A newly identified polymorphism in the apolipoprotein E enhancer gene region is associated with Alzheimer's disease and strongly with the epsilon 4 allele

Mui, Stina; Briggs, Megan; Chung, Hwan‐Suck; Rb, Wallace; Gómez-Isla, Teresa; Rebeck, G. William; Hyman, B. T.

doi:10.1212/wnl.47.1.196

Cited by 66 publications

(38 citation statements)

References 13 publications

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“…An enhancer sequence has also been identified in intron 1 of APOE, and a variant at position 1163 was found in this region as well (Fig. 1b;Mui et al 1996). Although both of these sites lie in regulatory regions, neither is located in one of the mapped protein-binding sequences identified in APOE (Fig.…”

Section: Apoe Sequence Variants In the Core Samplementioning

confidence: 81%

“…; J. Stengård, in prep.) A number of recent studies have focused attention on SNPs in the 5Ј flanking region of APOE that could alter gene expression and be involved in the phenotypic associations with Alzheimer's disease and CVD risk (Mui et al 1996;Artiga et al 1998a,b;Bullido et al 1998;Lambert et al 1998a,b;Lambert et al 2000). Several of these SNPs, known as -491A/T (position 560) and -427 C/T (position 624), have been associated with an increased risk of Alzheimer's disease that is independent of the 4 status of the individual (Artiga et al 1998a,b;Bullido et al 1998;Martin et al 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Although APOE is often presented as a paradigm for SNP analysis in the human genome, there has yet to be a systematic survey of sequence variation within this gene. Furthermore, it has become clear that not all individuals with the same APOE protein genotype are at equivalent risk, and variants in the regulatory regions unrelated to the protein isoforms have been identified that may have functional relevance and complicate the simple subdivision into three haplotypes (Mui et al 1996;Artiga et al 1998a,b;Bullido et al 1998;Lambert et al 1998a,b). Therefore, we have undertaken a comprehensive analysis of the genomic sequence of APOE to gain a better understanding of the natural variation in this gene.…”

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confidence: 99%

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Sequence Diversity and Large-Scale Typing of SNPs in the Human Apolipoprotein E Gene

Nickerson¹,

Taylor²,

Fullerton³

et al. 2000

Genome Res.

163

110

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A common strategy for genotyping large samples begins with the characterization of human single nucleotide polymorphisms (SNPs) by sequencing candidate regions in a small sample for SNP discovery. This is usually followed by typing in a large sample those sites observed to vary in a smaller sample. We present results from a systematic investigation of variation at the human apolipoprotein E locus (APOE), as well as the evaluation of the two-tiered sampling strategy based on these data. We sequenced 5.5 kb spanning the entire APOE genomic region in a core sample of 72 individuals, including 24 each of African-Americans from Jackson, Mississippi; European-Americans from Rochester, Minnesota; and Europeans from North Karelia, Finland. This sequence survey detected 21 SNPs and 1 multiallelic indel, 14 of which had not been previously reported. Alleles varied in relative frequency among the populations, and 10 sites were polymorphic in only a single population sample. Oligonucleotide ligation assays (OLA) were developed for 20 of these sites (omitting the indel and a closely-linked SNP). These were then scored in 2179 individuals sampled from the same three populations (n = 843, 884, and 452, respectively). Relative allele frequencies were generally consistent with estimates from the core sample, although variation was found in some populations in the larger sample at SNPs that were monomorphic in the corresponding smaller core sample. Site variation in the larger samples showed no systematic deviation from Hardy-Weinberg expectation. The large OLA sample clearly showed that variation in many, but not all, of OLA-typed SNPs is significantly correlated with the classical protein-coding variants, implying that there may be important substructure within the classical 2, 3, and 4 alleles. Comparison of the levels and patterns of polymorphism in the core samples with those estimated for the OLA-typed samples shows how nucleotide diversity is underestimated when only a subset of sites are typed and underscores the importance of adequate population sampling at the polymorphism discovery stage.

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Section: Apoe Sequence Variants In the Core Samplementioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Sequence Diversity and Large-Scale Typing of SNPs in the Human Apolipoprotein E Gene

Nickerson¹,

Taylor²,

Fullerton³

et al. 2000

Genome Res.

