Methyl-CpG binding domain 1 gene polymorphisms and risk of primary lung cancer.
The methyl-CpG binding domain 1 (MBD1) protein plays an important role for transcriptional regulation of gene expression. Polymorphisms and haplotypes of the MBD1 gene may have an influence on MBD1 activity on gene expression profiles, thereby modulating an individual's susceptibility to lung cancer. To test this hypothesis, we investigated the association of MBD1 -634G>A, -501delT (-501 T/T, T/-, -/-), and Pro(401)Ala genotypes and their haplotypes with the risk of lung cancer in a Korean population. The MBD1 genotype was determined in 432 lung cancer patients and in 432 healthy control subjects who were frequency matched for age and gender. The -634GG genotype was associated with a significantly increased risk of overall lung cancer compared with the -634AA genotype [adjusted odds ratio (OR), 3.10; 95% confidence interval (95% CI), 1.24-7.75; P = 0.016]. When analyses were stratified according to the tumor histology, the -634GG genotype was associated with a significantly increased risk of adenocarcinoma compared with the -634AA genotype (adjusted OR, 4.72; 95% CI, 1.61-13.82; P = 0.005). For the MBD1 -501delT and Pro(401)Ala polymorphisms, the -501 T/T genotype was associated with a marginal significantly increased risk of adenocarcinoma compared with the -501(-/-) genotype (adjusted OR, 2.07; 95% CI, 1.02-4.20; P = 0.045), and the Pro/Pro genotype was associated with a significantly increased risk of adenocarcinoma compared with the Ala/Ala genotype (adjusted OR, 3.41; 95% CI, 1.21-9.60; P = 0.02). Consistent with the genotyping analyses, the -634G/-501T/(401)Pro haplotype was associated with a significantly increased risk of overall lung cancer and adenocarcinoma compared with the -634A/-501(-)/(401)Ala haplotype (adjusted OR, 1.44; 95% CI, 1.08-1.91; P = 0.012 and P(c) = 0.048; adjusted OR, 1.75; 95% CI, 1.20-2.56; P = 0.004 and P(c) = 0.016, respectively). On a promoter assay, the -634A allele had significantly higher promoter activity compared with the -634G allele in the Chinese hamster ovary cells and A549 cells (P < 0.05 and P < 0.001, respectively), but the -501delT polymorphism did not have an effect on the promoter activity. When comparing the promoter activity of the MBD1 haplotypes, the -634A/-501(-) haplotype had a significantly higher promoter activity than the -634G/-501T haplotype (P < 0.001). These results suggest that the MBD1 -634G>A, -501delT, and Pro(401)Ala polymorphisms and their haplotypes contribute to the genetic susceptibility for lung cancer and particularly for adenocarcinoma.
Jang
Jin-Sung
JS
Department of Internal Medicine, School of Medicine, Kyungpook National University, Samduk 2Ga 50, Daegu, 700-412, Korea.
Lee
Su Jeong
SJ
Choi
Jin Eun
JE
Cha
Sung Ick
SI
Lee
Eung Bae
EB
Park
Tae In
TI
Kim
Chang Ho
CH
Lee
Won Kee
WK
Kam
Sin
S
Choi
Je-Yong
JY
Kang
Young Mo
YM
Park
Rang-Woon
RW
Kim
In-San
IS
Cho
Young Lae
YL
Jung
Tae Hoon
TH
Han
Sung Beom
SB
Park
Jae Yong
JY
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics*; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007723:Korea; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D004268:DNA-Binding Proteins; C066141:MBD1 protein, human; D014157:Transcription Factors