Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.

BACKGROUND Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies. METHODS Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided. RESULTS Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer. CONCLUSIONS In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.

Paul Brennan | Yun-Chul Hong | Kari Stefansson | Peter Nürnberg | Eric J Duell | Keitaro Matsuo | Hermann Brenner | Jin Hee Kim | Christopher I Amos | Thomas Illig | Kazuo Tajima | M Dawn Teare | Ping Yang | Joshua E Muscat | Philip Lazarus | Chen Ying | Angela Risch | John K Wiencke | Gad Rennert | Shanbeh Zienolddiny | Angeline S Andrew | Karl T Kelsey | Margaret Wrensch | James D McKay | H-Erich Wichmann | Thorunn Rafnar | Xifeng Wu | John McLaughlin | Heike Bickeböller | Ruoxiang Jiang | Therese Truong | L. Kiemeney | K. Stefánsson | H. Brenner | M. Spitz | H. Dienemann | L. Marchand | G. Rennert | Xifeng Wu | C. Amos | L. Le Marchand | T. Illig | T. Rafnar | J. Mayordomo | A. Andrew | Zuo-Feng Zhang | Shen-Chih Chang | T. Truong | H. Müller | K. Matsuo | A. Risch | Ping Yang | H. Bickeböller | E. Stoelben | K. Kelsey | Geoffrey Liu | E. Duell | R. Hung | M. Teare | S. Zienolddiny | A. Haugen | M. Wrensch | J. Wiencke | P. Nürnberg | A. Schwartz | J. McLaughlin | Yun-Chul Hong | P. Brennan | H. Hansen | H. Wichmann | S. Benhamou | J. McLaughlin | J. McKay | A. Wenzlaff | J. McLaughlin | J. Muscat | R. Kaaks | F. Lejbkowicz | K. Tajima | C. Bouchardy | P. Lazarus | C. Gallagher | X. Xue | A. Rosenberger | A. Seow | H. F. M. van der Heijden | D. Isla | J. H. Kim | Margaret R Spitz | Hendrik Dienemann | Lambertus A Kiemeney | Loïc Le Marchand | Simone Benhamou | W. Sauter | Zuo-Feng Zhang | Adeline Seow | Shen-Chih Chang | Heiko Müller | Rayjean J Hung | Geoffrey Liu | Ann G Schwartz | Wiebke Sauter | Albert Rosenberger | Erich Stoelben | Flavio Lejbkowicz | A. Staratschek-Jox | Rudolph Kaaks | Christine Bouchardy | Carla J Gallagher | Jose Ignacio Mayordomo | Aage Haugen | Ruoxiang Jiang | C. Ying | J. Wolf | Dolores Isla | Andrea Staratschek-Jox | Helen Hansen | Jürgen Wolf | Henricus F M van der Heijden | Xiaoyan Xue | Angie Wenzlaff | H. F. M. Heijden | Y.-C. Hong | A. Staratschek‐Jox | H. V. D. van der Heijden | J. Mckay | H. Müller | Thérèse Truong | Zuo‐Feng Zhang | Kari Stefansson | Simone Benhamou | Thérèse Truong | John McLaughlin | John R McLaughlin | S. Benhamou | Kári Stefánsson | Heiko Müller | Yun-Chul Hong

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