Low-frequency coding variants at 6p21.33 and 20q11.21 are associated with lung cancer risk in Chinese populations.
Genome-wide association studies have successfully identified a subset of common variants associated with lung cancer risk. However, these variants explain only a fraction of lung cancer heritability. It has been proposed that low-frequency or rare variants might have strong effects and contribute to the missing heritability. To assess the role of low-frequency or rare variants in lung cancer development, we analyzed exome chips representing 1,348 lung cancer subjects and 1,998 control subjects during the discovery stage and subsequently evaluated promising associations in an additional 4,699 affected subjects and 4,915 control subjects during the replication stages. Single-variant and gene-based analyses were carried out for coding variants with a minor allele frequency less than 0.05. We identified three low-frequency missense variants in BAT2 (rs9469031, c.1544C>T [p.Pro515Leu]; odds ratio [OR] = 0.55, p = 1.28 × 10(-10)), FKBPL (rs200847762, c.410C>T [p.Pro137Leu]; OR = 0.25, p = 9.79 × 10(-12)), and BPIFB1 (rs6141383, c.850G>A [p.Val284Met]; OR = 1.72, p = 1.79 × 10(-7)); these variants were associated with lung cancer risk. rs9469031 in BAT2 and rs6141383 in BPIFB1 were also associated with the age of onset of lung cancer (p = 0.001 and 0.006, respectively). BAT2 and FKBPL at 6p21.33 and BPIFB1 at 20q11.21 were differentially expressed in lung tumors and paired normal tissues. Gene-based analysis revealed that FKBPL, in which two independent variants were identified, might account for the association with lung cancer risk at 6p21.33. Our results highlight the important role low-frequency variants play in lung cancer susceptibility and indicate that candidate genes at 6p21.33 and 20q11.21 are potentially biologically relevant to lung carcinogenesis.
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China.
Guangfu
G
Jin
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Meng
M
Zhu
Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University Affiliated Cancer Hospital, Nanjing 210009, China.
Rong
R
Yin
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Wei
W
Shen
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Jia
J
Liu
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Jie
J
Sun
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Cheng
C
Wang
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Juncheng
J
Dai
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Hongxia
H
Ma
State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Chen
C
Wu
Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110001, China.
Zhihua
Z
Yin
Medimmune, Gaithersburg, MD 20878, USA.
Jiaqi
J
Huang
Medimmune, Gaithersburg, MD 20878, USA.
Brandon W
BW
Higgs
Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University Affiliated Cancer Hospital, Nanjing 210009, China.
Lin
L
Xu
Medimmune, Gaithersburg, MD 20878, USA.
Yihong
Y
Yao
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA.
David C
DC
Christiani
Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
Christopher I
CI
Amos
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University Affiliated Cancer Hospital, Nanjing 210009, China.
Zhibin
Z
Hu
Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110001, China.
Baosen
B
Zhou
Ministry of Education Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China.
Yongyong
Y
Shi
State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Dongxin
D
Lin
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: hbshen@njmu.edu.cn.
Hongbing
H
Shen
D044466:Asian People; D001324:Autoantigens / Q000235:genetics; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D050556:Fatty Acid-Binding Proteins; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020104:Immunophilins / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D011506:Proteins / Q000235:genetics; D012307:Risk Factors; D022021:Tacrolimus Binding Proteins
D001324:Autoantigens; C568077:BPIFB1 protein, human; C400101:FKBPL protein, human; D050556:Fatty Acid-Binding Proteins; D011506:Proteins; C092008:PRRC2A protein, human; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins