Abstract
Background: Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer's disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD. Results: Seventeen non-APOE SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ∼2,000 AD and ∼4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are associated with AD risk and age-of-onset. Additionally, rs3846662 was associated with HMGCR exon 13 splicing in human liver but not brain, possibly obscured by CNS cell-type heterogeneity. However, rs3846662 was associated with HMGCR exon 13 splicing in liver- and brain-derived cell lines. Conclusions: Cholesterol-associated SNPs outside of APOE confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset. Rs3846662 is associated with HMGCR exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD.
Original language | English |
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Article number | 62 |
Journal | Molecular Neurodegeneration |
Volume | 6 |
Issue number | 1 |
DOIs | |
State | Published - 2011 |
Bibliographical note
Funding Information:Funding of this work was provided by the National Institutes of Health and National Institute on Aging grants P01-AG030128 (SE), RO1-AG18023 (SGY), T32-AG000242 (CRS) as well as the Mayo Alzheimer’s Disease Research Center P50-AG16574 (SGY). We would like to thank the University of Kentucky AD Center, which is supported by P30-AG028383, for providing human tissue. We also thank Dave Fardo for assistance with statistical methods.
Keywords
- Alzheimer
- GWAS
- HMGCR
- SNP
- cholesterol
- genetics
- statin
ASJC Scopus subject areas
- Molecular Biology
- Clinical Neurology
- Cellular and Molecular Neuroscience