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[P1–004]: ASTROCYTE RESPONSE TO HYPERHOMOCYSTEINEMIA (HHCY)
Author(s) -
Price Brittani R.,
Sudduth Tiffany L.,
Weekman Erica M.,
Wilcock Donna M.,
Woolums Abigail
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.071
Subject(s) - homocysteine , cystathionine beta synthase , astrocyte , hyperhomocysteinemia , endocrinology , medicine , potassium channel , methylenetetrahydrofolate reductase , glial fibrillary acidic protein , biology , methionine , chemistry , biochemistry , central nervous system , amino acid , immunohistochemistry , gene , genotype
Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). Genetic polymorphisms in and around the HMGCR gene were extracted, and logistic regressions were performed in plink (pngu. mgh.harvard.edu) to identify variants associated with either risk or protection. Further analyses were performed in SPSS; KaplanMeier for conversion rate analysis, ANCOVA for expression analysis andMann-Whitney U test for CSF biomarker analyses. Results: We identified three new single nucleotide polymorphisms (SNPs) associated with marked increased risk of AD (ORs 1⁄4 2.4 2.7, ps < 0.05), however only in subjects also positive for the APOE4 allele. Survival analysis further revealed that carriers of the risk alleles exhibit an accelerated conversion rate, but again only in APOE4 carriers (Xs > 6.6, ps < 0.01). HMGCR risk alleles were also associated with an increased gene expression in peripheral lymphocytes (Fs > 6.7, ps < 0.01); with no interaction with APOE4 status. Finally, a significant increase in CSF phospho-tau/ tau ratio was observed in carriers of the risk alleles, specifically in APOE4 positive females (Us 1⁄4 245.5, ps 1⁄4 0.017), but not for Ab levels. Conclusions:We have identified three new SNPs in the HMGCR locus associated with risk of AD, accelerated conversion rate to AD, and increased CSF phospho-tau/tau ratio, specifically in APOE4 carriers. In line with our hypothesis that protection is mediated by reduction in HMG-CoA reductase activity, the identified risk alleles were shown to be significantly associated with increased HMGCR expression. We are now in the process of replicating these findings in an independent cohort composed of autopsy-confirmed AD cases and age-matched controls from a population isolate form eastern Canada.