promoter is a risk factor for bladder cancer.

Adult↗

PubMed2006

Abdominal aortic aneurysm is associated with high serum levels of tenascin-X and decreased aneurysmal tissue tenascin-X.

BACKGROUND: Tenascin-X is a large extracellular matrix protein that is abundantly expressed in several connective tissues. A 140-kDa C-terminal fragment of tenascin-X is present in human serum. Complete deficiency of tenascin-X is associated with Ehlers-Danlos syndrome, and these patients show major connective tissue alterations in their skin, as well as blood vessel fragility. In this study, we investigated whether tenascin-X is present in normal human aorta and abdominal aortic aneurysm (AAA) tissues and whether an association exists between serum tenascin-X levels and AAA. METHODS AND RESULTS: Five normal aortas and 5 AAA tissues were immunostained for tenascin-X and elastin. Tenascin-X was present throughout the entire aorta and was especially abundant near the elastic lamellae, whereas tenascin-X expression was strongly decreased in AAA tissue. Measurement of tenascin-X serum concentration by enzyme-linked immunosorbent assay (ELISA) in 87 AAA patients and 86 controls demonstrated an increasing risk for AAA with increasing tenascin-X serum concentrations. After adjustment for established risk factors, tenascin-X serum concentrations in the highest quartile were associated with a 5-fold increase in risk of AAA (odds ratio, 5.3; 95% confidence interval, 2.0 to 13.8). CONCLUSIONS: Tenascin-X expression is markedly decreased in AAA tissue, and AAA is associated with high serum concentrations of tenascin-X.

Aged↗

PubMed2006

Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation.

AIMS: Periconceptional folate supplementation prevents neural tube defects and possibly congenital heart defects (CHD) as well. The search for candidate genes involved in the folate metabolism includes the methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism. We studied the association between MTHFR 677C > T variants and CHD risk. The interaction with periconceptional folate supplementation was also investigated. METHODS AND RESULTS: A case-control study and a family-based transmission disequilibrium test (TDT) were conducted to explore this association. In 133 triads, the TDT revealed no association of the fetal 677T allele with the development of a heart defect. In 158 mothers with a CHD-affected child, the maternal MTHFR 677CT and TT genotypes in combination with no use of periconceptional folate supplements were associated with, respectively, a three-fold (OR 3.3 95% CI 1.46-7.32) and six-fold (OR 6.3 95% CI 2.32-17.27) increased risk for conotruncal heart defects in offspring. In a case-only study, the interaction between periconceptional folate supplementation and maternal MTHFR genotype was significant (P = 0.012). CONCLUSION: The maternal MTHFR 677C > T variants are a risk factor for CHD in offspring, confined to conotruncal heart defects. A gene-environment interaction between maternal MTFHR 677CT and TT genotypes with periconceptional folate supplementation was observed. These findings provide a mechanism of the protective role of folate and support the thesis that periconceptional folate supplementation might prevent CHD.

Adolescent↗

PubMed2006

Neural tube defects and folate: case far from closed.

Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents approximately 50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.

Animals↗

PubMed2006

MTRR 66A>G polymorphism in relation to congenital heart defects.

BACKGROUND: Evidence is accumulating that periconceptional folic acid supplementation may prevent congenital heart defects (CHD). The methionine synthase reductase (MTRR) enzyme restores methionine synthase (MTR) enzyme activity and therefore plays an essential role in the folate- and vitamin B(12)-dependent remethylation of homocysteine to methionine. We studied the influence of the MTRR 66A>G polymorphism on CHD risk. In addition, possible interaction between this variant and plasma methylmalonic acid (MMA) concentrations, as an indicator of intracellular vitamin B(12) status, was investigated. METHODS: Case-control and case-parental studies were conducted to explore this association. In total, 169 CHD patients and 213 child controls, and 159 mothers with a CHD-affected child and 245 female controls were included. RESULTS: The maternal MTRR 66AG and GG vs. AA genotypes revealed an odds ratio (OR) of 1.3 (95% CI 0.72-2.20) and 1.3 (0.71-2.37), respectively. Family-based transmission disequilibrium analysis did not reveal a significant association of the foetal 66G allele with the development of a heart defect in children (chi(2)=2.94, p=0.086). Maternal 66GG genotype in combination with high MMA concentration (above the 80th percentile) was associated with a three-fold (OR 3.3, 95% CI 0.86-12.50) increased risk for all types of CHD in offspring. CONCLUSIONS: These data indicate that maternal MTRR 66A>G polymorphism is not a risk factor for CHD. Maternal MTRR 66GG genotype with compromised vitamin B(12) status may possibly result in increased CHD risk. In addition to folate, vitamin B(12) supplementation may contribute to the prevention of CHD.

