Human Molecular Genetics Advance Access published online on December 8, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm365
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sex-dependent Association of a Common Low Density Lipoprotein Receptor Polymorphism with RNA Splicing Efficiency in the Brain and Alzheimers Disease
1 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 2 Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA 3 Rush Alzheimers Disease Center, Rush University Medical Center, Chicago, IL, USA 4 Department of Neurology, Mayo Clinic, Rochester, MN 55905 5 Department of Neurology, Mayo Clinic, Jacksonville, FL 32224 6 Biostatistics Unit, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224
* Address correspondence to Steven Estus, 800 S. Limestone St., Lexington, KY 40536-0230 Tel: (859) 323-3985, ext. 264, Fax: (859) 323-2866, Email: sestus2{at}email.uky.edu
Received October 18, 2007; Revised December 5, 2007; Accepted December 5, 2007
Since apoE allele status is the predominant Alzheimers disease (AD) genetic risk factor, functional single nucleotide polymorphisms (SNP)s 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 the female human liver and in minigene transfected HepG2 cells. Moreover, the rs688T minor allele associated with significantly higher LDL and total cholesterol in women in the Framingham Offspring Study. 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 rs688T reduces exon 12 inclusion in this neural model. We then evaluated rs688 association with exon 12 splicing efficiency in vivo by quantifying LDLR splicing in human anterior cingulate tissue obtained at autopsy; the rs688T allele associated with decreased LDLR exon 12 splicing efficiency in aged men but not women. Lastly, we evaluated whether rs688 associates with AD by genotyping DNA from 1,457 men and 2,055 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.
# these authors contributed equally to this work.