Promoter Polymorphisms and Transcript Levels of Nicotinic Receptor CHRNA5

被引：36

作者：

Falvella, Felicia S. ^{[1
]}

Galvan, Antonella ^{[1
]}

Colombo, Francesca ^{[1
]}

Frullanti, Elisa ^{[1
]}

Pastorino, Ugo ^{[2
]}

Dragani, Tommaso A. ^{[1
]}

机构：

[1] Fdn IRCCS Ist Nazl Tumori, Dept Predict & Prevent Med, I-20133 Milan, Italy

[2] Fdn IRCCS Ist Nazl Tumori, Dept Thorac Surg, I-20133 Milan, Italy

来源：

JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2010年 / 102卷 / 17期

关键词：

LUNG-CANCER; SUSCEPTIBILITY LOCUS; 15Q25; LOCUS; RISK; DEPENDENCE; DEREGULATION; ASSOCIATION; GENES;

D O I：

10.1093/jnci/djq264

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Chromosomal locus 15q25, implicated in lung cancer risk and nicotine dependence, shows extensive linkage disequilibrium that complicates identification of causal variation. Cholinergic receptor nicotinic alpha 5 (CHRNA5) has been identified as a lung cancer risk factor. We identified by sequence analysis three haplotypes (delTTC, insATC, and insTGG) in the 5' promoter region and three at the 3'-untranslated region of CHRNA5. Linkage disequilibrium analysis of the 5' variants showed that the insTGG haplotype is associated with three tightly linked risk alleles (nicotine dependence, lung cancer, and chronic obstructive pulmonary disease). The three CHRNA5 promoter haplotypes were statistically significantly associated with lung CHRNA5 transcript levels, determined by real-time polymerase chain reaction. In nontumor lung parenchyma from 68 patients who underwent lung lobectomy, the delTTC haplotype was associated with the highest CHRNA5 transcript levels (relative quantification units = 1.82), whereas the insTGG haplotype was associated with the lowest (0.88 units, P(diff) < .001, Welch t test; all statistical tests were two-sided). Luciferase reporter assays in human lung cancer cell lines A549, H460, H520, and H596 also showed that the 5' region haplotypes were statistically significantly associated with changes in CHRNA5 promoter activity, whereas the 3'-untranslated region variants were not.

引用

页码：1366 / 1370

页数：5

共 10 条

[1] Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 [J].

Amos, Christopher I. ;

Wu, Xifeng ;

Broderick, Peter ;

Gorlov, Ivan P. ;

Gu, Jian ;

Eisen, Timothy ;

Dong, Qiong ;

Zhang, Qing ;

Gu, Xiangjun ;

Vijayakrishnan, Jayaram ;

Sullivan, Kate ;

Matakidou, Athena ;

Wang, Yufei ;

Mills, Gordon ;

Doheny, Kimberly ;

Tsai, Ya-Yu ;

Chen, Wei Vivien ;

Shete, Sanjay ;

Spitz, Margaret R. ;

Houlston, Richard S. .

NATURE GENETICS, 2008, 40 (05) :616-622

[2] JLIN: A java']java based linkage disequilibrium plotter [J].

Carter, KW ;

McCaskie, PA ;

Palmer, LJ .

BMC BIOINFORMATICS, 2006, 7 (1)

[3]

Falvella FS, 2009, CLIN CANCER RES, V15, P5599, DOI 10.1158/1078-0432.CCR-09-1441

[4] Transcription Deregulation at the 15q25 Locus in Association with Lung Adenocarcinoma Risk [J].

Falvella, Felicia S. ;

Galvan, Antonella ;

Frullanti, Elisa ;

Spinola, Monica ;

Calabro, Elisa ;

Carbone, Antonino ;

Incarbone, Matteo ;

Santambrogio, Luigi ;

Pastorino, Ugo ;

Dragani, Tommaso A. .

CLINICAL CANCER RESEARCH, 2009, 15 (05) :1837-1842

[5] A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 [J].

Hung, Rayjean J. ;

Mckay, James D. ;

Gaborieau, Valerie ;

Boffetta, Paolo ;

Hashibe, Mia ;

Zaridze, David ;

Mukeria, Anush ;

Szeszenia-Dabrowska, Neonilia ;

Lissowska, Jolanta ;

Rudnai, Peter ;

Fabianova, Eleonora ;

Mates, Dana ;

Bencko, Vladimir ;

Foretova, Lenka ;

Janout, Vladimir ;

Chen, Chu ;

Goodman, Gary ;

Field, John K. ;

Liloglou, Triantafillos ;

Xinarianos, George ;

Cassidy, Adrian ;

McLaughlin, John ;

Liu, Geoffrey ;

Narod, Steven ;

Krokan, Hans E. ;

Skorpen, Frank ;

Elvestad, Maiken Bratt ;

Hveem, Kristian ;

Vatten, Lars ;

Linseisen, Jakob ;

Clavel-Chapelon, Francoise ;

Vineis, Paolo ;

Bueno-de-Mesquita, H. Bas ;

Lund, Eiliv ;

Martinez, Carmen ;

Bingham, Sheila ;

Rasmuson, Torgny ;

Hainaut, Pierre ;

Riboli, Elio ;

Ahrens, Wolfgang ;

Benhamou, Simone ;

Lagiou, Pagona ;

Trichopoulos, Dimitrios ;

Holcatova, Ivana ;

Merletti, Franco ;

Kjaerheim, Kristina ;

Agudo, Antonio ;

Macfarlane, Gary ;

Talamini, Renato ;

Simonato, Lorenzo .

