Prevalence of prothrombin G20210A, factor V G1691A (Leiden), and methylenetetrahydrofolate reductase (MTHFR) C677T in seven different populations determined by multiplex allele-specific PCR.

Individuals belonging to six racial groups (African American, Asian Indian, Caucasian, Hispanic, Korean, Native American), and a seventh group comprised of referred patients with thrombosis were genotyped for the prothrombin G20210A mutation, the factor V G1691A (Leiden) mutation, and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation by multiplexed allele-specific PCR. The prothrombin 20210A and factor V 1691A allele frequencies in the thrombosis patients, 3.2% and 9.5%, were significantly higher than those in the random Caucasians, 1.3% and 1.8%, (p = 0.043 and p <0.001, respectively). The relative risk of venous thrombosis was determined to be 2.4-fold for carriers of the prothrombin 20210A allele (odds ratio = 2.54; 95% confidence interval = 0.94, 6.82) and 4.5-fold for carriers of the factor V 1691A allele (odds ratio = 5.06; 95% confidence interval = 2.25, 11.36). Among the seven populations, significant differences were observed in the MTHFR 677T allele distribution, however this mutation was not determined to be a risk factor for venous thrombosis in the patient group studied, either alone or in combination with the prothrombin 20210A and/or the factor V 1691A allele(s).     

Homocysteine and methylenetetrahydrofolate reductase polymorphism in Alzheimer's disease

Homocysteine metabolism is influenced by genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR 677 C-->T and 1298 A-->C) and transcobalamin genes (TCN1 776 C-->G ). We evaluated the association of homocysteine with Alzheimer's disease (AD) and the influence of related polymorphisms and APOE, in 180 cases and 181 controls from southern Italy. Homocysteine (upper tercile) was associated with AD risk, with an odds ratio of 2.8 (95% confidence interval (CI) 1.54-5.22, p=0.0008), which was increased 2.2- and 2.0-fold by MTHFR 677T (odds ratio 6.28, 95% CI 2.88-16.20, p < 0.0001) and APOE epsilon4 (odds ratio: 5.60, 95% CI 1.12-28.05, p=0.0361), respectively. In conclusion, association of homocysteine with AD was aggravated by MTHFR 677T and APOE epsilon4 alleles.     

Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent--the N?mes Obstetricians and Haematologists Study5 (NOHA5).

BACKGROUND: Women with familial thrombophilia have an increased risk of still birth. We postulated that the presence of asymptomatic risk factors for venous thrombosis might be a risk factor for late foetal loss. METHODS: We performed a case-control study on the prevalence of heritable thrombophilic defects, of antiphospholipid-related markers and of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with at least one episode of late unexplained foetal loss and in control women with successful pregnancies. Partners of cases and controls were also studied. Written conclusions of the pathological examination of the placentas, when available, were also reviewed. RESULTS: We found at least one positive biological risk factor for venous thrombosis in 21.1% of the patients and in 3.9% of the controls (p < 10(-4)). In women, the crude odds ratio for still birth associated with any positive biological risk factor for venous thrombosis was 5.5, 95% confidence interval (95%CI) [3.4-9.0]. No difference was found between partners of cases and controls (5.2% and 4.7%). Using conditional logistic regression analysis, 4 adjusted risk factors for still birth remained: protein S deficiency, positive anti beta2 glycoprotein I IgG antibodies, positive anticardiolipin IgG antibodies and the factor V Leiden mutation. The C677T mutation in the MTHFR gene was not an individual risk factor but an homozygous genotype was strongly associated with the former 4 risk factors (16.8% of patients vs. 0.9% of controls). In women with such associations, still births always occurred in absence of folic acid supplementation during pregnancy. Available conclusions of pathological analysis of placentas were found to have a very high proportion of "maternal vascular disease of the placenta" in patients with at least one positive risk marker for thromboembolism, specially in case of association with the C677T MTHFR homozygous genotype, compared to patients with negative markers (p <10(-4)). CONCLUSIONS: Late foetal loss, through placenta thrombosis, may sometimes be the consequence of a maternal multifactorial prothrombotic state associating traditional heritable or acquired thrombosis risk factors to conditions predisposing to an acute mild hyperhomocysteinaemia (coexistence of a genetic predisposition with late pregnancy-related increased folate needs).     

