Genetic variants ofABCA1 modify Alzheimer disease risk and quantitative traits related to ?-amyloid metabolism

Abstract

Linkage studies have provided evidence that one or more loci on chromosome 9q influence Alzheimer disease (AD). The gene encoding the ATP-binding cassette A1 transporter (ABCA1) resides within proximity of previously identified linkage peaks and represents a plausible biological candidate for AD due to its central role in cellular lipid homeostasis. Several single nucleotide polymorphisms (SNPs) spanning ABCA1 have been genotyped and haplotype-based association analyses performed in four independent case-control samples, consisting of over 1,750 individuals from three European populations representing both early and late-onset AD. Prominent effects were observed for a common (H2) and rarer haplotype (H5) that were enriched in AD cases across studied populations (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.36-1.82; P<0.00001 and OR 2.90; 95% CI 2.54-3.27; P<0.00001, respectively). Two other common haplotypes in the studied region (H1 and H3) were significantly under-represented in AD cases, suggesting that they may harbor alleles that decrease disease risk (OR 0.79, 95% CI 0.64-0.94; P=0.0065 and OR 0.70, 95% CI 0.46-0.93; P=0.011, respectively). While findings were significant in both early and late-onset samples, haplotype effects were more distinct in early-onset materials. For late-onset samples, ancillary evidence was obtained that both single marker alleles and haplotypes of ABCA1 contribute to variable cerebrospinal fluid tau and beta amyloid (Abeta42) protein levels, and brain Abeta load. Results indicate that variants of ABCA1 may affect the risk of AD, providing further support for a genetic link between AD and cholesterol metabolism.

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

“…We also note that an independent AD study suggested that the R variant was associated with earlier age-at-onset (AAO) in AD (Wollmer et al 2003). However, we observed no AAO effect in this sample, consistent with our previous observations (Katzov et al 2004) (data not shown).…”

“…This may have a bearing on the success or failure of future studies that attempt to relate ABCA1 variation to other disease phenotypes, but may also serve as a point to revisit in large published studies, such as that of Frikke-Schmidt et al (2004). In particular, our own results on AD (Katzov et al 2004) and on CSF Ab 1-42 levels in the present study may be influenced by this potential modification. Unfortunately, it is uncommon for AD sample collection strategies to include information about smoking or other lifestyle data, and this is admittedly true for the majority of our own samples.…”

“…To begin exploring this latter possibility in the CVD sample (since it affords the most power to detect such effects), genotyping of the I883M and R1587K variants was performed, and ANOVA used to model the potential independent main effects in a joint analysis of all three markers (including R219K). We noted that LD is very weak between these sites (Katzov et al 2004) and therefore assumed that colinearity would likely not be a problem. In smokers, the main effect for R219K improved when adjusting for the other sites from F 2,943 =8.4, P=0.00024 in isolation to F 2,898 =9.9, P=0.000055 when all three markers were included.…”

“…This sample consists of both AD (n=156) and frontotemporal dementia (FTD) cases (n=70). This sample was not examined in our previous work on ABCA1 (Katzov et al 2004). For analyses involving ANOVA, a sample identifier was included as a covariate to adjust for differences in average Ab 1-42 levels between AD and FTD groups.…”

“…Genotyping was performed using Dynamic Allele Specific Hybridization (DASH) (Prince et al 2001). DASH and PCR were performed using previously published oligonucleotide sequences and assay conditions (Katzov et al 2004). …”