NATURE, 2008, 452 (7187) :633-637

[6] A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci [J].

Pillai, Sreekumar G. ;

Ge, Dongliang ;

Zhu, Guohua ;

Kong, Xiangyang ;

Shianna, Kevin V. ;

Need, Anna C. ;

Feng, Sheng ;

Hersh, Craig P. ;

Bakke, Per ;

Gulsvik, Amund ;

Ruppert, Andreas ;

Carlsen, Karin C. Lodrup ;

Roses, Allen ;

Anderson, Wayne ;

Rennard, Stephen I. ;

Lomas, David A. ;

Silverman, Edwin K. ;

Goldstein, David B. .

PLOS GENETICS, 2009, 5 (03)

[7] Multiple Distinct Risk Loci for Nicotine Dependence Identified by Dense Coverage of the Complete Family of Nicotinic Receptor Subunit (CHRN) Genes [J].

Saccone, Nancy L. ;

Saccone, Scott F. ;

Hinrichs, Anthony L. ;

Stitzel, Jerry A. ;

Duan, Weimin ;

Pergadia, Michele L. ;

Agrawal, Arpana ;

Breslau, Naomi ;

Grucza, Richard A. ;

Hatsukami, Dorothy ;

Johnson, Eric O. ;

Madden, Pamela A. F. ;

Swan, Gary E. ;

Wang, Jen C. ;

Goate, Alison M. ;

Rice, John P. ;

Bierut, Laura J. .

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 2009, 150B (04) :453-466

[8] A variant associated with nicotine dependence, lung cancer and peripheral arterial disease [J].

Thorgeirsson, Thorgeir E. ;

Geller, Frank ;

Sulem, Patrick ;

Rafnar, Thorunn ;

Wiste, Anna ;

Magnusson, Kristinn P. ;

Manolescu, Andrei ;

Thorleifsson, Gudmar ;

Stefansson, Hreinn ;

Ingason, Andres ;

Stacey, Simon N. ;

Bergthorsson, Jon T. ;

Thorlacius, Steinunn ;

Gudmundsson, Julius ;

Jonsson, Thorlakur ;

Jakobsdottir, Margret ;

Saemundsdottir, Jona ;

Olafsdottir, Olof ;

Gudmundsson, Larus J. ;

Bjornsdottir, Gyda ;

Kristjansson, Kristleifur ;

Skuladottir, Halla ;

Isaksson, Helgi J. ;

Gudbjartsson, Tomas ;

Jones, Gregory T. ;

Mueller, Thomas ;

Gottsater, Anders ;

Flex, Andrea ;

Aben, Katja K. H. ;

de Vegt, Femmie ;

Mulders, Peter F. A. ;

Isla, Dolores ;

Vidal, Maria J. ;

Asin, Laura ;

Saez, Berta ;

Murillo, Laura ;

Blondal, Thorsteinn ;

Kolbeinsson, Halldor ;

Stefansson, Jon G. ;

Hansdottir, Ingunn ;

Runarsdottir, Valgerdur ;

Pola, Roberto ;

Lindblad, Bengt ;

van Rij, Andre M. ;

Dieplinger, Benjamin ;

Haltmayer, Meinhard ;

Mayordomo, Jose I. ;

Kiemeney, Lambertus A. ;

Matthiasson, Stefan E. ;

Oskarsson, Hogni .

NATURE, 2008, 452 (7187) :638-U9

[9] Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5 [J].

Wang, Jen C. ;

Cruchaga, Carlos ;

Saccone, Nancy L. ;

Bertelsen, Sarah ;

Liu, Pengyuan ;

Budde, John P. ;

Duan, Weimin ;

Fox, Louis ;

Grucza, Richard A. ;

Kern, Jason ;

Mayo, Kevin ;

Reyes, Oliver ;

Rice, John ;

Saccone, Scott F. ;

Spiegel, Noah ;

Steinbach, Joseph H. ;

Stitzel, Jerry A. ;

Anderson, Marshall W. ;

You, Ming ;

Stevens, Victoria L. ;

Bierut, Laura J. ;

Goate, Alison M. .

HUMAN MOLECULAR GENETICS, 2009, 18 (16) :3125-3135

[10] Lung cancer gene associated with COPD: triple whammy or possible confounding effect? [J].

Young, R. P. ;

hophins, R. J. ;

Hay, B. A. ;

Epton, M. J. ;

Black, P. N. ;

Gamble, G. D. .

EUROPEAN RESPIRATORY JOURNAL, 2008, 32 (05) :1158-1164

← 1 →