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; Lok, Johann; Zhu, Haiyan; Ling, I-Fang; Simpson, James; 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

doi:10.1093/hmg/ddm365

Cited by 54 publications

(56 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, rs5925 has not been associated with increased cholesterol in other studies (Boright et al, 1998;Knoblauch et al, 2002;Knoblauch et al, 2004). The rs688 genotype has been associated with coronary artery disease (Martinelli et al, 2010) and Alzheimer's disease in men (Zou et al, 2008). However, other studies have not found an association between the single LDLR gene polymorphism rs5925 and Alzheimer's disease or thrombotic disorders (Rodriguez et al, 2006;Bertram et al, 2007;Lee et al, 2012).…”

Section: Figmentioning

confidence: 89%

Mutual Effect of rs688 and rs5925 in Regulating Low-Density Lipoprotein Receptor Splicing

Km²,

Tc³

et al. 2014

DNA and Cell Biology

View full text Add to dashboard Cite

Analysis of the low-density lipoprotein receptor (LDLR) gene based on the rs688 and rs5925 genetic polymorphisms has provided evidence suggesting that haplotypes related to rs688 and rs5925 are associated with ischemic cerebrovascular diseases. Both rs688 and rs5925 have been empirically identified as exon-splicing enhancers in silico, and rs688 has been shown to be a functional polymorphism that modulates LDLR exon 12 splicing efficiency both in vitro and in vivo. The aim of this study was to evaluate whether rs688 and rs5925 and their haplotypes may alter the splicing efficiency of exons 12 and 13 both in vivo and in vitro. When the minigenes were evaluated for splicing efficiency, we found that converting rs688C to the T allele reduced exon 12 splicing efficiency. In parallel, converting rs688T to the C allele increased the efficiency of exon 12 inclusion. The apparent difference in splicing efficiency was 9.36%±2.58% between the C and T alleles. When rs688C existed in the minigene, the major and minor rs5925 alleles were also sufficient to account for the differences in splicing efficiency of LDLR involving exon 13. The apparent splicing efficiency difference was 5.43%±2.87%. Sequential mutations of rs688 and rs5925 were performed to generate four different haplotypes in the LDLR minigene system. The splicing efficiencies for the haplotypes CC, CT, TC, and TT were 79.60%±1.38%, 76.68%±0.85%, 69.02%±1.79%, and 68.54%±1.38%, respectively. The splicing efficiency of the four haplotype groups differed significantly. In vivo analysis of human leukocyte samples was also compatible with in vitro analysis, indicating a mutual effect between rs688 and rs5925 in regulating LDLR splicing efficiency.

show abstract

Section: Figmentioning

confidence: 89%

Mutual Effect of rs688 and rs5925 in Regulating Low-Density Lipoprotein Receptor Splicing

Km²,

Tc³

et al. 2014

DNA and Cell Biology

View full text Add to dashboard Cite

show abstract

“…Estus and colleagues ( 274,275 ) then went on to show that the splicing effi ciencies of minigene-derived transcripts containing the rare allele were, relative to common allele bearing transcripts, decreased by ‫ف‬ 9 and 15% in both HepG2 and SH-SY5Y (neuroblastoma) cells. Additionally, in human tissue samples, the rare variant was associated with less effi cient exon 12 splicing: in female, postmortem liver and male anterior cingulate region of brain, the decreases were 8.6% ( P = 0.024) and 8% ( P = 0.041), respectively.…”