Protein C and protein S deficiencies are the most important risk factors associated with thrombosis in Chinese venous thrombophilic patients in Taiwan

The relative risks (odds ratio, OR) of various risk factors for venous thrombophilia, including sex, antithrombin III, protein C (PC), protein S (PS) and plasminogen deficiencies, and C677T homozygous mutation of methylenetetrahydrofolate reductase gene were assessed using age matched (+/-5 years) conditional logistic regression analysis in 116 Chinese venous thrombophilic patients (58 males; 58 females; mean age 47.5+/-17.7 [SD] years) and 125 healthy controls (67 males; 58 females; mean age 45.5+/-15.7 years). None of the patients had prothrombin G20210A and factor V Leiden mutation or an activated PC sensitivity ratio of less than 2. One hundred and five age-matched patients and 105 controls were entered in this analysis. Only PC and PS deficiencies were significantly associated with increased risk for the development of thrombosis with an OR of 10.6 and 6.7, respectively. The findings of this study suggest that PC deficiency and PS deficiency are the most important risk factors for thrombosis in Chinese venous thrombophilic patients.     

Methylenehydrofolate reductase (C677T) polymorphism and large artery ischemic stroke subtypes

They‐They TP, Nadifi S, Rafai MA, Battas O, Slassi I. Methylenehydrofolate reductase (C677T) polymorphism and large artery ischemic stroke subtypes.
Acta Neurol Scand: 2011: 123: 105–110.
© 2010 John Wiley & Sons A/S. Background – The role for the methylenetetrahydrofolate reductase C677T gene variants in the risk of ischemic stroke is controversial. Method – This first case–control study including 91 cases affected by ischemic stroke and 182 controls matched for age, sex, and same area was conducted in Casablanca, Morocco. Allele and genotype frequency were characterized by using PCR followed by HinfI enzymatic digestion. Results – We found no statistic association of T allele carriers genetic factors with stroke; odds ratio, 1.1; 95% confidence interval (CI), 0.59–2.04, P = 0.303. The results shown significant association of T allele carriers genetic factors with atherothrombotic subtype stroke (n = 42); odds ratio, 2.1; 95% CI: 1.17–3.8; P = 0.012, and adjusted odds ratio of 6.5; 95% CI: 1.86–23.1, P = 0.003, for TT genotype variant compared with CC wild genotype. Conclusion – We suggested that MTHFR C677T variant may be a determinant of atherothrombotic event of ischemic stroke in Morocco.     

Interaction of heritable and estrogen-induced thrombophilia: possible etiologies for ischemic optic neuropathy and ischemic stroke

Our specific aim was to assess how thrombophilic exogenous estrogens interacted with heritable thrombophilias leading to non-arteritic ischemic optic neuropathy (NAION) and ischemic stroke. Coagulation measures were performed in a 74 year old patient and her immediate family. The proband had a 47 year history of 9 previous thrombotic episodes, and developed unilateral NAION 4 years after starting estrogen replacement therapy (ERT). The proband was heterozygous for two thrombophilic gene mutations (G20210A prothrombin gene, platelet glycoprotein IIIa P1A1/A2 polymorphism), and homozygous for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. Of 238 normal controls, none had these 3 gene mutations together. The proband's mother and brother had deep venous thrombosis (DVT). The proband's brother, sister, nephew, daughter, and two granddaughters were homozygous for the C677T MTHFR mutation. The proband's brother was heterozygous for the G20210A prothrombin gene mutation. The proband's niece was heterozygous for the G20210A prothrombin gene mutation, homozygous for the C677T MTHFR mutation, homozygous for the hypofibrinolytic 4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene, and heterozygous for the platelet glycoprotein IIIa P1A1/A2 polymorphism. Of 238 normal controls, none had the niece's combination of 4 gene mutations. When ERT-mediated thrombophilia was superimposed on the proband's heritable thrombophilias, unilateral ischemic optic neuropathy developed, her tenth thrombotic event over a 5 decade period. When estrogen-progestin oral contraceptives were given to the proband's niece, she had an ischemic stroke at age 22. Exogenous estrogen-mediated thrombophilia superimposed on heritable thrombophilia and hypofibrinolysis is associated with arterial and venous thrombi, and appears to be a preventable, and potentially reversible etiology for ischemic optic neuropathy and ischemic stroke.     