Adolescent↗

PubMed2006

No added value of the methionine loading task in assessment for venous thrombosis and cardiovascular disease risk.

Homocysteine is a risk factor for cardiovascular disease and venous thrombosis. Clinical guidelines differ in their recommendation whether or not to measure homocysteine after methionine loading. In this study, we investigated the added value of the methionine loading test next to fasting homocysteine levels for identifying subjects at risk for venous thrombosis or cardiovascular disease, using Receiver Operating Characteristic (ROC) curves. The analysis was performed in 185 patients with recurrent venous thrombosis, 130 patients with cardiovascular disease and 601 controls. The discriminatory power of the fasting homocysteine measurement alone for identifying subjects at risk of venous thrombosis expressed as the area under the ROC curve (AUC) was 0.61 (95%CI 0.56-0.66). Using both a fasting homocysteine measurement and a methionine loading test together yielded a similar AUC of 0.65 (95%CI 0.60-0.69), indicating no added value of methionine loading next to fasting homocysteine measurement in identifying subjects at risk for thrombosis. Similar results where found for cardiovascular disease,with an AUC of 0.62 (95%CI 0.57-0.67) for the fasting homocysteine measurement alone and an AUC of 0.62 (95% CI0.57-0.67) for the combination of both the fasting and the post-load homocysteine measurement. The methionine loading test has no added value next to measuring fasting homocysteine levels for identifying subjects at risk for venous thrombosis or cardiovascular disease and for that reason should not be used in clinical practice.

Aged↗

PubMed2006

Low fasting methionine concentration as a novel risk factor for recurrent venous thrombosis.

Hyperhomocysteinemia is a risk factor for venous thrombosis, but the underlying mechanism is unclear. If the thiol-group of homocysteine interferes with components of the clotting system, we expect that high cysteine will be also a risk factor for venous thrombosis. If high homocysteine reflects a disturbed methyl-group donation by S-adenosylmethionine, we expect that low methionine will be a risk factor for thrombosis. We performed a case-control study in 185 patients with recurrent venous thrombosis and in 500 control subjects. We determined methionine, homocysteine, cysteine and assessed the associated thrombotic risk. Low fasting methionine was associated with an increased risk on recurrent venous thrombosis [OR(bottom vs. top quartile) = 3.3 (95%CI 1.9-5.7)]. Low methionine remained a risk factor [OR(bottom vs. top quartile) = 3.5 (95%CI 2.0-6.0)] after adjusting for homocysteine and cysteine, whereas the thrombotic risk for homocysteine was lost [OR = 1.0 (95%CI 0.6-1.9)] after adjustment. Cysteine yielded a highest odds ratio of 2.1(top vs. bottom quartile) (95%CI 1.0-4.0) after adjustment. In conclusion, we found that low fasting methionine is a risk factor for recurrent venous thrombosis. This risk association was stronger for methionine than for homocysteine or cysteine. This supports the hypothesis that impaired methylation may be involved in the pathogenesis of venous thrombosis.

Adult↗

PubMed2005

Thyroid function and prevalence of anti-thyroperoxidase antibodies in a population with borderline sufficient iodine intake: influences of age and sex.

