Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE

被引：80

作者：

Bekris, Lynn M. ^{[1
,2
]}

Lutz, Franziska ^{[2
]}

Yu, Chang-En ^{[2
]}

机构：

[1] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA

[2] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA

来源：

JOURNAL OF HUMAN GENETICS | 2012年 / 57卷 / 01期

基金：

美国国家卫生研究院;

关键词：

APOC1; APOE; BCR; enhancer; luciferase reporter assay; ME1; regulation; TOMM40; GENOME-WIDE ASSOCIATION; APOLIPOPROTEIN-E GENE; ONSET ALZHEIMERS-DISEASE; LINKAGE DISEQUILIBRIUM; SUSCEPTIBILITY GENES; QUANTITATIVE TRAIT; PROTEIN-LEVELS; EXPRESSION; BRAIN; RISK;

D O I：

10.1038/jhg.2011.123

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genetic variation within the apolipoprotein E gene (APOE) locus is associated with late-onset Alzheimer's disease risk and quantitative traits as well as apoE expression in multiple tissues. The aim of this investigation was to explore the influence of APOE locus cis-regulatory element enhancer region genetic variation on regional gene promoter activity. Luciferase reporter constructs containing haplotypes of APOE locus gene promoters; APOE, APOC1 and TOMM40, and regional putative enhancers; TOMM40 intervening sequence (IVS) 2-4, TOMM40 IVS6 poly-T, as well as previously described enhancers; multienhancer 1 (ME1), or brain control region (BCR), were evaluated for their effects on luciferase activity in three human cell lines. Results of this investigation demonstrate that in SHSY5Y cells, the APOE promoter is significantly influenced by the TOMM40 IVS2-4 and ME1, and the TOMM40 promoter is significantly influenced by the TOMM40 IVS6 poly-T, ME1 and BCR. In HepG2 cells, the TOMM40 promoter is significantly influenced by all four enhancers, whereas the APOE promoter is not influenced by any of the enhancers. The main novel finding of this investigation was that multiple APOE locus cis-elements influence both APOE and TOMM40 promoter activity according to haplotype and cell type, suggesting that a complex transcriptional regulatory structure modulates regional gene expression. Journal of Human Genetics (2012) 57, 18-25; doi: 10.1038/jhg.2011.123; published online 17 November 2011

引用

页码：18 / 25

页数：8

共 33 条

[1] Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene [J].

Artiga, MJ ;

Bullido, MJ ;

Sastre, I ;

Recuero, M ;

García, MA ;

Aldudo, J ;

Vázquez, J ;

Valdivieso, F .

FEBS LETTERS, 1998, 421 (02) :105-108

[2] Haploview: analysis and visualization of LD and haplotype maps [J].

Barrett, JC ;

Fry, B ;

Maller, J ;

Daly, MJ .

BIOINFORMATICS, 2005, 21 (02) :263-265

[3]

Bekris LM, 2008, J ALZHEIMERS DIS, V13, P255

[4] Genetics of Alzheimer Disease [J].

Bekris, Lynn M. ;

Yu, Chang-En ;

Bird, Thomas D. ;

Tsuang, Debby W. .

JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY, 2010, 23 (04) :213-227

[5] APOE mRNA and Protein Expression in Postmortem Brain Are Modulated by an Extended Haplotype Structure [J].

Bekris, Lynn M. ;

Galloway, Nichole M. ;

Montine, Thomas J. ;

Schellenberg, Gerard D. ;

Yu, Chang-En .

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 2010, 153B (02) :409-417

[6] Genome-wide association studies in Alzheimer's disease [J].

Bertram, Lars ;

Tanzi, Rudolph E. .

HUMAN MOLECULAR GENETICS, 2009, 18 :R137-R145

[7] A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia [J].

Bullido, MJ ;

Artiga, MJ ;

Recuero, M ;

Sastre, I ;

Garcia, MA ;

Aldudo, J ;

Lendon, C ;

Han, SW ;

Morris, JC ;

Frank, A ;

Vázquez, J ;

Goate, A ;

Valdivieso, F .

NATURE GENETICS, 1998, 18 (01) :69-71

[8] Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease [J].

Carrasquillo, Minerva M. ;

Zou, Fanggeng ;

Pankratz, V. Shane ;

Wilcox, Samantha L. ;

Ma, Li ;

Walker, Louise P. ;

Younkin, Samuel G. ;

Younkin, Curtis S. ;

Younkin, Linda H. ;

Bisceglio, Gina D. ;

Ertekin-Taner, Nilufer ;

Crook, Julia E. ;

Dickson, Dennis W. ;

Petersen, Ronald C. ;

Graff-Radford, Neill R. ;

Younkin, Steven G. .

NATURE GENETICS, 2009, 41 (02) :192-198

[9] A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease [J].

Coon, Keith D. ;

Myers, Amanda J. ;

Craig, David W. ;

Webster, Jennifer A. ;

Pearson, John V. ;

Lince, Diane Hu ;

Zismann, Victoria L. ;

Beach, Thomas G. ;

Leung, Doris ;

Bryden, Leslie ;

Halperin, Rebecca F. ;

Marlowe, Lauren ;

Kaleem, Mona ;

Walker, Douglas G. ;

Ravid, Rivka ;

Heward, Christopher B. ;

Rogers, Joseph ;

Papassotiropoulos, Andreas ;

Reiman, Eric M. ;

Hardy, John ;

Stephan, Dietrich A. .

JOURNAL OF CLINICAL PSYCHIATRY, 2007, 68 (04) :613-618

[10] Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited [J].

Deelen, Joris ;

Beekman, Marian ;

Uh, Hae-Won ;

Helmer, Quinta ;

Kuningas, Maris ;

Christiansen, Lene ;

Kremer, Dennis ;

van der Breggen, Ruud ;

Suchiman, H. Eka D. ;

Lakenberg, Nico ;

van den Akker, Erik B. ;

Passtoors, Willemijn M. ;

Tiemeier, Henning ;

van Heemst, Diana ;

de Craen, Anton J. ;

Rivadeneira, Fernando ;

de Geus, Eco J. ;

Perola, Markus ;

van der Ouderaa, Frans J. ;

Gunn, David A. ;

Boomsma, Dorret I. ;

Uitterlinden, Andre G. ;

Christensen, Kaare ;

van Duijn, Cornelia M. ;

Heijmans, Bastiaan T. ;

Houwing-Duistermaat, Jeanine J. ;

Westendorp, Rudi G. J. ;

Slagboom, P. Eline .

AGING CELL, 2011, 10 (04) :686-698

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