Single nucleotide polymorphisms of IGFBP-3 gene and lung cancer risk in a Korean population

Sle Gi Lo Han, Kyong Hwa Park, Jae Sook Sung, Young Mi Whang, Yeon Jung Kim, Eun Soon Shin, Jae Won Lee, Hyo Jung Lee, Jeong Seon Ryu, In Keun Choi, Jae Hong Seo, Yeul Hong Kim

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Insulin-like growth factor binding protein-3 (IGFBP-3) is a putative tumor suppressor and inhibits the mitogenic and antiapoptotic activity of insulin-like growth factor (IGF) by blocking the binding to its receptors or by IGF-independent manner. Epidemiological studies have suggested that serum level of IGFBP-3 is associated with lung cancer risk. The present study was conducted to evaluate the association between single nucleotide polymorphisms (SNPs) of the IGFBP-3 gene and susceptibility to lung cancer and the effect of the SNPs on the serum levels of IGFBP-3, total IGF-I and free IGF-I in a Korean population. After a preliminary study for polymorphism screening of the promoter region of the IGFBP-3 gene in randomly selected 41 lung cancer patients, two polymorphisms (-1590 C > A; -202 A > C) were identified with PCR-based restriction fragment length polymorphism (PCR-RFLP) and SNaPshot primer extension assay in 415 Korean lung cancer patients and 415 matched normal controls. Although the genotype and allele frequency distribution of each SNP did not differ significantly between cases and controls in the single-locus analysis, we found that the polymorphisms of -1590A and -202C were associated with increased risk for lung cancer in females (-1590 C > A; adjusted OR = 2.11, 95% CI = 1.08-4.12, -202 A > C; adjusted OR = 1.96, 95% CI = 1.02-3.75, respectively) and never-smokers (-1590 C > A; adjusted OR = 2.06, 95% CI = 1.12-3.78, -202 A > C; adjusted OR = 1.99, 95% CI = 1.10-3.62, respectively) in a dominant model after stratification for gender and smoking history. Haplotype analysis showed that carriers of A-C had significantly higher risk for lung cancer in females (dominant aOR = 2.05, 95% CI = 1.14-3.68) and in never-smokers (codominant aOR = 1.71, 95% CI = 1.11-2.64 and dominant aOR = 1.99, 95% CI = 1.17-3.40). Functional analysis in H1703 cell line using DNA fragments containing A-C haplotype of the promoter region showed significantly decreased transcriptional activity. Furthermore, there was a negative correlation between the number of polymorphic alleles in -1590/-202 loci and serum levels of IGFBP-3 in lung cancer patients, but it was not statistically significant in the test for linear trend. These results suggest that IGFBP-3 promoter polymorphisms of -1590 C > A and -202 A > C might be a genetic risk factor for lung cancer by means of decreased IGFBP-3 expression among females or never-smoking Koreans.

Original languageEnglish
Pages (from-to)152-161
Number of pages10
JournalLung Cancer
Volume62
Issue number2
DOIs
Publication statusPublished - 2008 Nov 1

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Insulin-Like Growth Factor Binding Protein 3
Single Nucleotide Polymorphism
Lung Neoplasms
Population
Genes
Insulin-Like Growth Factor I
Genetic Promoter Regions
Haplotypes
Smoking
Serum
Somatomedin Receptors
Somatomedins
Gene Frequency
Restriction Fragment Length Polymorphisms
Epidemiologic Studies
History
Alleles
Genotype
Cell Line
Polymerase Chain Reaction

Keywords

  • IGFBP-3
  • Lung cancer
  • SNP

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Single nucleotide polymorphisms of IGFBP-3 gene and lung cancer risk in a Korean population. / Han, Sle Gi Lo; Park, Kyong Hwa; Sung, Jae Sook; Whang, Young Mi; Kim, Yeon Jung; Shin, Eun Soon; Lee, Jae Won; Lee, Hyo Jung; Ryu, Jeong Seon; Choi, In Keun; Seo, Jae Hong; Kim, Yeul Hong.

In: Lung Cancer, Vol. 62, No. 2, 01.11.2008, p. 152-161.

Research output: Contribution to journalArticle

Han, SGL, Park, KH, Sung, JS, Whang, YM, Kim, YJ, Shin, ES, Lee, JW, Lee, HJ, Ryu, JS, Choi, IK, Seo, JH & Kim, YH 2008, 'Single nucleotide polymorphisms of IGFBP-3 gene and lung cancer risk in a Korean population', Lung Cancer, vol. 62, no. 2, pp. 152-161. https://doi.org/10.1016/j.lungcan.2008.03.017
Han, Sle Gi Lo ; Park, Kyong Hwa ; Sung, Jae Sook ; Whang, Young Mi ; Kim, Yeon Jung ; Shin, Eun Soon ; Lee, Jae Won ; Lee, Hyo Jung ; Ryu, Jeong Seon ; Choi, In Keun ; Seo, Jae Hong ; Kim, Yeul Hong. / Single nucleotide polymorphisms of IGFBP-3 gene and lung cancer risk in a Korean population. In: Lung Cancer. 2008 ; Vol. 62, No. 2. pp. 152-161.
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T1 - Single nucleotide polymorphisms of IGFBP-3 gene and lung cancer risk in a Korean population

