P2‐093: Polymorphism in Cytochrome P450 Gene is Associated with Alzheimer’s Pathology
Alzheimer's & Dementia(2016)
摘要
The cytochromes P450 (CYP) are known for their role in metabolizing several endogenous and exogenous substrates. In the brain, they modulate blood-flow regulation, metabolize cholesterol, and participate in neuroinflammatory processes. CYP activity is also implicated in Alzheimer’s disease (AD), particularly in amyloid-β (Aβ) accumulation in CSF. We examined whether genetic polymorphisms of CYP are associated with AD pathology. [18F]florbetapir-PET imaging was employed to assess brain Aβ levels in 256 subjects from a discovery cohort (ADNI: 186CN, 105 lMCI, 47AD). Linear regression models examined the association of 30 SNPs from four genes of CYP (CYP3A4, CYP2C9, CYP2C19 and CYP1A1) with global [18F]florbetapir-SUVR, adjusting for age, sex, and ApoE-e4carriage status. Significant signals were interrogated at the voxel level using RMINC-tool, and, separately, tested for associations with CSF Aβ and Aβ/p-tau ratio. Neuropathologic data from the Rush ROS and MAP cohorts were used to generalize the findings to Aβ load and PHFtau tangle density by immunocytochemistry in post-mortem brains (302 CN, 180 aMCI, 259 AD). The analysis of [18F]florbetapir identified an intronic variant in the CYP2C19 gene (rs4388808; P=0.0005), in which carriers of the minor-allele (G) had lower global SUVR (Figure 1). The voxel-wise analysis showed a significant effect of the SNP in the frontal and posterior cingulate cortices, as well as in the inferior parietal cortex (Figure 2). Carriers of the minor-allele were also associated with higher CSF Aβ (P=0.003) and higher Aβ/p-tau ratio (P=0.01). In post-mortem brains, minor-allele carriers had a lower Aβ load (P=0.04), lower PHFtau tangle density (P=0.03) as well as better episodic memory (P=0.008). The rs4388808, an intronic variant of the CYP2C19 gene is implicated in Aβ load, tau pathology and episodic memory, where the minor-allele protects against AD pathology. Comparison between non-carriers(-) and carriers(+) of the minor allele of rs4388808 (CYP2C19). A significant difference was observed in brain amyloid load (A), CSF Aβ levels (B) and CSF Aβ/p-tau ratio (C) using ADNI cohort. Results were generalized using post-mortem data from Rush ROS and MAP cohorts, where a concordant pattern was observed in amyloid load (D), PHF-tau tangle density (E) and episodic memory scores (F). The linear models were adjusted for age, gender and ApoE-e4 carriage status. Voxel-wise comparison between minor allele non-carriers(-) and carriers(+) of the polymorphism rs4388808 of CYP2C19. A significant difference was observed in the frontal and posterior cingulate cortices, as well as in the inferior parietal cortex. The voxel-wise analysis was adjusted for age, gender and ApoE-e4 carriage status.
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关键词
cytochrome p450 gene,alzheimers,polymorphism
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