163

110

View full text Add to dashboard Cite

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“…It has earlier been shown that the region between ϩ44 and ϩ262 (IRE1) has enhancer activity, 24 but the ϩ113 allelic status in that study is unknown because the SNP was identified almost 10 years later. 25 We studied the enhancer activity using a smaller 50-bp region (from ϩ89 to ϩ138) of the first intron region in the APOE gene. Our transcription experiments showed that primarily the ϩ113C allele has an effect on the luciferase gene expression, mainly acting as a transcriptional enhancer.…”

Section: Apoe ؉113g/c Snp Region Can Act As An Enhancermentioning

confidence: 99%

Interactions of Functional Apolipoprotein E Gene Promoter Polymorphisms With Smoking on Aortic Atherosclerosis

Viiri

Ilveskoski

et al. 2008

Circ Cardiovasc Genet

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Background-Apolipoprotein E gene (APOE) interacts with environmental factors in defining risk for atherosclerosis. We studied whether the APOE 2/3/4 genotype or APOE promoter polymorphisms Ϫ219G/T and ϩ113G/C might interact with smoking on the development of fatty streaks. We also studied the previously unknown effects of ϩ113G/C on transcriptional activity. Methods and Results-The fatty streak areas of aorta were measured morphometrically in subjects of the Helsinki Sudden Death Study. Within APOE 3/3 subjects, there was a strong interaction between smoking and both Ϫ219G/T (Pϭ0.009) and ϩ113G/C (Pϭ0.003) promoter polymorphisms on abdominal aorta fatty streak area: the Ϫ219T-and ϩ113C-allele carriers had larger lesion areas compared with G/G (12.7% versus 5.9%, Pϭ0.007; 12.9% versus 6.3%, Pϭ0.010, respectively) within nonsmokers. Within smokers, the associations were inverse. Moreover, smoking increased the fatty streak area within Ϫ219G/G or ϩ113G/G genotypes and Ϫ219G/ϩ113G/3 haplotype carriers. Functional studies in reporter assay showed that in comparison with the ϩ113G allele, the ϩ113C allele had higher transcriptional activity and bound transcription factors from liver cell nuclear extract with significantly lower affinity. Conclusions-In middle-aged Finnish men with APOE 3/3 genotype, the APOE promoter polymorphisms Ϫ219G/T and ϩ113G/C interact with smoking in modulating aortic atherosclerosis. The ϩ113G/C polymorphism has an effect on transcriptional activity. (Circ Cardiovasc Genet. 2008;1:107-116.)

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“…Another SNP of APOE, -219G/T, located in the promoter of APOE, was reported to be significantly associated with APOE promoter activity, apoE plasma concentration, and CAD (7,8,10). In addition, the 113G/C SNP of APOE may be relevant for APOE regulation because of its location in the APOE intron-1 enhancer element that constitutes a binding site for specific nuclear protein factors (15,16).…”

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confidence: 99%

Apolipoprotein E gene polymorphisms and thrombosis and restenosis after coronary artery stenting

Koch

Mehilli

Pfeufer

et al. 2004

Journal of Lipid Research

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Experimental data support a protective function of apolipoprotein E (apoE) against restenosis, the main factor limiting the long-term benefit of percutaneous coronary interventions. We investigated the possibility that the single nucleotide polymorphisms (SNPs) -219G/T, 113G/C, 334T/C, and 472C/T of the gene encoding apoE (APOE) are associated with the incidence of death and myocardial infarction or restenosis after stenting in coronary arteries. In addition, we asked whether the apoE isotype-related 2/ 3/ 4 polymorphism, defined by specific allele combinations (haplotypes) of the 334T/C and 472C/T polymorphism, and other APOE haplotypes, derived from all four SNPs investigated, are associated with adverse clinical and angiographic outcomes after stenting. Our study included 1,850 consecutive patients with symptomatic coronary artery disease (CAD) who underwent stent implantation. Follow-up angiography was performed in 1,556 patients (84.1%) at 6 months after the intervention. We found that none of the APOE SNPs is associated with death and myocardial infarction or restenosis after stenting. In addition, we observed no relationship between APOE haplotypes and adverse outcomes. In conclusion, the APOE -219G/T, 113G/C, 334T/C, and 472C/T polymorphisms, either alone or in combination, do not represent genetic markers of the risk of thrombotic and restenotic complications in patients with CAD treated with coronary stenting. -

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A newly identified polymorphism in the apolipoprotein E enhancer gene region is associated with Alzheimer's disease and strongly with the epsilon 4 allele

Cited by 66 publications

References 13 publications

Sequence Diversity and Large-Scale Typing of SNPs in the Human Apolipoprotein E Gene

Sequence Diversity and Large-Scale Typing of SNPs in the Human Apolipoprotein E Gene

Interactions of Functional Apolipoprotein E Gene Promoter Polymorphisms With Smoking on Aortic Atherosclerosis

Apolipoprotein E gene polymorphisms and thrombosis and restenosis after coronary artery stenting

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