MTHFR C677T gene mutation as a risk factor for arterial stroke: a hospital based study.

Elevated homocysteine level is an independent risk factor for ischemic stroke, thrombotic and cardiovascular diseases. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating the levels of homocysteine. A C677T mutation in this gene results in reduced activity. Sixty-nine patients with arterial stroke, six patients with venous stroke (confirmed by computed tomography and/or magnetic resonance imaging) with hyperhomocysteinemia were selected for the study. Forty-nine subjects with no past history of stroke served as controls. MTHFR genotypes were determined by PCR using specific primers, followed by restriction digestion and gel analysis. The prevalence of the mutated homozygous and heterozygous C677T MTHFR genotype in the patients with arterial stroke was 1.4% (one of 69) and 31.88% (21 of 69), respectively. There frequency was 16.6% (one of six) and 33.3% (two of six) in venous stroke. The genotyping results from controls showed that there was only one heterozygote out of the 49 studied (2.08%). There was a significant difference between the control and the patient groups. Odds ratio for the probability of the C677T MTHFR gene mutation in the patients versus control group was 22.29 (95% CI 4.89-98.8). This indicates that C677T MTHFR mutation is strongly associated with arterial stroke especially in young adults. MTHFR allele evaluation will help in preventing/reducing morbidity caused by stroke.     

Folate,vitamin B12, homocysteine,and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study

BACKGROUND: An association between depression and folate status has been demonstrated in clinical studies, whereas data are sparse on the relationship between depression and other components of 1-carbon metabolism such as vitamin B12, homocysteine, and the methylenetetrahydrofolate reductase 677C-->T polymorphism. The relationship between anxiety and these components is less well known. This study examined the associations between folate, total homocysteine, vitamin B12, and the methylenetetrahydrofolate reductase 677C-->T polymorphism, and anxiety and depression in a large population-based study. METHODS: Anxiety and depression, measured by the Hospital Anxiety and Depression Scale, were assessed in 5948 subjects aged 46 to 49 years (mean, 47.4 years) and 70 to 74 years (mean, 71.9 years) from the Hordaland Homocysteine Study cohort. By means of logistic regression models, anxiety and depression scores were examined in relation to the factors listed above. RESULTS: Overall, hyperhomocysteinemia (plasma total homocysteine level > or =15.0 micro mol/L [> or =2.02 mg/dL]) (odds ratio, 1.90; 95% confidence interval, 1.11-3.25) and T/T methylenetetrahydrofolate reductase genotype (odds ratio, 1.69; 95% confidence interval, 1.09-2.62), but not low plasma folate or vitamin B12 levels, were significantly related to depression without comorbid anxiety disorder. Plasma folate level was inversely associated with depression only in the subgroup of middle-aged women. None of the investigated parameters showed a significant relationship to anxiety. CONCLUSION: Our results provide further evidence of a role of impaired 1-carbon metabolism in depression.     

Gene polymorphisms of homocysteine metabolism-related enzymes in Chinese patients with occlusive coronary artery or cerebral vascular diseases.

