Human Molecular Genetics Advance Access originally published online on December 8, 2007
Human Molecular Genetics 2008 17(7):929-935; doi:10.1093/hmg/ddm365
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Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer’s disease
1 Department of Neuroscience 2 Department of Neurology and 3 Biostatistics Unit, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA 4 Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone Street, Lexington, KY 40536-0230, USA 5 Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA 6 Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
* To whom correspondence should be addressed. Tel: +1 8593233985; Fax: +1 8593232866; Email: sestus2{at}email.uky.edu
Received October 18, 2007; Accepted December 5, 2007
Since apoE allele status is the predominant Alzheimer's disease (AD) genetic risk factor, functional single nucleotide polymorphisms (SNPs) in brain apoE receptors represent excellent candidates for association with AD. Recently, we identified a SNP, rs688, as modulating the splicing efficiency of low-density lipoprotein receptor (LDLR) exon 12 in female human liver and in minigene-transfected HepG2 cells. Moreover, the rs688T minor allele was associated with significantly higher LDL and total cholesterol in women within the Framingham Offspring Study cohort. Since LDLR is a major apoE receptor in the brain, we hypothesized that rs688 modulates LDLR splicing in neural tissues and associates with AD. To evaluate this hypothesis, we first transfected LDLR minigenes into SH-SY5Y neuroblastoma cells and found that the rs688T allele reduces exon 12 inclusion in this neural model. We then evaluated the association of rs688 allele with exon 12 splicing efficiency in vivo by quantifying LDLR splicing in human anterior cingulate tissue obtained at autopsy; the rs688T allele is associated with decreased LDLR exon 12 splicing efficiency in aged males, but not females. Lastly, we evaluated whether rs688 associates with AD by genotyping DNA from 1457 men and 2055 women drawn from three case-control series. The rs688T/T genotype was associated with increased AD odds in males [recessive model, odds ratio (OR) of 1.49, 95% confidence interval (CI) of 1.13–1.97, uncorrected P = 0.005], but not in females. In summary, these studies identify a functional apoE receptor SNP that is associated with AD in a sex-dependent fashion.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.