Development of a bivalent conjugate vaccine candidate against malaria transmission and typhoid fever.

Immune responses to poorly immunogenic antigens, such as polysaccharides, can be enhanced by conjugation to carriers. Our previous studies indicate that conjugation to Vi polysaccharide of Salmonella Typhi may also enhance immunogenicity of some protein carriers. We therefore explored the possibility of generating a bivalent vaccine against Plasmodium falciparum malaria and typhoid fever, which are co-endemic in many parts of the world, by conjugating Vi polysaccharide, an approved antigen in typhoid vaccine, to Pfs25, a malaria transmission blocking vaccine antigen in clinical trials. Vi-Pfs25 conjugates induced strong immune responses against both Vi and Pfs25 in mice, whereas the unconjugated antigens are poorly immunogenic. Functional assays of immune sera revealed potent transmission blocking activity mediated by anti-Pfs25 antibody and serum bactericidal activity due to anti-Vi antibody. Pfs25 conjugation to Vi modified the IgG isotype distribution of antisera, inducing a Th2 polarized immune response against Vi antigen. This conjugate may be further developed as a bivalent vaccine to concurrently target malaria and typhoid fever.

Macrolide resistance mechanisms and virulence factors in erythromycin-resistant Campylobacter species isolated from chicken and swine feces and carcasses.

Resistance to antimicrobials was measured in 73 isolates of Campylobacter jejuni (C. jejuni) and 121 isolates of Campylobacter coli (C. coli) from chicken and swine feces and carcasses in Korea. Both bacterial species showed the highest resistance to (fluoro) quinolones (ciprofloxacin and nalidixic acid) out of the nine antimicrobials tested. Erythromycin resistance was much higher in C. coli (19.0%, 23/121) than in C. jejuni (6.8%, 5/73). The mutation in the 23S rRNA gene was primarily responsible for macrolide resistance in Campylobacter isolates. Several amino acid substitutions in the L4 and L22 ribosomal proteins may play a role in the mechanism of resistance, but the role requires further evaluation. A total of eight virulence genes were detected in 28 erythromycin-resistant Campylobacter isolates. All C. jejuni isolates carried more than four such genes, while C. coli isolates carried fewer than three such genes. The high rate of resistance highlights the need to employ more prudent use of critically important antimicrobials, such as fluoroquinolones and macrolides, in swine and poultry production, and to more carefully monitor antimicrobial resistance in Campylobacter isolates in food animals.

Preparation and testing of a Haemophilus influenzae Type b/Hepatitis B surface antigen conjugate vaccine.

The majority of conjugate vaccines focus on inducing an antibody response to the polysaccharide antigen and the carrier protein is present primarily to induce a T-cell dependent response. In this study conjugates consisting of poly(ribosylribitolphosphate) (PRP) purified from Haemophilus influenzae Type b bound to Hepatitis B virus surface antigen (HBsAg) virus like particles were prepared with the aim of inducing an antibody response to not only the PRP but also the HBsAg. A conjugate consisting of PRP bound to HBsAg via an adipic acid dihydrazide (ADH) spacer induced strong IgG antibodies to both the PRP and HBsAg. When conjugation was performed without the ADH spacer the induction of an anti-PRP response was equivalent to that seen by conjugate with the ADH spacer, however, a negligible anti-HBsAg response was induced. For comparison, PRP was conjugated to diphtheria toxoid (DT) and Vi polysaccharide purified from Salmonella Typhi conjugated to HBsAg both using an ADH spacer. The PRPAH-DT conjugate induced strong anti-PRP and anti-DT responses, the Vi-AHHBsAg conjugate induced a good anti-HBsAg response but not as strong as that induced by the PRPAH-HBsAg conjugate. This study demonstrated that in mice it was possible to induce robust antibody responses to both polysaccharide and carrier protein provided the conjugate has certain physico-chemical properties. A PRPAH-HBsAg conjugate with the capacity to induce anti-PRP and anti-HBsAg responses could be incorporated into a multivalent pediatric vaccine and simplify formulation of such a vaccine.

Prevalence and molecular characterization of CTX-M ß-lactamase-producing Escherichia coli isolated from healthy swine and cattle.