The mutations in homocysteine (Hcy) metabolism-related enzyme genes including methylenetetrahydrofolate reductase (MTHFR) C677T, cystathionine beta-synthase (CBS) 844ins68, and methionine synthase (MS) A2756G have been identified as genetic risk factors for thromboembolic events. It has been noticed that these gene mutations have heterogeneous distributions among different ethnic groups or geographic areas. The data on the prevalence of the gene mutations in Chinese population is not yet available. In the present study, we have investigated the frequency of the MTHFR C677T, CBS 844ins68, and MS A2756G mutations in 102 patients with ischemic stroke (IS), 73 patients with myocardial infarction (MI) and 100 healthy controls. The distributive frequencies of the gene variations are as follows: In the IS, MI and control groups, the mutant homozygote for MTHFR C677T is 15 (14.7%), 8 (11.7%) and 16 (16.0%), respectively, and the T allele frequency is 37.7%, 33.6% and 39.5%, respectively; the heterozygote for CBS 844ins68 is 1 (1.0%), 1 (1.4%) and 5 (5.0%), respectively; the heterozygote for MS A2756G is 18 (17.6%), 14 (19.2%) and 17 (17.0%), and the G allele frequency is 8.8%, 11.0% and 9.5%, respectively. The carrier of both MS A2756G and MTHFR C677T (combined mutations) is 14 (12.7%), 8(11.0%) and 12(12.0%), respectively. There is no statistically significant difference between the patient groups and the control group in the frequencies of these single mutation or combined mutations. The heterozygosity of CBS 844ins68 yields an odds ratio (OR) of 0.19 (95% confidence interval (CI) 0.02-1.43) for IS and 0.26 (95% CI 0.03-2.31) for MI. The T allele of MTHFR C677T yields an OR of 0.93 for IS (95% CI 0.62-1.39) and 0.77 for MI (95% CI 0.50-1.21). The G allele of MS A2756G yields an OR of 0.92(95% CI 0.47-1.81) for IS and 1.17 (95% CI 0.58-2.37) for MI. Our results suggest that neither single mutation nor combined mutations in MTHFR C677T, CBS 844ins68 and MS A2756G represent an independent risk factor for increasing IS and coronary artery disease risks in Chinese population. However, CBS 844ins68 may be a protective factor against vascular thromboembolic disease. The prevalence of CBS 844ins68 and MS A2756G in Chinese population is obviously lower than in Western Caucasian population.     

Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene with schizophrenia: association is significant in men but not in women

Schizophrenia is a complex and common psychiatric disorder with a polygenic inheritance. In our previous report, we showed an association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and schizophrenia in patients from Bakirkoy in Istanbul, Turkey [Sazci, A., Ergul, E., Guzelhan, Y., Kaya, G., Kara, I., 2003. Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Mol. Brain Res. 117, 104-107]. We wanted also independently to confirm this study in a gender-specific manner with schizophrenic patients from Erenkoy in Istanbul, Turkey. To investigate the role of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene in schizophrenia in a gender-specific manner, we analyzed the genotypes of MTHFR677 and MTHFR1298 of 297 schizophrenic patients and 341 healthy controls, using a polymerase chain reaction restriction fragment length polymorphism method. The MTHFR 677T allele was significantly distributed (chi2=7.312; P=0.026), between schizophrenic patients and healthy controls. The T677T genotype was overrepresented in the total schizophrenic patients (OR=1.938; 95%CI=1.133-3.315; chi2=5.996; P=0.014). Similarly, the T677T/A1298A compound genotype was the most significant one in the total schizophrenic patients (OR=2.397; 95% CI=1.327-4.330; chi2=8.821; P=0.003). The C1298C genotype was overrepresented in the total schizophrenic patients (OR=1.706; 95%CI=1.014-2.870; chi2=4.126; P=0.042). Likewise, the C677C/C1298C compound genotype was significant in the total schizophrenic patients (OR=1.689; 95%CI=0.985-2.894; chi2=3.695; P=0.055). When schizophrenic patients and healthy controls were stratified according to gender difference, the T677T genotype and T677T/A1298A compound genotype were significantly overrepresented (OR=2.184; 95% CI=1.069-4.462; chi2=4.767; P=0.029; OR=2.748; 95% CI=1.215-6.214; chi2=6.301; P=0.012, respectively) in men schizophrenic patients. However, neither the MTHFR C677T nor the A1298C polymorphisms are associated with schizophrenia in women. In conclusion, the MTHFR 677T allele and T677T, C1298C genotypes, and T677T/A1298A, C677C/C1298C compound genotypes are genetic risk factors for schizophrenia in men but not in women in a gender-specific manner.     

