Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk

Molecular Neurodegeneration

Steven Estus²  Steven G Younkin¹  Fanggeng Zou¹  Christopher R Simmons² 

[1] Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA;Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

关键词: statin;    HMGCR;    SNP;    GWAS;    cholesterol;    genetics;    Alzheimer;   

Others  :  865647
DOI  :  10.1186/1750-1326-6-62

 received in 2011-05-02, accepted in 2011-08-25,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Simmons et al; licensee BioMed Central Ltd.

【 图 表 】

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