To evaluate C to T substitution at nucleotide 677 of N(5), N(10)-methylenetetrahydrofolate reductase gene in women with prior preeclamptic or normotensive pregnancies.
Methylenetetrahydrofolate reductase genotypes were determined in 113 Finnish women with preeclamptic first pregnancies and 103 controls with one or more normotensive pregnancies, using polymerase chain reaction and restriction enzyme analysis. Preeclampsia was defined as severe in 100 women who fulfilled one or more of the subsequent criteria: systolic blood pressure (BP) at least 160 mmHg, diastolic BP at least 110 mmHg, or proteinuria at least 2 g per 24-hour urine collection.
There were no significant differences in prevalences of the methylenetetrahydrofolate reductase genotypes (CC, CT, and TT) between groups (57%, 40%, and 3% in the preeclamptic group and 54%, 39%, and 7%, respectively, in controls). The frequency of the T677 allele was 0.23 in the preeclamptic group and 0.26 in the control group (difference 0.03; 95% confidence interval -0.08, 0.14; P =.51). Our sample had 60% power to detect a difference of the allele frequencies similar to that (0.12) reported previously. The result was similar when analysis was restricted to patients with severe preeclampsia (T677 allele frequency 0.22).
A carrier status for the T677 allele of the methylenetetrahydrofolate reductase gene does not predispose to preeclampsia, at least in the Finnish population.
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.
The polyamine system has been implicated in a number of psychiatric conditions, which display both alterations in polyamine levels and altered expression of genes related to polyamine metabolism. Studies have identified associations between genetic variants in spermidine/spermine N1-acetyltransferase (SAT1) and both anxiety and suicide, and several polymorphisms appear to play important roles in determining gene expression.
We genotyped 63 polymorphisms, spread across four polyaminergic genes (SAT1, spermine synthase (SMS), spermine oxidase (SMOX), and ornithine aminotransferase like-1 (OATL1)), in 1255 French-Canadian individuals who have been followed longitudinally for 22 years. We assessed univariate associations with anxiety, mood disorders, and attempted suicide, as assessed during early adulthood. We also investigated the involvement of gene-environment interactions in terms of childhood abuse, and assessed internalizing and externalizing symptoms as endophenotypes mediating these interactions. Overall, each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). Several SAT1 polymorphisms displayed disease-specific risk alleles, and polymorphisms in this gene were involved in gene-gene interactions with SMS to confer risk for anxiety disorders, as well as gene-environment interactions between childhood physical abuse and mood disorders. Externalizing behaviors demonstrated significant mediation with regards to the association between OATL1 and attempted suicide, however there was no evidence that externalizing or internalizing behaviors were appropriate endophenotypes to explain the associations with mood or anxiety disorders. Finally, childhood sexual abuse did not demonstrate mediating influences on any of our outcomes.
These results demonstrate that genetic variants in polyaminergic genes are associated with psychiatric conditions, each of which involves a set of separate and distinct risk alleles. As several of these polymorphisms are associated with gene expression, these findings may provide mechanisms to explain the alterations in polyamine metabolism which have been observed in psychiatric disorders.
Cites: Am J Med Genet B Neuropsychiatr Genet. 2003 Apr 1;118B(1):36-4012627464
To investigate genetic factors of risk (RF) to develop venous thrombosis and pulmonary artery thromboembolism (PATE) in population of central Russia.
We studied polymorphism of the genes of coagulation factor II (G20210A), factor V (G1691A) and methylentetrahydrofolatereductase (MTHFR) with polymerase chain reaction and restriction analysis of DNA amplified sites. We estimated prevalence of the mutations in healthy population and in patients with flebothrombosis as well as effects of the mutations on a PATE rate in patients with thrombosis. We examined 97 patients with documented flebothrombosis. PATE was detected in 54 of them. The control group consisted of 56 healthy volunteers matched by age and gender.
G1691A mutation in the gene of coagulation factor V (Leiden mutation of factor V--LMFV) in healthy population occurred in 3.6%, in patients with flebothromboses--in 19.6% (OR = 6.58; 95% CI from 1.47 to 29.42; p = 0.006). Heterozygous mutation G20210A in prothrombine gene was detected in 8 (8.2%) patients (p = 0.027), while this mutation was registered in none controls. Polymorphism of MTHFR gene (C677T) was seen both in the control and patients (60.7 and 52.6%, respectively). LMFV occurrence in patients with flebothrombosis and PATE is less than in patients with flebothrombosis without TEPA (16.7 and 23%, respectively). The PATE risk is significantly higher in carriers of mutant allele 677CT and 677TT of MTHFR compared to patients free of this mutation (OR = 3.11; CI 95% from 1.35 to 7.15; p = 0.006). Homozygous inheritance of this mutation in males combined with PATE in 100% cases. Of 8 carriers of heterozygous mutation G20210A in prothrombin gene PATE was detected in 5 carriers.
LMFV and mutation G20210A in prothrombin gene are genetic risk factors of venous thrombosis. LMFV is not a PATE risk factor. Mutation C677T in MTHFR gene has no influence on the risk of venous thromboses but makes PATE much more probable. This suggests that it may be a genetic risk factor of PATE in this disease.
