Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer’s disease

• Published in: Human molecular genetics 2008-04, Vol.17 (7), p.929-935
• Main Authors: Zou, Fanggeng, Gopalraj, Rangaraj K., Lok, Johann, Zhu, Haiyan, Ling, I-Fang, Simpson, James F., Tucker, H. Michael, Kelly, Jeremiah F., Younkin, Samuel G., Dickson, Dennis W., Petersen, Ronald C., Graff-Radford, Neill R., Bennett, David A., Crook, Julia E., Younkin, Steven G., Estus, Steven
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Apolipoproteins E - metabolism; Biological and medical sciences; Brain - metabolism; Case-Control Studies; Cell Line, Tumor; Cell receptors; Cell structures and functions; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Exons; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Humans; Male; Medical sciences; Miscellaneous; Molecular and cellular biology; Mutagenesis, Site-Directed; Neurology; Odds Ratio; Polymorphism, Single Nucleotide; Receptors, LDL - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Splicing; Sex Characteristics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddm365

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.