Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor.
Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor.
复制标题
顺式调节XRN2表达的遗传变异有助于自发肺肿瘤的风险。
作者：
Lu Y;Liu P;James M;Vikis HG;Liu H;Wen W;Franklin A;You M
基因表达变异是复杂疾病易感性的重要机制。与烟草相关的肺癌发生相比，非吸烟者的肺癌可能涉及重要的、病因学上不同的因果途径。在本研究中，我们对近交系小鼠自发性肺肿瘤发病率进行了全基因组关联研究，并在小鼠2号染色体上发现了一个主要易感位点（rs27328255, P = 6.68 × 10−7）。然后，我们评估了正常肺中多态性与位置候选基因转录的相关性。单核苷酸多态性rs27328255与Xrn2转录物水平呈一致且强烈的顺式相关（P = 7.42 × 10−9）。我们进一步发现Xrn2促进人肺上皮细胞增殖并抑制鳞状分化，人类同源Xrn2多态性与人肺癌相关（rs2025811, P = 1.90 × 10−3,OR = 1.20）。我们得出结论，调节顺式Xrn2表达的遗传变异是小鼠自发性肺癌易感性的决定因素，并且在人类肺癌易感性中具有遗传等效性。确定Xrn2作为自发性肺癌的主要候选基因对于肺癌的诊断和治疗以及描述非吸烟者肺癌发生的潜在机制具有重要意义。
Gene expression variation is an important mechanism underlying susceptibility to complex disease. In comparison with tobacco-related lung carcinogenesis, lung cancer in nonsmokers may involve important and etiologically distinct causal pathways. In this study, we conducted a genome-wide association study on spontaneous lung tumor incidence in inbred mice and identified a major susceptibility locus on mouse chromosome 2 (rs27328255, P = 6.68 × 10−7). We then evaluated the correlations of polymorphisms with the transcription of positional candidate genes in normal lungs. Single-nucleotide polymorphism rs27328255 was consistently and strongly associated (P = 7.42 × 10−9) in cis with transcript levels of Xrn2. We further showed that Xrn2 promotes proliferation and inhibits squamous differentiation in human lung epithelial cells and polymorphisms in human homolog XRN2 are associated with human lung cancer (rs2025811, P = 1.90 × 10−3, OR = 1.20). We conclude that genetic variants regulating Xrn2 expression in cis are determinants of spontaneous lung tumor susceptibility in mice and have genetic equivalents in lung cancer susceptibility in human beings. Identifying Xrn2 as a major candidate for spontaneous lung cancer has important implications for the diagnosis and treatment of lung cancer as well as delineation of the mechanisms underlying the genesis of lung cancer in nonsmokers.
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影响因子：
30.8
作者：
McKay, James D.;Hung, Rayjean J.;Gaborieau, Valerie;Boffetta, Paolo;Chabrier, Amelie;Byrnes, Graham;Zaridze, David;Mukeria, Anush;Szeszenia-Dabrowska, Neonilia;Lissowska, Jolanta;Rudnai, Peter;Fabianova, Eleonora;Mates, Dana;Bencko, Vladimir;Foretova, Lenka;Janout, Vladimir;McLaughlin, John;Shepherd, Frances;Montpetit, Alexandre;Narod, Steven;Krokan, Hans E.;Skorpen, Frank;Elvestad, Maiken Bratt;Vatten, Lars;Njolstad, Inger;Axelsson, Tomas;Chen, Chu;Goodman, Gary;Barnett, Matt;Loomis, Melissa M.;Lubinski, Jan;Matyjasik, Joanna;Lener, Marcin;Oszutowska, Dorota;Field, John;Liloglou, Triantafillos;Xinarianos, George;Cassidy, Adrian;Zelenika, Diana;Boland, Anne;Delepine, Marc;Foglio, Mario;Lechner, Doris;Matsuda, Fumihiko;Blanche, Helene;Gut, Ivo;Heath, Simon;Lathrop, Mark;Brennan, Paul
通讯作者：
Brennan, Paul
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
对家族史与肺癌风险之间关系的系统评价。
影响因子：
8.8
作者：
Matakidou, A;Eisen, T;Houlston, RS
通讯作者：
Houlston, RS
DOI：
10.1513/pats.200607-143jg
发表时间：
2007-01-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Borczuk, Alain C;Powell, Charles A
通讯作者：
Powell, Charles A
影响因子：
2.9
作者：
KE, Y;REDDEL, RR;HARRIS, CC
通讯作者：
HARRIS, CC