Homozygous C677T mutation in the MTHFR gene as an independent risk factor for multiple small-artery occlusions

INTRODUCTION: Hyperhomocysteinemia is an independent risk factor for cerebrovascular disease and the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene can induce hyperhomocysteinemia. However, the association between this 677TT genotype and ischemic stroke still remains controversial. Therefore, we carried out this study to determine whether the MTHFR TT genotype is associated with certain subtypes of ischemic stroke. MATERIALS AND METHODS: We enrolled 195 ischemic stroke patients and 198 healthy individuals and checked their fasting plasma homocysteine levels and analyzed the C677T polymorphism in the MTHFR gene. RESULTS: Our findings concur with previous reports that stroke occurrence is associated with hyperhomocysteinemia, but not with the 677TT genotype. However, when we re-analyzed the data based on a subtype classification, the adjusted odds ratio (AOR) and 95% confidence intervals (CI) of the 677TT genotype were found to be significantly higher in patients with small-artery occlusion than that in controls (AOR, 2.92; 95% CI, 1.01-8.48). Moreover, the AOR of the 677TT genotype was found to be much bigger in patients with multiple small-artery occlusions (AOR, 6.90; 95% CI, 1.70-27.99), but not in those with single small-artery occlusion (AOR, 1.19; 95% CI, 0.27-5.35). CONCLUSIONS: The homozygous C677T mutation in the MTHFR gene is associated with multiple small-artery occlusions, but not with single small-artery occlusion. Our findings suggest a genetic basis for certain subtypes of ischemic stroke.     

Prevalence of hyperhomocysteinemia and the MTHFR C677T polymorphism in patients with arterial and venous thrombosis from North Western Russia

Conflicting data from Western European and USA population studies led us to investigate hyperhomocysteinemia (HHcy), the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and thrombotic disease in North Western Russia. Plasma total homocysteine (tHcy) levels, MTHFR C677T genotype, selected life style determinants and haemostatic factor activity were determined in patients with arterial (n=33), venous (n=40), arterial+venous (n=11) thrombosis and healthy controls (n=30). We found raised median tHcy levels in all patient groups vs. controls (p<0.05), with odds ratios (95% CI) for vascular disease among patients with HHcy (defined as>15 μmol/l) of 3.9 (0.6–14.3), 4.8 (1.2–18.8) and 15.8 (2.8–87.3) respectively. tHcy levels were a function of MTHFR C677T genotype, and all patients with tHcy levels>30 μmol/l had the MTHFR C677T homozygous substitution. Elevated tHcy levels (p<0.05) were identified in smokers and coffee drinkers, with the degree of elevation dependent on MTHFR C677T genotype. Of the studied haemostatic parameters increased factor VIII activity and vWF antigen and activity was observed in HHcy subjects. We conclude that HHcy and MTHFR C677T genotype are positively associated with arterial and venous thrombotic disease in the population of North Western Russia.     

Homocysteine and related genetic polymorphisms in Down's syndrome IQ

OBJECTIVE: Down's syndrome (DS) is the most frequent genetic cause of Alzheimer-type dementia. Its metabolic phenotype involves an increased trans-sulphuration of homocysteine. The aim of the present study was to investigate the influence of homocysteinaemia (t-Hcys), folate, vitamin B(12), and related polymorphisms on intelligence quotient (IQ) in DS. METHODS: The IQ of 131 patients with trisomy 21 from a specialist centre in Sicily was determined and classified according to DMS-IV. The effects of age, folate, vitamin B(12), t-Hcys, and genetic polymorphisms on IQ were evaluated separately and in combination using regression analyses. RESULTS: IQ was significantly lower in DS patients with t-Hcys >7.5 micromol/l (median) and in those who were carriers of methylenetetrahydrofolate reductase (MTHFR) 677 T allele and of methylenetetrahydrofolate reductase 677 T and transcobalamin 776 G combined alleles (p = 0.0013, p = 0.0165, and p = 0.0074, respectively). The IQ correlated significantly with t-Hcys and folate in single and multiple regression analyses, independently of age. In addition, t-Hcys >9.6 micromol/l (upper quartile) was found to be associated with low IQ (<40, median of study group) with an odds ratio of 2.61 (p = 0.0203). The odds ratio was increased by threefold in carriers of MTHFR 677T allele. The MTHFR 677T allele/transcobalamin 776 G allele combination was associated with the risk of DS patients to have an IQ less that the median with an odds ratio of 2.68 (95% CI 1.26 to 5.70, p = 0.0104). CONCLUSION: This study found evidence of an association between t-Hcys and MTHFR 677 T and transcobalamin 776 G alleles with IQ in patients with DS. The association may be related to a defective remethylation of homocysteine, affecting IQ.     

Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and cognitive impairment: the health in men study

High total plasma homocysteine (tHcy) has been associated with cognitive impairment in later life, but it is unclear if this association is causal or is due to confounding. The C677T polymorphism of the 5,10 methylenetetrahydrofolate reductase gene (MTHFR) increases basal tHcy, but its contribution to cognitive impairment has not been established. We designed this study to determine if tHcy is causally related to cognitive impairment in later life by investigating its association with high tHcy and the MTHFR-C677T polymorphism. We recruited 1778 older men from the Health in Men Study cohort and established caseness on the basis of the participants' scores on a Telephone Interview for Cognitive Status score 27 in 2008. Exposure to tHcy, gene status and other variables of interest were obtained from assessments 4-7 years earlier. Multivariate logistic regression showed that the odds of cognitive impairment increased with a doubling of tHcy (adjusted odds ratio, OR 1.36; 95% confidence interval, 95% CI 1.02-1.82). Compared with the wild CC genotype, participants with the MTHFR-TT genotype had 46% greater odds of cognitive impairment (OR 1.46, 95% CI 1.01-2.11, P=0.043). The results of this study are consistent with, but do not prove the hypothesis that high tHcy causes cognitive impairment in later life.     

The combination of homozygous MTHFR 677T and angiotensin II type-1 receptor 1166C variants confers the risk of small-vessel-associated ischemic stroke

Previous studies have suggested that both angiotensin II type-1 receptor (AT1R) 1166C and methylenetetrahydrofolate reductase (MTHFR) 677T variants can have disadvantageous effects on the small-vessel circulation under certain conditions. The purpose of this study was to analyze the possible consequences of the simultaneous distribution of these two genetic variants in different types of ischemic stroke. The genetic and clinical data on 357 ischemic stroke patients and 263 control subjects were analyzed by using univariate and logistic statistical approaches. Neither the MTHFR 677T nor the AT1R 1166C genetic variant alone conferred the risk of any subtype of ischemic stroke. The combination of the homozygous MTHFR 677TT genotype and at least one AT1R 1166C allele occurred more frequently in the ischemic stroke patients (8.68%) than in the controls (4.56%, p < 0.05). Specific subclassification of the patients revealed an accumulation of this combination in small-vessel-associated ischemic stroke (12.2%, p < 0.01); multivariate logistic regression analysis of the data confirmed this association, with an odds ratio of 2.66 (95% confidence interval, 1.28-7.89; p < 0.05). These findings suggest that the combination of these two genetic factors can contribute to the development of small-vessel cerebral infarcts. Although the exact mechanism of action is not known, addition of the unfavourable effects on the endothelial function can be presumed.     

Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia

To investigate the role of methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, we analyzed the genotypes of MTHFR677 and MTHFR1298 of 130 schizophrenic patients and 226 controls, using a polymerase chain reaction restriction fragment length polymorphism method. The MTHFR T677 allele was significantly distributed (chi(2)=7.900; P=0.019), between schizophrenic cases and healthy controls. The T677T genotype was overrepresented in the schizophrenic patients (OR=2.504; 95% CI=1.276-4.915; chi(2)=7.477; P=0.006). The T677T/A1298A, and C677T/C1298C compound genotypes were greater in the schizophrenic patients (OR=3.157; 95% CI=1.522-6.545; chi(2)=10.336; P=0.001 and OR=1.744; 95% CI=0.108-28.121; chi(2)=0.158; P=0.691, respectively). The MTHFR T677 allele and T677T and T677T/A1298A genotypes are genetic risk factors for schizophrenia.     