Homozygotes (TT genotype) for the C677T mutation in the gene of methylenetetrahydrofolate reductase (C677T/MTHFR mutation) constitute about 12% of the Caucasian population. They have mild hyperhomocysteinemia which is an established risk factor for cardiovascular disease. If the mutation is associated with premature death its prevalence is expected to be lower in the elderly than in the young. To test this we determined the C677T/MTHFR genotypes in 220 newborn and 222 elderly 80-108-year-old Swedes. In the newborn and elderly, the allele frequency, of the C677T/MTHFR mutation was 29.1 and 27.0% and the mutant homozygote frequency was 10.0 and 9.5%, respectively. In a meta analysis of the present and three previous studies including a total of 1388 elderly and 1415 younger subjects, the odds ratio (OR) representing the likelihood of the TT genotype to attain old age relative to the CC genotype was 0.87 (95% confidence interval (CI), 0.69-1.11) and relative to both the CC and CT genotypes was 0.83 (95% CI, 0.66-1.04). This finding does not suggest that the C677T/MTHFR mutation is a strong risk factor for diseases frequently leading to premature death.
Increased homocysteine levels are a risk factor for atherosclerosis and its sequelae. A common genetic mutation in methylenetetrahydrofolate reductase (MTHFR), an enzyme required for efficient homocysteine metabolism, creates a thermolabile enzyme with reduced activity. We determined the prevalence of this mutation in many subjects with and without vascular disease and related it to homocysteine and folate levels.
DNA from 247 older subjects with vascular disease and 594 healthy subjects without vascular disease (in three different control groups) was screened for the MTHFR 677 C-to-T mutation. Within each group, 9% to 17% of the subjects were homozygous for this mutation, and the mutant allele frequency was 31% to 39%. The genotype distributions, homozygote frequencies, and allele frequencies did not differ significantly between the study groups. In the vascular disease subjects, despite significantly lower folate levels in MTHFR homozygotes, there was no significant difference in homocysteine levels among the MTHFR genotype groups. The negative slope of the regression line relating homocysteine and folate was significantly steeper for those with a homozygous MTHFR mutation compared with those without this mutation.
Although the thermolabile MTHFR mutation is very common, it does not appear to be a significant genetic risk factor for typical late-onset vascular disease. Because MTHFR homozygotes have increased homocysteine with low folate levels, this mutation may contribute to early-onset or familial vascular disease. The genotype dependence of the folate-homocysteine correlation further suggests that homozygotes for this mutation may have both an exaggerated hyperhomocysteinemic response to folic acid depletion and a better response to folic acid therapy.
From 1992-93, we screened 18,043 subjects, aged 40-67 yr, and found 67 cases (0.4%) with total plasma homocysteine (tHcy) > or = 40 micromol/liter. Compared to 329 controls, the cases had lower plasma folate and cobalamin levels, lower intake of vitamin supplements, consumed more coffee, and were more frequently smokers. Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene was observed in 73.1% of the cases and 10.2% of the controls. Only seven cases with cobalamin deficiency and one with homocystinuria received specific therapeutic instructions. 2 yr after the screening, 58 subjects were reinvestigated. 41 still had tHcy > 20 micromol/liter, and in 37 of these, intervention with low dose folic acid (0.2 mg/d) was started. Notably, 34 of 37 (92%) had homozygosity for the C677T mutation. Plasma tHcy was reduced in all but two after 7 wk, and became normal within 7 mo in 21 of 37 subjects. Most of the remaining subjects obtained a normal tHcy level with 5 mg/d of folic acid. We conclude that most subjects with hyperhomocysteinemia > or = 40 micromol/liter in the general population have the C677T mutation combined with low folate status. Daily supplement of low dose folic acid will reduce and often normalize their tHcy level.
Folic acid and the methylenetetrahydrofolate reductase (MTHFR) gene have both been implicated in the etiology of orofacial clefts. The authors selected 261 case-parent triads (173 cases with cleft lip with or without cleft palate (CL/P) and 88 cases with cleft palate only (CPO)) from a Norwegian population-based study of orofacial clefts (May 1996-1998). A case-parent triad design was used to examine whether MTHFR variants C677T and A1298C, and their haplotypes, are risk factors for orofacial clefts. Among CL/P cases, the child's genotype at C677T or A1298C did not influence the risk. However, children of mothers carrying the C677T variant allele had a lower risk of CL/P. For CPO, children carrying the C677T variant allele had about a twofold increased risk, whereas the mother's genotypes did not contribute to the risk. The haplotype-based transmission/disequilibrium test showed that except for 677T/1298A (p = 0.06), none of the other haplotypes showed evidence of excess transmission to the offspring. The authors also explored interaction of C677T with maternal use of folic acid among children with CPO. Surprisingly, the risk associated with the child's carrying either CT or TT was higher (fourfold) when the mother used folic acid. These findings suggest a possible role of MTHFR and folic acid in the causation of orofacial clefts, but the strength and direction of these effects remain to be clarified.
To assess the folate status of Finnish adults using plasma folate and homocysteine as biomarkers and to evaluate dietary and supplementary folate intakes.
Plasma folate, vitamin B(12) and total homocysteine (tHcy) were determined in a random sample of 643 subjects aged 25-74 y living in the Helsinki area. The methylenetetrahydrofolate reductase (MTHFR)-genotypes were analyzed from a subsample (n=394). Dietary intake data by 24 h recall and use of vitamin supplements were collected.
Plasma folate was normal (>/=5 nmol/l) in 99% of subjects and optimal (>/=8 nmol/l) in terms of a minimum tHcy in 90%. Mean plasma folate of non-supplement users was 13.7 and 12.9 nmol/l and tHcy 11.3 and 9.2 micro mol/l for men and women, respectively. Elevated tHcy (>14 micro mol/l) was found in 11% of subjects. Homozygote frequency for MTHFR genotype TT was 5.0% and their plasma tHcy was 14.8 micro mol/l compared to the mean of the other subjects, 10.5 micro mol/l, P