Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels

Knijff, Peter de; Maagdenberg, van den; Frants, R.R.; Lm, Havekes

doi:10.1002/humu.1380040303

Cited by 122 publications

(62 citation statements)

References 181 publications

(60 reference statements)

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“…The major allele A of rs11122396 is the derived allele that introduces a miRNA-135b-5p binding site, implying that the ancestral G allele may be a risk allele that abolishes miRNA regulation. Unlike in Mendelian diseases where the risk allele is usually the derived allele, in common diseases the ancestral allele sometimes functions as a risk allele under modern environmental conditions (see Di Rienzo and Hudson 10 ), for example in the case of the e4 allele of APOE in coronary artery disease 11 and Alzheimer's disease. 12 Based on the publicly available BrainSpan Atlas mRNA and miRNA sequencing data (www.brainspan.org), miR-135b-5p and DISC1 are co-expressed in the human brain with the highest levels in the cerebellar cortex and mediodorsal nucleus of thalamus.…”

Section: Discussionmentioning

confidence: 99%

Allele-specific regulation of DISC1 expression by miR-135b-5p

et al. 2013

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Disrupted-in-schizophrenia-1 (DISC1) gene has been established as a risk factor for various neuropsychiatric phenotypes. Both coding and regulatory variants in DISC1 have been identified and associated with these phenotypes in genetic studies. MicroRNAs (miRNAs) are important regulators of protein coding genes. Since the miRNA-mRNA target recognition mechanism is vulnerable to disruption by DNA polymorphisms, we investigated whether polymorphisms in the DISC1 3 0 UTR affect binding of miRNAs and lead to allele-specific regulation of DISC1. We identified four predicted polymorphic miRNA target sites in the DISC1 3 0 UTR, and demonstrated that miR-135b-5p regulates the level of DISC1 mRNA. Moreover, DISC1 regulation by miR135b-5p is allele specific: miR-135b-5p only binds to the major allele (A) of rs11122396, not to the minor allele (G). Thus, the G allele may be functionally related to the DISC1-associated phenotypes by abolishing regulation by miR-135b-5p, leading to elevated DISC1 levels. European Journal of Human Genetics (2014) 22, 840-843; doi:10.1038/ejhg.2013 published online 30 October 2013 Keywords: DISC1; microRNA; miR-135b-5p; neuropsychiatric disorder; allele-specific regulation INTRODUCTIONGenetic variants of the Disrupted-in-schizophrenia-1 (DISC1) gene have been associated with various neuropsychiatric phenotypes. 1 The initially identified translocation 2 reduces DISC1 expression to half normal levels, suggesting haploinsufficiency as the mechanism of disease susceptibility in translocation carriers. 3 In addition, expression quantitative trait loci affecting the expression of DISC1 have been identified 4,5 and shown to associate with age of onset in recurrent major depression. 6 We hypothesized that differential regulation of DISC1 expression may contribute to the wide range of DISC1-associated disorders.MicroRNAs (miRNAs) are small non-coding RNA molecules that repress gene expression by binding to their target mRNAs. There are no previous reports on miRNA regulation of DISC1, although in general miRNAs regulate about half of human genes. We were especially interested in putative polymorphic miRNA target sites in the DISC1 3 0 UTR that could lead to differential regulation of DISC1. MATERIALS AND METHODSSee Supplementary Methods. RESULTSWe identified four SNPs (rs11122396, rs980989, rs9308481, and rs11803088) within putative binding sites of nine human miRNAs (miR-23a-3p, miR-23b-3p, miR-130a-5p, miR-135a-5p, miR-135b-5p, miR-323-3p, miR-409-3p, miR-548c-3p, and miR-559) (Table 1) through bioinformatic target prediction (see SupplementaryMethods). We first tested the effect of each of these miRNAs on endogenous DISC1 expression in vitro. We transfected a commercial miRNA precursor of each miRNA, a negative control miRNA, or a positive control siRNA, into HEK293FT cells and measured DISC1 mRNA levels by qRT-PCR. We found that two of the nine miRNAs, miR-135b-5p and miR-559, significantly reduced DISC1 mRNA expression: miR-559 by 23.7% (P ¼ 0.009) and miR-135b-5p by 16.2% (P ¼ 0.039), comp...

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Section: Discussionmentioning

confidence: 99%

Allele-specific regulation of DISC1 expression by miR-135b-5p

et al. 2013

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“…To date, ϳ30 apoE variants have been characterized (11 ). Fourteen variants have been found to be associated with familial dysbetalipoproteinemia, a genetic lipid disorder characterized by increased plasma cholesterol and TG concentrations and an increased risk of atherosclerosis, whereas 7 were found to be associated with other forms of hyperlipoproteinemia (11 ).…”

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confidence: 99%

Three Novel Mutations in the Apolipoprotein E Gene in a Sample of Individuals with Type 2 Diabetes Mellitus

et al. 2005

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Background: Apolipoprotein E (apoE) is found in association with triglyceride-rich lipoproteins and is the ligand for the removal of these particles from the plasma. Genetic variations in exon 4 lead to three common gene variants: E2, E3, and E4. Methods: We performed apoE genotyping in 765 individuals with type 2 diabetes. Results: We identified three new variant heteroduplex patterns. Sequencing of these variants revealed three novel mutations that were related to biochemical and clinical characteristics. One mutation produced a frameshift at amino acid position 166, which predicted termination of protein synthesis. This individual had a heteroduplex pattern and sequence of E3E3, which was associated with a change in the plasma isoelectric focusing pattern and a 70% lower plasma concentration of apoE compared with healthy individuals. The other mutations were both single base changes. A CGC>CAC change at amino acid position 150 predicted a substitution of Arg>His. This individual had a heteroduplex pattern and sequence of E2E2, which was not associated with major changes in plasma lipids or apoE concentration. The third individual had a CGC>CCC base change at amino acid position 114, which predicted an Arg>Pro change. This person had a heteroduplex pattern and

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“…Each muscle was thawed out in 0.5 ml of RNAlater (Ambion, Abingdon, UK) and sliced into small pieces, followed by isolation of total RNA with Trizol Reagent (Life Technologies), according to the manufacturer's instructions. DNase treated RNA (1 g) was reverse transcribed with Superscript II RNase H -Reverse Transcriptase (Life Technologies) and an oligo (dT) [12][13][14][15][16][17][18] primer at 42°C, following the manufacturer's instructions. The derived cDNA (1 l from a 20 l reaction) was used to amplify a 227 bp product using a primer set specific for the human apoE sequence.…”

Section: Rt-pcr Analysismentioning

confidence: 99%

“…[10][11][12] There are three major variant isoforms of apoE, designated apoE2, apoE3 and apoE4 (encoded by polymorphic alleles, ⑀2, ⑀3 and ⑀4), of which apoE3 is the most common functional isoform. 6,13 Genetic deficiency in apoE and also the presence of apo⑀2 and apo⑀4 genes in the population are associated with predisposition to atherosclerosis and Alzheimer's disease, respectively. 13,14 In particular homozygosity for apo⑀2 is associated with type III hyperlipoproteinaemia, which is characterised by elevated levels of the chylomicron remnants, VLDL and IDL, with concomitant increases in cholesterol and triglyceride levels and with consequent predisposition to premature atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%