Migraine and MTHFR C677T genotype in a population-based sample

OBJECTIVE: Migraine with aura is associated with increased risk of stroke. The MTHFR C677T genotype has been associated with increased risk of migraine in selected clinical samples and with elevated homocysteine, a risk factor for stroke. We assessed the association of the MTHFR C677T variant with migraine and the mediating effect of cardiovascular risk factors and metabolic markers of genotype status. METHODS: We compared adult migraineurs with aura (MA; n = 187), without aura (MO; n = 226), and nonmigraineurs (n = 1,212) from the population-based Genetic Epidemiology of Migraine study. RESULTS: Compared with the wild-type genotype, the T/T genotype was associated with increased odds of MA (odds ratio [OR], 2.05; 95% confidence interval, 1.2-3.4; p < 0.006), with a trend of increasing numbers of T alleles (OR, 1.40; 95% confidence interval, 1.1-1.8; p < 0.007). ORs were slightly attenuated after adjusting for homocysteine. INTERPRETATION: Risk of MA is associated with MTHFR C674T homozygosity, independent of other cardiovascular risk factors.     

Sudden infant death syndrome, childhood thrombosis, and presence of genetic risk factors for thrombosis

Sudden infant death syndrome or "cot death" has until the late eighties been a significant cause of death in children between the ages of 1 month and 1 year. Approximately two per 1000 children born alive dies of sudden infant death syndrome each year in Western Europe, North America, and Australia. The vulnerability of the infant brain stem to ischemia has been suggested to be a conceivable cause of sudden infant death syndrome. This is compatible with a hypothesis that genetic risk factors for cerebral thrombosis could cause microinfarction in the brain stem during the first month of life, affecting vital centers or their blood supply. The presence of three common point mutations seen in families with thrombophilia (1691G-->A in the coagulation factor V gene, 677C-->T in the methylenetetrahydrofolate reductase gene, and the 20210G-->A mutation in the prothrombin gene) could increase the risk for thrombosis in the child. This prompted us to investigate these genetic markers of thromboembolic disease in 121 cases of sudden infant death syndrome and in relevant controls, in the expectation of a more frequent occurrence of these markers if thrombosis is an etiological factor in sudden infant death syndrome. The frequency of homozygous 1691G-->A mutation in SIDS cases was higher than expected (odds ratio: 7.3, 95% confidence interval, 1.2-45.8). The allele frequencies (theta;) in cases of sudden infant death syndrome of the 1691G-->A, 677C-->T, and 20210G-->A alleles was 2.6% (1.0-5.5), 32.6% (26.8-38.9), and 0.9% (0.1-3.4), respectively. None of the allele frequencies found in the background population (3.4% for the 1691G-->A allele, 29% for the 677C-->T allele, and 1% for the 20210G-->A allele) differed significantly from that in cases of sudden infant death syndrome. In 5,251,027 inhabitants in Denmark, the incidence of venous thromboembolism was 0.9 per 1000 per year in the background population, and less than one-thousandth of these were children. Consequently it is not likely that venous thrombosis is a major cause of sudden infant death syndrome. On the other hand, this does not exclude other known or unknown risk factors for thrombosis as possible etiological factors for sudden infant death syndrome. It is likely that we must continuously employ the exclusion principle on possible etiological causes in genetic material from a large group of victims of sudden infant death syndrome if the phenomenon of sudden infant death syndrome is to be ascribed to a specific hereditary disorder.     

Transient focal neurological deficits during pregnancy in carriers of inherited thrombophilia

BACKGROUND AND PURPOSE: The aim of our study was to investigate the association of transient ischemic cerebrovascular events during pregnancy and inherited thrombophilias. METHODS: The study group comprised previously healthy pregnant women who had their first ischemic event during pregnancy (n=12). The control group included 24 healthy women matched with the study women for age, ethnicity, and smoking status. All women were evaluated for factor V Leiden mutation, methylenetetrahydrofolate reductase C677T gene mutation, the G20210A mutation in the prothrombin gene, and deficiencies of plasma proteins C and S and antithrombin III. RESULTS: Inherited thrombophilia was detected in 83% of women with transient neurological manifestations compared with 17% of the control group (P<0.001). CONCLUSIONS: Transient cerebrovascular ischemic events during pregnancy are associated with a high rate of inherited thrombophilias. Pregnant women with focal neurological symptoms should be evaluated for thrombophilia.