AU - Han, Sle Gi Lo

AU - Park, Kyong Hwa

AU - Sung, Jae Sook

AU - Whang, Young Mi

AU - Kim, Yeon Jung

AU - Shin, Eun Soon

AU - Lee, Jae Won

AU - Lee, Hyo Jung

AU - Ryu, Jeong Seon

AU - Choi, In Keun

AU - Seo, Jae Hong

AU - Kim, Yeul Hong

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N2 - Insulin-like growth factor binding protein-3 (IGFBP-3) is a putative tumor suppressor and inhibits the mitogenic and antiapoptotic activity of insulin-like growth factor (IGF) by blocking the binding to its receptors or by IGF-independent manner. Epidemiological studies have suggested that serum level of IGFBP-3 is associated with lung cancer risk. The present study was conducted to evaluate the association between single nucleotide polymorphisms (SNPs) of the IGFBP-3 gene and susceptibility to lung cancer and the effect of the SNPs on the serum levels of IGFBP-3, total IGF-I and free IGF-I in a Korean population. After a preliminary study for polymorphism screening of the promoter region of the IGFBP-3 gene in randomly selected 41 lung cancer patients, two polymorphisms (-1590 C > A; -202 A > C) were identified with PCR-based restriction fragment length polymorphism (PCR-RFLP) and SNaPshot primer extension assay in 415 Korean lung cancer patients and 415 matched normal controls. Although the genotype and allele frequency distribution of each SNP did not differ significantly between cases and controls in the single-locus analysis, we found that the polymorphisms of -1590A and -202C were associated with increased risk for lung cancer in females (-1590 C > A; adjusted OR = 2.11, 95% CI = 1.08-4.12, -202 A > C; adjusted OR = 1.96, 95% CI = 1.02-3.75, respectively) and never-smokers (-1590 C > A; adjusted OR = 2.06, 95% CI = 1.12-3.78, -202 A > C; adjusted OR = 1.99, 95% CI = 1.10-3.62, respectively) in a dominant model after stratification for gender and smoking history. Haplotype analysis showed that carriers of A-C had significantly higher risk for lung cancer in females (dominant aOR = 2.05, 95% CI = 1.14-3.68) and in never-smokers (codominant aOR = 1.71, 95% CI = 1.11-2.64 and dominant aOR = 1.99, 95% CI = 1.17-3.40). Functional analysis in H1703 cell line using DNA fragments containing A-C haplotype of the promoter region showed significantly decreased transcriptional activity. Furthermore, there was a negative correlation between the number of polymorphic alleles in -1590/-202 loci and serum levels of IGFBP-3 in lung cancer patients, but it was not statistically significant in the test for linear trend. These results suggest that IGFBP-3 promoter polymorphisms of -1590 C > A and -202 A > C might be a genetic risk factor for lung cancer by means of decreased IGFBP-3 expression among females or never-smoking Koreans.

AB - Insulin-like growth factor binding protein-3 (IGFBP-3) is a putative tumor suppressor and inhibits the mitogenic and antiapoptotic activity of insulin-like growth factor (IGF) by blocking the binding to its receptors or by IGF-independent manner. Epidemiological studies have suggested that serum level of IGFBP-3 is associated with lung cancer risk. The present study was conducted to evaluate the association between single nucleotide polymorphisms (SNPs) of the IGFBP-3 gene and susceptibility to lung cancer and the effect of the SNPs on the serum levels of IGFBP-3, total IGF-I and free IGF-I in a Korean population. After a preliminary study for polymorphism screening of the promoter region of the IGFBP-3 gene in randomly selected 41 lung cancer patients, two polymorphisms (-1590 C > A; -202 A > C) were identified with PCR-based restriction fragment length polymorphism (PCR-RFLP) and SNaPshot primer extension assay in 415 Korean lung cancer patients and 415 matched normal controls. Although the genotype and allele frequency distribution of each SNP did not differ significantly between cases and controls in the single-locus analysis, we found that the polymorphisms of -1590A and -202C were associated with increased risk for lung cancer in females (-1590 C > A; adjusted OR = 2.11, 95% CI = 1.08-4.12, -202 A > C; adjusted OR = 1.96, 95% CI = 1.02-3.75, respectively) and never-smokers (-1590 C > A; adjusted OR = 2.06, 95% CI = 1.12-3.78, -202 A > C; adjusted OR = 1.99, 95% CI = 1.10-3.62, respectively) in a dominant model after stratification for gender and smoking history. Haplotype analysis showed that carriers of A-C had significantly higher risk for lung cancer in females (dominant aOR = 2.05, 95% CI = 1.14-3.68) and in never-smokers (codominant aOR = 1.71, 95% CI = 1.11-2.64 and dominant aOR = 1.99, 95% CI = 1.17-3.40). Functional analysis in H1703 cell line using DNA fragments containing A-C haplotype of the promoter region showed significantly decreased transcriptional activity. Furthermore, there was a negative correlation between the number of polymorphic alleles in -1590/-202 loci and serum levels of IGFBP-3 in lung cancer patients, but it was not statistically significant in the test for linear trend. These results suggest that IGFBP-3 promoter polymorphisms of -1590 C > A and -202 A > C might be a genetic risk factor for lung cancer by means of decreased IGFBP-3 expression among females or never-smoking Koreans.

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