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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.

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.

SUBMITTER: Zou F

PROVIDER: S-EPMC2361153 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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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 F Gopalraj Rangaraj K RK Lok Johann J Zhu Haiyan H Ling I-Fang IF Simpson James F JF Tucker H Michael HM Kelly Jeremiah F JF Younkin Samuel G SG Dickson Dennis W DW Petersen Ronald C RC Graff-Radford Neill R NR Bennett David A DA Crook Julia E JE Younkin Steven G SG Estus Steven S

Human molecular genetics 20071208 7

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 c ...[more]

PMID: 18065781

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Project description:BACKGROUND:We sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol. METHODS:We conducted a meta-analysis of the association between a common Trp719Arg polymorphism in the kinesin-like protein 6 (KIF6) gene and the risk of cardiovascular disease (CVD), and a meta-regression analysis to measure the effect modification of this polymorphism on the association between LDL cholesterol and the risk of CVD. We used this measure of genetic effect modification to predict the expected difference in clinical benefit among KIF6 719Arg allele carriers and non-carriers in response to therapies that reduce LDL cholesterol. We then conducted a meta-analysis of statin trials to compare the expected difference in clinical benefit with the observed difference during treatment with a statin. RESULTS:In a meta-analysis involving 144,931 participants, the KIF6 719Arg allele was not associated with the relative risk (RR) of CVD (RR: 1.02, 95%CI: 0.98-1.07, p=0.288). Meta-regression analysis involving 88,535 participants, however, showed that the 719Arg allele appears to influence the effect of LDL cholesterol on the risk of CVD. KIF6 carriers experienced a 13% greater reduction in the risk of CVD per mmol/L decrease in LDL cholesterol than non-carriers. We interpreted this difference as the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower LDL cholesterol. The difference in clinical benefit predicted by the increased vulnerability to LDL cholesterol among KIF6 carriers (ratio of RR: 0.87, 95%CI: 0.80-0.94, p?=?0.001) agreed very closely with the observed difference among 50,060 KIF6 carriers and non-carriers enrolled in 8 randomized trials of statin therapy (ratio of RR: 0.87, 95%CI: 0.77-0.99, p=0.038). CONCLUSION:The KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol.

Project description:Background Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sex-specific differential effect of genetically increased low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) and other lipid-associated diseases. Methods and Results This is a 2-sample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80-variant LDL-C weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sex-specific LDL-C effects on lipids, carotid-intima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDL-C effect on CVD events was sex specific: per SD genetically increased LDL-C, female participants had a higher LDL-C increase but an attenuated CVD risk increase compared with male participants (LDL-C: female participants 0.71 mmol/L, 95% CI, 0.70-0.72 and male participants 0.57 mmol/L, 95% CI, 0.56-0.59. P for interaction: 5.03×10-60; CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24-1.40 and male participants: OR, 1.52; 95% CI, 1.46-1.58. P for interaction: 9.88×10-5). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDL-C results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDL-C was also associated with an attenuated carotid-intima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sex-specific weighted genetic scores showed similar results. Conclusions We found that genetically increased LDL-C has a sex-specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDL-C might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDL-C targeted therapies for CVD management than female patients and warranting investigations into the sex-specific relative contribution of risk factors for CVD.

Dataset Information

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

Publications

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

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