Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer's disease
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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DOI：
10.1093/hmg/ddm365
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Estus, Steven
中科院分区：
文献类型：
--
作者：
Zou, Fanggeng;Gopalraj, Rangaraj K.;Estus, Steven
由于apoE等位基因状态是阿尔茨海默病（AD）的主要遗传风险因素，脑apoE受体的功能性单核苷酸多态性（SNP）代表了与AD相关的极好候选者。最近，我们确定了一个SNP，rs688，作为调节剪接效率的低密度脂蛋白受体（LDLR）外显子12在女性人类肝脏和小基因转染的HepG 2细胞。此外，rs688 T次要等位基因与Frachial Offspring研究队列中女性的LDL和总胆固醇显著升高相关。由于LDLR是大脑中主要的apoE受体，我们假设rs688调节神经组织中的LDLR剪接并与AD相关。为了评估这一假设，我们首先将LDLR小基因转染到SH-SY 5 Y神经母细胞瘤细胞中，发现rs688 T等位基因减少了该神经模型中的外显子12包含。然后，我们评估了rs688等位基因与外显子12剪接效率在体内通过定量LDLR剪接在人前扣带回组织在尸检中获得的关联; rs688 T等位基因与老年男性，但不是女性的LDLR外显子12剪接效率降低。最后，我们评估是否rs688与AD的基因分型DNA从1457名男性和2055名女性从三个病例对照系列。rs688 T/T基因型与男性AD风险增加相关[隐性模型，风险比（OR）为1.49，95%置信区间（CI）为1.13-1.97，未校正P = 0.005]，但与女性无关。总之，这些研究确定了一个功能性apoE受体SNP，与AD的性别依赖性的方式。
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.