BACKGROUND: We present a large European population-based study of thyroid function, performed in a population with longstanding borderline sufficient iodine intake. METHODS: The Nijmegen Biomedical Study is a population-based survey conducted in the eastern part of The Netherlands. Randomly selected inhabitants received a postal questionnaire on lifestyle and medical history, which was filled out by 9371 individuals (41.7%). We measured serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), and anti-thyroperoxidase antibodies (TPOAbs) in 6434 responders. A reference population of 5167 individuals was selected by excluding those at risk for thyroid disease. RESULTS: Overt thyrotoxicosis was found in 0.4% of the total population and subclinical thyrotoxicosis in 0.8%. Overt hypothyroidism was found in 0.4% and subclinical hypothyroidism in 4.0%. In individuals older than 60 years, mean FT4 concentrations increased with age. Mean TSH decreased with age, from 1.46 mIU/L at 18-24 years to 1.07 mIU/L after 85 years. The mean TSH in the total population did not differ from the mean TSH in the reference population; the exclusion of those at risk for thyroid disease, however, lowered the upper limit of the TSH reference interval considerably. In the total population, 8.6% of males and 18.5% of females had positive TPOAbs. The presence of TPOAbs was associated with abnormally high and low TSH concentrations. CONCLUSION: In inhabitants of the eastern part of The Netherlands, serum TSH gradually decreases with age, whereas after age 60, serum FT4 increases, possibly because of the development of thyroid autonomy after longstanding borderline sufficient iodine intake.

Adolescent↗

PubMed2005

Sequential balancing: a simple method for treatment allocation in clinical trials.

Although minimisation methods have frequently been advocated for treatment allocation in clinical trials, they are not widely used. As this may partly be due to the complexity of the methods, we devised a new and simple minimisation method to balance for prognostic factors, called sequential balancing. Each factor is dealt with sequentially and when a new subject enters the trial, he or she is allocated the treatment that leads to improved balance of the first factor over the treatments. If the balance of the first factor was already satisfactory, then the treatment is allocated that leads to improved balance of the second factor and so on. The algorithm requires no calculations. We simulated a realistic trial and compared the performance of this method to the performance of alternative allocation strategies: the variance minimisation method, simple randomisation and stratification. The sequential balancing method led to better balance than randomisation and stratification. In the case of four factors or less, the performance of the sequential balancing method and the variance minimisation method were comparable and the sequence of the factors was not very relevant. When more factors were introduced, the balance of the sequential method remained comparable with the balance achieved with the variance minimisation method for the first four factors, but it started to decrease from the fifth factor onwards. We conclude that the ease and simplicity of the new method make it an attractive option when balance is required for four factors or less. If there are more than four factors, the sequential balancing method may still be an acceptable option, but the advantage of simplicity has to be weighed against the loss of performance compared to other minimisation methods.

Age Factors↗

PubMed2005

Decreased adiponectin levels in familial combined hyperlipidemia patients contribute to the atherogenic lipid profile.

Familial combined hyperlipidemia (FCH) is characterized by increased levels of total cholesterol, triglycerides, and/or apolipoprotein B. Other features of FCH are obesity and insulin resistance. Adiponectin is a secretory product of the adipose tissue. Low levels of adiponectin are associated with insulin resistance and accelerated atherosclerosis. The aim of this study was to determine whether decreased adiponectin levels are associated with FCH and its phenotypes. The study population comprised 644 subjects, including 158 patients with FCH. Serum adiponectin levels were determined using a commercially available ELISA. For both males and females, the mean adiponectin level (microg/ml) was significantly lower in FCH patients [2.0 (1.8-2.2) and 2.5 (2.3-2.8), respectively] compared with normolipidemic relatives [2.3 (2.2-2.5) and 3.1 (2.8-3.3), respectively] and spouses [2.4 (2.1-2.7) and 3.2 (2.8-3.6), respectively]. These differences remain significant after adjusting for waist circumference and insulin resistance. Low adiponectin level in FCH patients was a superior independent predictor of the atherogenic lipid profile, including high triglyceride levels, low HDL-cholesterol levels, and the amount of small, dense LDL present, compared with both obesity and insulin resistance. Low adiponectin levels may contribute to the atherogenic lipid profile in FCH, independent of insulin resistance and obesity, as measured by waist circumference. This finding implies a role of adipose tissue metabolism in the pathophysiology of FCH.

Adiponectin↗

PubMed2005

Stable-isotope dilution liquid chromatography-electrospray injection tandem mass spectrometry method for fast, selective measurement of S-adenosylmethionine and S-adenosylhomocysteine in plasma.