The purpose of this study was to determine the prevalence and characteristics of CTX-M ß-lactamases in Escherichia coli among healthy swine and cattle in Korea. A total of 1212 fecal samples obtained from healthy pigs (n=558) and cattle (n=654) were screened for CTX-M-type extended spectrum ß-lactamase (ESBL)-producing E. coli isolates. One hundred and twenty-one E. coli that produced ESBL were subjected to phenotypic and genotypic characterization. A high number (120/558, 21.5%) of swine fecal samples showed the presence of CTX-M ß-lactamase-producing E. coli compared to cattle samples (1/654, 0.2%). The most predominant CTX-M-type identified was CTX-M-14 (n=82), followed by CTX-M-15 (n=16). Isolates producing CTX-M-3, CTX-M-27, CTX-M-55, and CTX-M-65 were also identified. Overall, the bla(TEM-1) gene was associated with CTX-M ß-lactamase in 55 E. coli isolates. Transfer of bla(CTX-M) gene was demonstrated from 76 out of 121 bla(CTX-M)-positive E. coli isolates to the recipient E. coli J53 by conjugation. Plasmid DNA isolation from the transconjugants revealed a large (90-120 Kb) conjugative plasmid. ISEcp1 and IS903 were detected upstream and downstream of bla(CTX-M) genes in 117 and 91 E. coli isolates, respectively. Our results demonstrated that a combination of clonal expansion and horizontal transmission is spreading bla(CTX-M) genes among swine E. coli. The horizontal dissemination of bla(CTX-M) genes among E. coli was mostly mediated by IncF or IncI1-Iγ plasmids. To the best of our knowledge, this study represents the first report of CTX-M-3, CTX-M-27, CTX-M-55, and CTX-M-65 ß-lactamases in bacterial isolates from food animals in Korea. This study revealed that the CTX-M ß-lactamase-producing E. coli are widely disseminated among healthy pigs but very rare in cattle in Korea. Increasing prevalence of bla(CTX-M) genes in intestinal E. coli of food animals is a matter of concern and should be carefully monitored.

Prevalence of plasmid-mediated quinolone resistance determinants among Escherichia coli isolated from food animals in Korea.

The aim of this study was to investigate the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants in Escherichia coli isolated from food-producing animals and to characterize the PMQR-positive isolates. A total of 365 E. coli isolates which were either nalidixic acid resistant and ciprofloxacin susceptible (NAL(R)-CIP(S); n=185), or nalidixic acid and ciprofloxacin resistant (NAL(R)-CIP(R); n=180) were assessed for the presence of PMQR determinants by polymerase chain reaction. PMQR-positive isolates were further characterized by mutation analysis within the quinolone resistance-determining region (QRDR) of gyrA, gyrB, parC, and parE, phylogenetic group analysis, and pulsed-field gel electrophoresis (PFGE). Fourteen NAL(R)-CIP(S) (n=8) and NAL(R)-CIP(R) (n=6) E. coli isolates were positive for PMQR genes. Among them, qnrB4, qnrS1, and aac(6')-Ib-cr genes were detected in two (0.5%), eight (2.2%), and four (1.1%) isolates, respectively. None of the isolates harbored qnrA, qnrC, qnrD, and qepA genes. All but one PMQR-positive isolates harbored one or more point mutations in the QRDR of gyrA, and five of these isolates had additional mutations in the parC gene. Furthermore, one isolate each had additional substitutions in gyrB and parE genes, respectively. The most prevalent mutation was Ser83-Leu within the QRDR of gyrA. Phylogenetic analysis identified three major phylogenetic lineages, with phylogroups A (n=7) and D (n=4) being the most common phylogroups. None of the isolates belonged to virulent phylogroup B2. PFGE demonstrated that a combination of clonal and horizontal gene transmission is disseminating PMQR genes among the veterinary E. coli isolates in Korea. To our knowledge, this is the first report of occurrence of qnrB, qnrS, and aac(6')-Ib-cr genes in E. coli isolated from food-producing animals in Korea. Isolation of PMQR genes from food animals is a matter of concern since they could be transmitted to humans via food animals.

Molecular characterization of extended-spectrum-ß-lactamase-producing and plasmid-mediated AmpC ß-lactamase-producing Escherichia coli isolated from stray dogs in South Korea.

