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

Fanggeng Zou, Rangaraj K. Gopalraj, Johann Lok, Haiyan Zhu, I. Fang Ling, James F. Simpson, H. Michael Tucker, Jeremiah F. Kelly, Samuel G. Younkin, Dennis W Dickson, Ronald Carl Petersen, Neill R Graff Radford, David A. Bennett, Juliana Crook, Steven G Younkin, Steven Estus

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)929-935
Number of pages7
JournalHuman Molecular Genetics
Volume17
Issue number7
DOIs
StatePublished - Apr 1 2008

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RNA Splicing
LDL Receptors
Brain Diseases
Alzheimer Disease
Low Density Lipoprotein Receptor-Related Protein-1
Alleles
Exons
Single Nucleotide Polymorphism
Gyrus Cinguli
Hep G2 Cells
Brain
Apolipoproteins E
Neuroblastoma
LDL Cholesterol
Autopsy
Cohort Studies
Odds Ratio
Genotype
Confidence Intervals
Liver

ASJC Scopus subject areas

  • Genetics

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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. / 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 Carl; Graff Radford, Neill R; Bennett, David A.; Crook, Juliana; Younkin, Steven G; Estus, Steven.

In: Human Molecular Genetics, Vol. 17, No. 7, 01.04.2008, p. 929-935.

Research output: Contribution to journalArticle

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 Carl ; Graff Radford, Neill R ; Bennett, David A. ; Crook, Juliana ; Younkin, Steven G ; Estus, Steven. / Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer's disease. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 7. pp. 929-935.
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abstract = "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.",
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AU - Zou, Fanggeng

AU - Gopalraj, Rangaraj K.

AU - Lok, Johann

AU - Zhu, Haiyan

AU - Ling, I. Fang

AU - Simpson, James F.

AU - Tucker, H. Michael

AU - Kelly, Jeremiah F.

AU - Younkin, Samuel G.

AU - Dickson, Dennis W

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Bennett, David A.

AU - Crook, Juliana

AU - Younkin, Steven G

AU - Estus, Steven

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N2 - 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.

AB - 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.

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