CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer’s disease risk in an APOE-dependent manner

ArticleinBrain Imaging and Behavior 6(1):16-26 · September 2011with7 Reads
DOI: 10.1007/s11682-011-9137-0 · Source: PubMed
Abstract
Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer's disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318 AD or mild cognitive impairment (MCI) subjects from the Alzheimer's Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.
    • "In APOE ε4 carriers, the V allele of residue 405 of cholesteryl ester transfer protein (CETP) which decreases CETP and increases HDL is associated with less brain atrophy. However, the I allele, which increases CETP and decreases HDL, is associated with less brain atrophy and lower risk of dementia in APOE ε4 non-carriers [9]. Some genes such as cystatin C and TNFRSF6 are associated with AD only in APOE ε4 carriers [11, 12]. "
    [Show abstract] [Hide abstract] ABSTRACT: APOE ε4 allele is a major risk factor in Late-Onset Alzheimer's Disease (AD). Distinct phenotypes that depend on the APOE ε4 status have been demonstrated. The genetic etiology of APOE ε4 non-carriers is still elusive. Thus we investigated the genetic components of AD that is independent of APOE ε4 by combining genome association analysis with quantitative trait analyses in non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Five top susceptible single nucleotide polymorphisms (SNPs) in three loci in ZNF827, KDM2B and NANP were initially identified in APOE ε4 non-carriers and four of these SNPs were confirmed in mild cognitive impairment. These SNPs and one nominally significant SNP are located in three haplotype blocks. Quantitative trait analyses of these haplotype blocks demonstrated that the haplotype block in ZNF827 was associated with CSF Aβ42 level, and the haplotype block in KDM2B with CSF p-tau181p and p-tau181p/Aε42 ratio. The haplotype block between NANP and NINL was associated with brain atrophy. Moreover, these SNPs took additive effects on AD incidence and demonstrated the interaction with APOE ε4 status. Therefore, we conclude that these novel loci are associated with AD in APOE ε4 non-carriers. This study indicates the distinct genetic risk genes for AD non-carrying APOE ε4 and provides new insight to the molecular mechanisms of AD.
    Full-text · Article · Mar 2015
    • "d with these previous reports suggest that CETP I405V is not a LOAD risk factor. It has been suggested that CETP I405V and APOE e4 interact to affect LOAD risk. Vásquez et al. (2007) found an increase in AD risk for CETP individuals homozygous for the valine allele without APOE ε4 but no association with the risk of AD in carriers of the ε4 allele. Murphy et al. (2012) reported that carriers of the APOE ε4 with the V allele had less atrophy in the entorhinal and hippocampal cortices (early predictive places for memory problems and AD development) butTable 1 Demographics. Age (mean/SD; age at onset is presented for AD group), percent female , follow-up time (mean/SD), percent of APOE e4 carriers genoty"
    [Show abstract] [Hide abstract] ABSTRACT: Cholesterol has been implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD) and the cholesteryl ester transfer protein (CETP) is critical to cholesterol regulation within the cell, making CETP an Alzheimer's disease candidate gene. Several studies have suggested that CETP I405V (rs5882) is associated with cognitive function and LOAD risk, but findings vary and most studies have been conducted using relatively small numbers of samples. To test whether this variant is involved in cognitive function and LOAD progression, we genotyped 4486 subjects with up to 12 years of longitudinal cognitive assessment. Analyses revealed an average 0.6-point decrease per year in the rate of cognitive decline for each additional valine (p < 0.011). We failed to detect the association between CETP I405V and LOAD status (p < 0.28). We conclude that CETP I405V is associated with preserved cognition over time but is not associated with LOAD status.
    Full-text · Article · Aug 2014
    • "@BULLET 7(3) @BULLET 2012 @BULLET 419-430 DOI: 10.2478/s11535-012-0042-3 CETP levels as compared to the B1 allele, and that the CETP TaqIB genotype is strongly associated with the risk of cardiovascular diseases (CVD), carriers of B2B2 genotypes having higher levels of HDL cholesterol and a lower risk of CVD [9]. Recently, Murphy et al. showed that CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer's disease risk in an APOEdependent manner [10], raising the importance to study the variations of the two genes in a interaction approach. The aim of our study was to determine the association between APOE and CETP TaqIB gene polymorphisms with healthy ageing in a Romanian population. "
    [Show abstract] [Hide abstract] ABSTRACT: The association of cholesteryl ester transfer protein (CETP) and apolipoprotein E (APOE) gene polymorphisms with mild cognitive impairment (MCI) is under debate. Our aim was to evaluate the relationship between APOE and CETP genotypes with healthy ageing. We analysed 267 elderly subjects (55 to 80+ years), 163 with MCI and 104 healthy, and 50 healthy control subjects (35 to 55 years) from a Romanian population. Biochemical parameters and thyroid hormones were assayed in plasma. APOE and CETP TaqIB gene polymorphisms were determined. Elderly subjects had higher frequency of ɛ3/ɛ2 genotype (14.6% vs. 4%, P<0.001) than controls. Elderly subjects with MCI had lower high density lipoproteins (HDL) cholesterol (P=0.031), apoA-I (P=0.018), T3 (P=0.002), T4 (P=0.028) and TSH (P=0.001) hormone levels, higher systolic blood pressure (P=0.005), lower frequency of CETP B2 allele than the age-matched subjects. Healthy elderly subjects had CETP B2 allele associated with higher plasma apoA-I (P=0.021), lower circulating collagen (P=0.001) levels, and an increased frequency of the combined APOE ɛ2- CETP B2 genotype (18.3%) relative to MCI elderly subjects (7.6%, P=0.011). Healthy elderly subjects are characterized by higher HDL cholesterol, apoA-I levels and higher frequency of the combined APOE ɛ2 and CETP B2 alleles, indicating this pattern as representative for healthy ageing.
    Full-text · Article · Jun 2012
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