BACKGROUND: It has been postulated that changes in S-adenosylhomocysteine (AdoHcy), a potent inhibitor of transmethylation, provide a mechanism by which increased homocysteine causes its detrimental effects. We aimed to develop a rapid and sensitive method to measure AdoHcy and its precursor S-adenosylmethionine (AdoMet). METHODS: We used stable-isotope dilution liquid chromatography-electrospray injection tandem mass spectrometry (LC-ESI-MS/MS) to measure AdoMet and AdoHcy in plasma. Acetic acid was added to prevent AdoMet degradation. Solid-phase extraction (SPE) columns containing phenylboronic acid were used to bind AdoMet, AdoHcy, and their internal standards and for sample cleanup. An HPLC C(18) column directly coupled to the LC-MS/MS was used for separation and detection. RESULTS: In plasma samples, the interassay CVs for AdoMet and AdoHcy were 3.9% and 8.3%, and the intraassay CVs were 4.2% and 6.7%, respectively. Mean recoveries were 94.5% for AdoMet and 96.8% for AdoHcy. The quantification limits were 2.0 and 1.0 nmol/L for AdoMet and AdoHcy, respectively. Immediate acidification of the plasma samples with acetic acid prevented the observed AdoMet degradation. In a group of controls (mean plasma total Hcy, 11.2 mumol/L), plasma AdoMet and AdoHcy were 94.5 and 12.3 nmol/L, respectively. CONCLUSIONS: Stable-isotope dilution LC-ESI-MS/MS allows sensitive and rapid measurement of AdoMet and AdoHcy. The SPE columns enable simple cleanup, and no metabolite derivatization is needed. The instability of AdoMet is a serious problem and can be prevented easily by immediate acidification of samples.

Chromatography, Liquid↗

PubMed2005

Elevated leptin levels in subjects with familial combined hyperlipidemia are associated with the increased risk for CVD.

Familial combined hyperlipidemia (FCH) is characterized by hypercholesterolemia and/or hypertriglyceridemia and is associated with premature cardiovascular disease (CVD). Other features of FCH are obesity and insulin resistance. Serum leptin levels have been associated with obesity, insulin resistance and CVD. The aim of this study was to determine whether increased leptin levels contribute to the FCH phenotype and its increased risk for CVD. The study population comprised 644 subjects, including 158 FCH patients. Leptin levels were determined, using a commercially available ELISA. For both males and females, the mean leptin level (ng/ml) was higher in FCH patients compared to normolipidemic relatives and spouses. However, after standardization for BMI and insulin resistance, these differences disappeared. The 90th percentile of the leptin level, standardized for BMI, insulin resistance and gender, was associated with an increased risk for CVD in FCH patients (odds ratio=2.9, 95% CI=1.1-8.0) and in non-FCH subjects (odds ratio=3.4, 95% CI=1.3-9.0). The overall increased risk for CVD, associated with a leptin level >90th percentile, was 3.3 (95% CI=1.7-6.4). We conclude that in patients with FCH, leptin levels are increased in proportion to their higher BMI and the presence of insulin resistance. These increased leptin levels are associated with an increased risk for CVD both in FCH patients and non-FCH subjects, independent of BMI, insulin resistance and gender.

Adult↗

PubMed2005

Homocysteine levels--before and after methionine loading--in 51 Dutch families.

Elevated levels of homocysteine are a risk factor for vascular disease, thrombosis, neural tube defects and dementia. The 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene appears to be the most important single determinant of plasma homocysteine concentration. In the current study, we estimated heritability and fit a series of models of inheritance for both fasting and postmethionine-load homocysteine levels in the HOFAM-study (HOmocysteine in FAMilies study), which included 306 participants from 51 pedigrees, ascertained through a hyperhomocysteinemic proband. The crude heritability was 21.6% for fasting and 67.5% for postloading homocysteine. After adjustment for MTHFR 677C>T genotype, heritability dropped to 5.2 and 63.9%, respectively. Segregation analysis revealed that a nongenetic model with equal transmission was the best fitting and most parsimonious model for fasting homocysteine levels, while a two-distribution, Mendelian model with residual familial correlation was best for postmethionine-load homocysteine levels. This study shows that postload homocysteine levels have a stronger genetic determination than do fasting homocysteine levels. The heritability of postload homocysteine levels were not strongly affected by adjustment for MTHFR 677C>T genotype, in contrast to fasting homocysteine levels. Further studies are needed to identify the genes responsible for the inheritance of postload homocysteine levels.

Adult↗