Fine mapping of chromosome 5p15.33 identifies novel lung cancer susceptibility loci in Han Chinese.
Genome-wide association studies in European and Asian populations have consistently identified chromosome 5p15.33 as a lung cancer susceptibility region. To investigate further the genetic architecture of common variants in this region, we conducted a two-stage fine-mapping analysis discovered by targeted resequencing of 200 cases and 300 controls individually, and validated in multiethnic lung cancer Genome wide association studies (GWASs) with 12,843 cases and 12,639 controls. Two independent variants were identified in approximate conditional analysis with GCTA and consistently validated in lung cancer GWASs in both Asian and European populations. These were rs10054203 in TERT (resequencing: OR = 1.69, p = 2.70 × 10-4; validation: OR = 1.34, p = 2.10 × 10-23for Asian, and OR = 1.09, p = 6.00 × 10-3for European), and rs397640 in CLPTM1L (resequencing: OR = 0.37, p = 1.19 × 10-4; validation: OR = 0.75, p = 5.89 × 10-8for Asian, and OR = 0.90, p = 2.40 × 10-2for European). Expression quantitative trait loci analysis showed the risk allele (C) of rs10054203 was significantly associated with lower mRNA expression of CTD-2245Ef15.3 (p = 0.019) and Tubulin Polymerization-Promoting Protein (TPPP, p = 0.031) in 167 lung tissues. In conclusion, in this largest and first resequencing-based fine-mapping analysis of 5p15.33 region in Han Chinese, we identified two novel variants associated with lung cancer susceptibility. Further validation studies and functional work is required to confirm the roles of the newly discovered variants.
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Jing
J
Dong
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Yang
Y
Cheng
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Meng
M
Zhu
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Yang
Y
Wen
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.
Yuzhuo
Y
Wang
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Liguo
L
Geng
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.
Zhihua
Z
Li
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Jiahui
J
Zhang
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China.
Hongxia
H
Ma
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China.
Juncheng
J
Dai
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer 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.|Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China.
Zhibin
Z
Hu
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China.
Hongbing
0000-0002-2581-5906
H
Shen
D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D019098:Telomerase / Q000235:genetics*
D014408:Biomarkers, Tumor; C422445:CLPTM1L protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C509186:TERT protein, human; D019098:Telomerase
Chinese population; chromosome 5p15.33; fine mapping; lung cancer; susceptibility loci