rs803424

Increasing evidence supports a role for epigenetic modifications in AD pathogenesis. Folate metabolism, also known as one-carbon metabolism, is required for the production of S-adenosylmethionine (SAM), which is the major DNA methylating agent. AD individuals are characterized by decreased serum folate values, as well as increased plasma homocysteine (Hcy) levels, and there is indication of impaired DNA methylation potential (SAM/SAH levels) in AD tissues. Some polymorphisms of genes participating in one-carbon metabolism have been associated with AD risk and/or with folate, Hcy or vitamin B12 levels in AD individuals. However, it is not yet clear wheter impairments in one-carbon metabolism are causative of AD or rather a consequence of the disease. Studies in rodents and in neuroblastoma cell cultures have shown that dietary restrictions of folate and other B vitamins result in epigenetic modifications of AD related genes as well as altered production of enzymes involved in DNA methylation, and that SAM treatment is able to restore both methylation and expression levels of those genes. Exposure to lead (Pb) resulted in epigenetic modification of AD related genes in rodents, monkeys and cell cultures. Moreover the amyloid-beta peptide itself possesses epigenetic properties. A few studies have been performed in human postmortem specimens, suggesting that some genes might be epigenetically modified within the disease pathogenesis. This chapter focuses on the current knowledge on DNA methylation in AD tissues, cell cultures and animal models.

2013 · Fabio Coppedè

… Subsequent genotyping of SNPs in high LD (r 2> 0.8) with rs11754661 in this case-control set identified statistically significant associations in multiple SNPs (rs803424, P= 0.016; …

2010 · AC Naj, GW Beecham, ER Martin…

Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold (alpha=1.03x10(-7)) were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, P=1.9x10(-36)). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (P=4.70x10(-8); Bonferroni-corrected P=0.022). Subsequent genotyping of SNPs in high linkage disequilibrium (r2>0.8) with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P=0.016; rs2073067, P=0.03; rs2072064, P=0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P=0.002 (P=1.90x10(-10) in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P=0.005; rs803422, P=0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development.

2010 · Adam C Naj, Gary W. Beecham, Eden R. Martin, Paul J. Gallins, Eric Powell, Ioanna Konidari, Patrice L. Whitehead, Guiqing Cai, Vahram Haroutunian, William K. Scott, Jeffery M. Vance, Michael A. Slifer, Harry E. Gwirtsman, John R. Gilbert, Jonathan L. Haines, Joseph D. Buxbaum, Margaret A. Pericak‐Vance