Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer's disease.
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.
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Fanggeng
F
Zou
Rangaraj K
RK
Gopalraj
Johann
J
Lok
Haiyan
H
Zhu
I-Fang
IF
Ling
James F
JF
Simpson
H Michael
HM
Tucker
Jeremiah F
JF
Kelly
Samuel G
SG
Younkin
Dennis W
DW
Dickson
Ronald C
RC
Petersen
Neill R
NR
Graff-Radford
David A
DA
Bennett
Julia E
JE
Crook
Steven G
SG
Younkin
Steven
S
Estus
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D011973:Receptors, LDL / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics
D001057:Apolipoproteins E; D011973:Receptors, LDL