Section: Common Ldlr Variants Associated With Ldl-c Levelsmentioning

confidence: 99%

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

Calandra

Tarugi

Speedy

et al. 2011

Journal of Lipid Research

View full text Add to dashboard Cite

This review covers the dietary and biochemical origins and fates of key classes of sterol molecules in humans, namely, cholesterol and the relatively under-recognized and often unappreciated noncholesterol sterols and stanols; the intra-and intercellular systems that govern their transport; and the contribution of innate genetic programs to the biochemically observed levels of plasma LDL-cholesterol (LDL-C). The reasons for these foci are both biological and medical. The former is the burgeoning knowledge of the normal physiological roles that cholesterol performs within cell membranes in supporting receptor-mediated signaling activities ( 1-4 ), the movement of diverse molecules through different membranebound compartments (5)(6)(7)(8), and multiple other cell functions (9)(10)(11), including myelination ( 12 ). The latter, Abstract This review integrates historical biochemical and modern genetic fi ndings that underpin our understanding of the low-density lipoprotein (LDL) dyslipidemias that bear on human disease. These range from life-threatening conditions of infancy through severe coronary heart disease of young adulthood, to indolent disorders of middle-and oldage. We particularly focus on the biological aspects of those gene mutations and variants that impact on sterol absorption and hepatobiliary excretion via specifi c membrane transporter systems ( NPC1L1 , ABCG5/8 ); the incorporation of dietary sterols ( MTP ) and of de novo synthesized lipids ( HMGCR, TRIB1 ) into apoB-containing lipoproteins ( APOB ) and their release into the circulation ( ANGPTL3, SARA2, SORT1 ); and receptor-mediated uptake of LDL and of intestinal and hepatic-derived lipoprotein remnants ( LDLR, APOB, APOE, LDLRAP1, PCSK9, IDOL ).The insights gained from integrating the wealth of genetic data with biological processes have important implications for the classifi cation of clinical and presymptomatic diagnoses of traditional LDL dyslipidemias, sitosterolemia, and newly emerging phenotypes, as well as their management through both nutritional and pharmaceutical means. -Calandra, S., P. Tarugi Abbreviations: ABCG5, ATP-binding cassette, subfamily G, member 5; ABCG8, ATP-binding cassette, subfamily G, member 8; ABL, abetalipoproteinemia; ADH, autosomal dominant hypercholesterolemia; ANGPTL3, angiopoietin-like 3; ARH, autosomal recessive hypercholesterolemia; BMI, body mass index; CAC, coronary artery calcifi cation; CAD, coronary artery disease; CHD, coronary heart disease; CMRD, chylomicron retention disease; CYP7A1 , cholesterol 7 ␣ -hydroxylase; EGF, epidermal growth factor; ER, endoplasmic reticulum; FCHL, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHBL, familial hypobetalipoproteinemia; GWAS, genome-wide association study; HMGCR, HMGCoA reductase; IDOL, inducible degrader of LDLR; LD, linkage disequilibrium; LDL-C, LDL-cholesterol; LDLR, LDL receptor; LRP1, LDLRAP1, LDLR-associated protein 1; LDLR-related protein 1; LXR, liver X receptor; MI, myocardial infarction; MTP, m...

show abstract

“…Despite a number of studies finding no association between the LDLR gene polymorphism rs5925 and Alzheimer’s disease (Bertram et al ., 2007; Rodriguez et al ., 2006), one study has found that a different polymorphism (rs688) may be related to Alzheimer’s disease – at least in men (Zou et al ., 2008). With the exception of one study where there was a genetic association between LRP and Alzheimer’s disease in a sample of Chinese patients (Zhou et al ., 2008), other studies have found no significant association between LRP polymorphisms and Alzheimer’s disease (Bahia et al ., 2008; Sagare et al ., 2007) or learning and memory during aging in non-demented subjects (Reynolds et al ., 2006).…”

Section: Low-density Lipoprotein Receptorsmentioning

confidence: 99%

The effects of cholesterol on learning and memory

Schreurs

2010

Neuroscience & Biobehavioral Reviews

View full text Add to dashboard Cite

Cholesterol is vital to normal brain function including learning and memory but that involvement is as complex as the synthesis, metabolism and excretion of cholesterol itself. Dietary cholesterol influences learning tasks from water maze to fear conditioning even though cholesterol does not cross the blood brain barrier. Excess cholesterol has many consequences including peripheral pathology that can signal brain via cholesterol metabolites, proinflammatory mediators and antioxidant processes. Manipulations of cholesterol within the central nervous system through genetic, pharmacological, or metabolic means circumvent the blood brain barrier and affect learning and memory but often in animals already otherwise compromised. The human literature is no less complex. Cholesterol reduction using statins improves memory in some cases but not others. There is also controversy over statin use to alleviate memory problems in Alzheimer's disease. Correlations of cholesterol and cognitive function are mixed and association studies find some genetic polymorphisms are related to cognitive function but others are not. In sum, the field is in flux with a number of seemingly contradictory results and many complexities. Nevertheless, understanding cholesterol effects on learning and memory is too important to ignore.

show abstract

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

Cited by 54 publications

References 33 publications

Mutual Effect of rs688 and rs5925 in Regulating Low-Density Lipoprotein Receptor Splicing

Mutual Effect of rs688 and rs5925 in Regulating Low-Density Lipoprotein Receptor Splicing

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

The effects of cholesterol on learning and memory

Contact Info

Product

Resources

About