Genetic variants in MGMT and risk of lung cancer in southeastern Chinese:: A haplotype based analysis

被引:44
作者
Hu, Zhibin
Wang, Haifeng
Shao, Minhua
Jin, Guangfu
Sun, Weiwei
Wang, Yi
Liu, Hongliang
Wang, Ying
Ma, Hongxia
Qian, Ji
Jin, Li
Wei, Qingyi
Lu, Daru
Huang, Wei
Shen, Hongbing [1 ]
机构
[1] Nanjing Med Univ, Canc Res Ctr, Dept Epidemiol & Biostat, Nanjing 210029, Peoples R China
[2] Shanghai S Gene Technol Co Ltd, Shanghai, Peoples R China
[3] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China
[4] Chinese Natl Human Genome Ctr, Dept Genet, Shanghai, Peoples R China
[5] Shanghai Jiao Tong Univ, Rui Jin Hosp, Sch Med, Shanghai 200030, Peoples R China
[6] Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA
关键词
MGMT; SNP; haplotype; multifactor dimensionality reduction; lung cancer;
D O I
10.1002/humu.20462
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
O-6-alkylguanine-DNA alkyltransferase (MGMT) is a universal DNA repair protein involved in the DNA direct reversal repair pathway that copes with alkylating carcinogens. Reduced MGMT expression as well as enzyme activity may result in an increased susceptibility to cancers. To elucidate the role of sequence variation in MGMT in the etiology of lung cancer, we conducted a comprehensive association study focusing on linkage disequilibrium (LD) structure of common variations across the MGMT sequence and its modification effect on smoking,related lung cancer risk. We rebuilt the LD block of MGMT by genotyping 39 SNPs and selected a subset of 10 haplotype-tagging SNPs (htSNP) and three pre- and interblock SNPs to capture variation across MGMT By using a haplotype,based multifactor dimensionality reduction (MDR) analysis, we found that there were significant more-than,multiplicative interactions between diplotypes in block 5 and cumulative smoking and additive interaction between genotypes of preblock SNP rs1625649:C>A and smoking status in relation on lung cancer risk. Diplotypes in block 3 and block 5, genotypes of rs1625649:C>A, and trichotomized cumulative smoking are the four factors included in the MDR-defined best model on lung cancer risk. When these variables were combined and dichotomized, we found that subjects carrying the combined risk stratum had a significantly increased risk for lung cancer of 4.10-fold (odds ratio [OR] = 4.10, 95 % confidence interval [CI] = 3.12-5.37, P = 2.09 x 10(-24)). These findings suggest that genetic variants in MGMT may modulate the risk of smoking,related lung cancer. This haplotype-based interaction analysis might provide a "proof-of principle" approach for studying candidate genes in cancer susceptibility.
引用
收藏
页码:431 / 440
页数:10
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