The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61:660-662 (2006)
© 2006 The Gerontological Society of America
Genetic Association Between USF 1 and USF 2 Gene Polymorphisms and Japanese Alzheimer's Disease
Nobuto Shibata,
Tohru Ohnuma,
Shinji Higashi,
Maiko Higashi,
Chie Usui,
Taku Ohkubo,
Tomoko Watanabe,
Ritsuko Kawashima,
Akiyoshi Kitajima,
Akira Ueki,
Masatsugu Nagao and
Heii Arai
1 Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan.
2 Department of Neurology, Omiya Medical Center, Jichi Medical School, Saitama-shi, Japan.
3 Department of Psychiatry, Nagao Hospital, Kure-shi, Japan.
Address correspondence to Nobuto Shibata, MD, Department of Psychiatry, Juntendo University School of Medicine. 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan. E-mail: nobuto.shibata{at}nifty.ne.jp
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Abstract
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To investigate the effect of single nucleotide polymorphisms (SNPs) of the upstream stimulatory factor (USF) 1 and 2 genes on the onset of Alzheimer's disease (AD), a case–control study was performed. The SNPs were genotyped by a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method in 236 AD patients and 120 age-matched controls of Japanese descent. We observed no significant association between the three SNPs of the USF 1 gene and AD in our Japanese participants. In addition, the SNPs studied did not affect plasma cholesterol levels in our AD cases. For the USF 2 gene, the two SNPs did not show significant association with onset of AD. Our study suggests that the three SNPs of the USF 1 gene and two SNPs of the USF 2 gene presented here are not associated with onset of AD.
ALZHEIMER'S disease (AD) is the most common neurodegenerative disease causing dementia. Both genetic and environmental factors are thought to be involved in the pathogenesis of AD (1). Moreover, several lines of evidence have suggested an association between AD and cholesterol metabolism. Epidemiological studies have indicated that the use of cholesterol-lowering drugs may suppress the development of AD (2). In vitro experiments have also shown that cholesterol affects the interaction between ß-amyloid (Aß) and membranes (1). In addition, several studies have revealed an association between plasma cholesterol levels and risk for AD. Aside from the 
4 allele of the apolipoprotein E (Apo E) gene (3), which is a risk factor for sporadic AD, the genetic association between cholesterol and AD has not been proven.
Upstream stimulatory factors (USFs) are mediators of Ca2+-responsive transcription in neurons (4). USFs are also reported to interact with GABAB receptors, which play a critical role in synaptic plasticity (5). USFs have been reported to affect the production of Aß protein by activating the ß-amyloid precursor protein (APP) promoter (6,7). USFs play important roles to activate brain-derived neurotrophic factor gene (8). Genetic mutations in the USF 1 gene were reported to cause autosomal dominant hypercholesterolemia (ADH) (9–11). Furthermore, a specific haplotype of the USF 1 gene was reported to affect plasma cholesterol levels (12). The region of the USF 2 gene on chromosome 19q is a candidate for AD risk (13). We performed a case–control study to identify genetic association between USF 1 and USF 2 polymorphisms and risk for AD. We also assessed the linkage disequilibrium (LD) between the USF gene polymorphisms in our Japanese participants. In addition, we analyzed the relationship between the USF 1 gene single nucleotide polymorphism (SNP) genotypes and plasma cholesterol levels in our AD cohort.
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MATERIALS AND METHODS
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The sporadic Japanese AD cases (n = 236, men/women = 110:126) were recruited from the in-/outpatient clinic of the hospitals where the authors work. The mean age of the AD group (69.1 years, standard deviation 8.8 years, range: 42–90 years) was not significantly different from that of the control group (70.1 years, standard deviation 8.2 years, range: 51–93 years). All the AD cases were diagnosed according to The National Institute for Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS–ADRDA) criteria, and none had any family history of AD. The control cases (n = 120, men/women = 71:49) were obtained from healthy volunteers with no history of dementia or other neuropsychiatric diseases. The purpose and significance of this study was explained in detail to each patient and his/her family, and all participants provided their informed consent. The Ethics Committee of the Juntendo University School of Medicine approved the study protocol.
Genomic DNA was extracted from white blood cells using a standard method. Information on the SNPs was derived from the SNP database established by the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/SNP/). The chosen SNPs were studied by using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis method (Table 1). The distribution of genotypes between the AD and control groups were compared using Fisher's exact probability test. To assess the LD between each SNP, the estimate haplotype frequencies (EH) program was used. We tested the relationship between the USF 1 gene SNP genotypes and plasma cholesterol levels in our AD cohort by applying the Kruskal–Wallis test.
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Table 1. Details of the Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR–RFLP) Method Used to Determine the Genotype for Each Single Nucleotide Polymorphism (SNP).
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RESULTS
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USF 1
The genotypic distribution of the three SNPs is shown in Table 2. There was no significant difference in genotypic distribution for any polymorphism between the control and AD groups. The SNPs rs7546890 and rs3737787 were in strong LD in both the AD and control groups (p <.001). The SNP rs3766382 was in weak LD with rs7546890 and rs3737787 (p <.02 and p <.02, respectively) in both groups. No significant association was observed between any SNP genotype and total plasma cholesterol levels (Table 4).
USF 2
We found a borderline p value (p =.04) in genotypic distribution for rs12742 between the control and the AD groups (Table 3). There was no significant difference in genotypic distribution for rs916145 between the control and the AD groups. Strong LD was shown between rs12742 and rs916145 in both groups (p <.001).
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DISCUSSION
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To the best of our knowledge, this is the first study to evaluate the association between SNPs of the USF 1 and USF 2 genes and AD. A tight LD between rs7546890 and rs3737787 was observed in our Japanese participants. The result of our study suggests that the third SNP is in weak LD with the other two. This weak LD covers a 5.2 kb region of the gene, and the results of our study indicate that the three SNPs in the USF 1 gene do not alter risk for AD. A specific haplotype of the USF 1 gene was reported to be associated with lipid homeostasis (12). Our results did not show any association between the three SNPs and total plasma cholesterol levels in our AD cohort. The discrepancy between the two studies could be due to several factors. LD might differ depending on ethnicity. Our cases were AD patients, and theirs were healthy young men. Another large cohort study suggested that there were no relationship between plasma total cholesterol and onset of AD (14). More genetic studies among the SNPs of the USF 1 gene, total plasma cholesterol level, and risk for AD should be performed.
For the USF 2 gene, a borderline p value was found for the genotypic distribution of rs12742. Because rs916145 showed negative results in our samples and tight LD was observed between these two SNPs, the result for rs12742 was considered a false positive. Our study is limited by the fact that our cohort consists only of Japanese participants and that we could not cover the entire USF 2 gene. More genetic studies of USF 2 should be performed on larger data sets including other ethnic groups to further understand its biological role.
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Acknowledgments
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This study was in part funded by a High Technology Research Center Grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology and by a research grant from the Japanese Ministry of Health, Labour and Welfare of Japan.
We are grateful for the technical assistance of K. Yamamoto and S. Itakura.
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Footnotes
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Decision Editor: James R. Smith, PhD
Received October 17, 2005
Accepted January 2, 2006
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References
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Abstract
Materials and Methods
