Identification of TRPCs genetic variants that modify risk for lung cancer based on the pathway and two-stage study.
OBJECTIVE
Store operated calcium channels (SOCCs) and Receptor-operated calcium channels (ROCCs) are important pathways participating in regulation of intracellular Ca(2 +) concentration in various cell types. The purpose of our study is to determine whether genetic variations in key components of SOCCs and ROCCs are associated with lung cancer risk.


METHODS
We identified 236 tagSNPs in 9 key genes related to SOCCs and ROCCs (TRPC1, TRPC3, TRPC4, TRPC6, TRPC7, ORAI1, ORAI2, STIM1, and STIM2) and evaluated their association with lung cancer risk in a two-stage case-control study with a total of 2433 lung cancer cases and 2433 cancer-free controls using Illumina high throughput genotyping platform.


RESULTS
We found consistently significant associations of TRPC4 rs9547991 and rs978156, and TRPC7 rs11748198 with increased risk of lung cancer among the three kinds of sources of populations (additive model in combined population: adjusted OR = 1.33, 95% CI = 1.11-1.59 for rs9547991; adjusted OR = 1.21, 95% CI = 1.08-1.35 for rs978156; and adjusted OR = 1.28, 95% CI = 1.10-1.47 for rs11748198). When combining the effects of TRPC7 rs11748198, and TRPC4 rs9547991 and rs978156, subjects carrying "≥ 1" variant alleles had a 1.29-fold increased risk of lung cancer (95% CI = 1.15-1.46), compared with those carrying "0" variant allele. Lung cancer risk significantly increased with the increasing number of variant alleles of the three SNPs in a dose-dependent manner (P for trend = 7.2 × 10(- 7)).


CONCLUSIONS
These findings suggested that TRPC4 rs9547991 and rs978156, and TRPC7 rs11748198 were candidate susceptibility markers for lung cancer in Chinese population. Our study provides the epidemiological evidence supporting a connection between TRPC members and lung cancer risks.
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Zili
Z
Zhang
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Jian
J
Wang
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Jianxing
J
He
Department of Respiratory Medicine, Xiangyang Central Hospital, Xiangyang, China.
Xiansheng
X
Zeng
The First Municipal Hospital of Lufeng, Lufeng, China.
Xindong
X
Chen
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Mingmei
M
Xiong
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Qipeng
Q
Zhou
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Meihua
M
Guo
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Defu
D
Li
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; Department of Laboratory Medicine, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Wenju
W
Lu
CI, confidence interval; Genetic variants; HWE, Hardy-Weinberg equilibrium; LD, linkage disequilibrium; Lung cancer; MAF, minor allele frequency; OR, odds ratio; ROCCs; ROCCs, receptor-operated Ca2 + channels; SNP, single nucleotide polymorphism; SOCCs; SOCCs, Store-operated Ca2 + channels; SOCE, Store-operated Ca2 + entry channels; TRPCs; tagSNPs, tagging single nucleotide polymorphisms