MTHFR Gene Polymorphism as a Risk Factor for Silent Brain Infarcts and White Matter Lesions in the Japanese General Population

Abstract

Background and Purpose-Silent brain infarcts (SBI) and white matter lesions are relatively common neuroimaging findings, especially in the elderly population. The genetic background for SBI and white matter lesions in a large Japanese general population was investigated. Methods-Subjects were recruited from participants in the National Institute for Longevity Sciences, Longitudinal Study of Aging. Genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T gene mutation and brain MRI examination were performed in 1721 subjects free of any history of stroke. SBI and white matter lesions were diagnosed from MRI findings. Results-Of 1721 MRI examinations, SBI was observed in 178 (10.3%). The prevalence of SBI and white matter lesions increased with age. Key Words: amine oxidoreductases Ⅲ brain infarction Ⅲ elderly Ⅲ polymorphism Ⅲ white matter S ilent brain infarcts (SBI) and white matter lesions, which are often incidentally identified during CT or MRI scanning in asymptomatic individuals, are relatively common neuroimaging findings, especially in the elderly population. 1-3 However, the presence of SBI and white matter lesions has been identified as an independent risk factor for the development of future symptomatic stroke 4,5 and dementia. 6 Accordingly, the underlying mechanisms have been the focus of much research. [1][2][3]7,8 Population-based studies have been performed to identify risk factors for SBI. 2,3 It has been demonstrated that classic risk factors such as hypertension and smoking are involved in the development of SBI. [1][2][3]7,8 The genetic predisposition to SBI has also been studied. 9,10 However, a population-based study to identify a candidate gene for SBI has not been performed.Methylenetetrahydrofolate reductase (MTHFR) catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which serves as a methyl donor in the reaction converting homocysteine (Hcy) to methionine. 11,12 An increased plasma Hcy level has consistently been shown to be an independent risk factor for atherosclerotic disorders in several meta-analyses. 11-13 On the other hand, a common mutation of MTHFR, which results in a mild increase in the plasma level of Hcy, has not been reported as a consistent risk factor for atherothrombotic disorders, including stroke. 11,12,14 Although there could be several possible mechanisms underlying the discrepancy, the sampling of cases and controls might account for part of the discrepancy.Two studies have evaluated the association between MTHFR gene C677T mutations and SBI. 9,10 Both studies failed to demonstrate significant associations. One evaluated subjects undergoing medical checkup. 9 To evaluate the genetic predisposition to SBI, community-based sampling of subjects would be less biased in the selection of cases and controls and would eliminate regional differences. Another study evaluated community-dwelling elderly subjects 10 ; however, the number of subjects was too small to reach a conclusion. The National Institute for Longevity ...

Genetic investigation of methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) in multiple sclerosis

“…In the present study, the MTHFR C677T mutation was studied in an MS sample from Australia and although the results showed a slight increase in the number of individuals with the low activity mutant genotype, these results failed to reach statistical significance (P = 0.15). Our results do not support any association of the tested C677T gene mutation with MS. A recent Japanese genotyping study investigating the same MTHFR C677T in 1721 subjects free of any history of stroke, but diagnosed with white matter lesions following brain MRI examination, showed an association of the MTHFR TT genotype with silent brain infarcts and advanced white matter lesions [13]. This prompted an investigation of the same gene in our Australian MS sample.…”

Endothelial nitric oxide synthase gene polymorphisms and the risk of silent brain infarction

“…At the genetic level, only a few genes have been reported as risk factors for SBI to date, which include apolipoprotein (a), methylenetetrahydrofolate reductase (MTHFR) angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R) (23,24,29). We have recently studied the role of angiotensin-converting enzyme (ACE) polymorphism in the development of stroke and SBI, and found that it is associated with stroke but not with SBI (25).…”

“…Considering the significance of SBI, which is known to increase the risk of developing into serious vascular diseases, such as stroke and dementia, there has been no epidemiological study on the eNOS polymorphisms in the SBI patients to our knowledge, although very few polymorphic studies of other genes have been reported (8,(23)(24)(25). Therefore, in the present study, we investigated the role of polymorphisms in the eNOS gene (-786T>C, 4a4b and 894G>T) as a risk factor for SBI.…”

The epidemiology of silent brain infarction: a systematic review of population-based cohorts

“…Vermeer et al [38] identified an odds ratio for SBI prevalence of 1.4 (95% CI: 1.0, 1.8) associated with female gender in the Rotterdam Scan Study; but this OR became non-significant (OR: 1.3; 95% CI: 0.9, 1.9) when [3,14,30,32,33,35,37,44,46]. Among women, it is interesting to note recent evidence that links early menopause with a four-fold increased risk of SBI [39].…”