A total of 47 extended-spectrum-cephalosporin-resistant Escherichia coli strains isolated from stray dogs in 2006 and 2007 in the Republic of Korea were investigated using molecular methods. Extended-spectrum ß-lactamase (ESBL) and AmpC ß-lactamase phenotypes were identified in 12 and 23 E. coli isolates, respectively. All 12 ESBL-producing isolates carried bla(CTX-M) genes. The most common CTX-M types were CTX-M-14 (n = 5) and CTX-M-24 (n = 3). Isolates producing CTX-M-3, CTX-M-55, CTX-M-27, and CTX-M-65 were also identified. Twenty-one of 23 AmpC ß-lactamase-producing isolates were found to carry bla(CMY-2) genes. TEM-1 was associated with CTX-M and CMY-2 ß-lactamases in 4 and 15 isolates, respectively. In addition to bla(TEM-1), two isolates carried bla(DHA-1), and one of them cocarried bla(CMY-2). Both CTX-M and CMY-2 genes were located on large (40 to 170 kb) conjugative plasmids that contained the insertion sequence ISEcp1 upstream of the bla genes. Only in the case of CTX-M genes was there an IS903 sequence downstream of the gene. The spread of ESBLs and AmpC ß-lactamases occurred via both horizontal gene transfer, accounting for much of the CTX-M gene dissemination, and clonal spread, accounting for CMY-2 gene dissemination. The horizontal dissemination of bla(CTX-M) and bla(CMY-2) genes was mediated by IncF and IncI1-Iγ plasmids, respectively. The clonal spread of bla(CMY-2) was driven mainly by E. coli strains of virulent phylogroup D lineage ST648. To our knowledge, this is the first report of bla(DHA-1) in E. coli strains isolated from companion animals. This study also represents the first report of CMY-2 ß-lactamase-producing E. coli isolates from dogs in the Republic of Korea.

Aberrant methylation of ADAMTS1 in non-small cell lung cancer.

ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs) is an extracellular matrix metalloproteinase with protease activity and antiangiogenic activity. It has been suggested that ADAMTS1 plays an important role in tumor growth and metastasis. In this study, we examined ADAMTS1 expression in non-small cell lung cancer (NSCLC), and we also evaluated whether the loss of ADAMTS1 expression is due to aberrant methylation of the gene. In addition, we examined the relationship between ADAMTS1 methylation and clinicopathologic features in NSCLC patients. ADAMTS1 expression was examined using reverse-transcription polymerase chain reaction (PCR), and the methylation status of the gene was evaluated by methylation-specific PCR in NSCLC cell lines (n=10) and primary NSCLC tumors (n=98). Down-regulation of ADAMTS1 was observed in 30% (3/10) of the NSCLC cell lines, and this down-regulation was found to be concordant with aberrant methylation of the gene. Furthermore, ADAMTS1 expression was restored after treatment with the demethylating agent, 5-Aza-2'-deoxycytidine, in cell lines that lacked ADAMTS1 expression. Aberrant methylation of the gene was observed in 31.6% (31 of 98) of the NSCLC tumors, while it was found in only 7.1% (7/98) of the corresponding nonmalignant tissues. Methylation in NSCLC tumors was not correlated with the clinicopathologic features of the patients, such as age, gender, and histology and pathologic staging of the tumor. Taken together, these results suggest that aberrant methylation of ADAMTS1 frequently occurs in NSCLCs and that it may play a role in the pathogenesis of NSCLC.

Identification of polymorphisms in the XIAP gene and analysis of association with lung cancer risk in a Korean population.

The X-linked inhibitor of apoptosis protein (XIAP) is a potent mammalian IAP, and has been shown to play an important role in development and progression of cancer. Polymorphisms in the XIAP gene may influence XIAP production or activity, thereby modulating susceptibility to lung cancer. To test this hypothesis, we first screened for polymorphisms in the XIAP gene by direct sequencing of genomic DNA samples from 27 healthy Korean women and then performed a case-control study to evaluate the association between the polymorphisms and the risk of lung cancer. The XIAP genotypes were determined by polymerase chain reaction amplification and melting curve analysis in 582 lung cancer patients and in 582 healthy control subjects who were frequency-matched for age and sex. We identified 12 single nucleotide polymorphisms (SNPs), one novel SNP [30051C>G (A321G) in exon 3] and the following 11 known SNPs: 192G>C (rs5956578), 262C>T (rs28382699), 318C>T (rs5958318), and 374C>T (rs12687176) in the putative promoter; 26615A>G (rs2355676) in intron 1; 41725A>G (rs5958338) in intron 5; 42009A>C (Q423P, rs5956583) in exon 6; 48162T>C (rs17334739) and 48228C>T (rs28382739) in intron 6; and 48542A>G (rs28382740) and 49333G>T (rs28382742) in 3'-UTR. Four of these 12 SNPs were selected for large-scale genotyping based on their frequencies and haplotype tagging status: 262C>T, 318C>T, 374C>T, and 42009A>C. The four XIAP polymorphisms and their haplotypes exhibited no apparent relationship with the risk of lung cancer. In addition, we observed no evidence of effect modification by age, sex, smoking history, or tumor histology. These results suggest that XIAP polymorphisms do not significantly affect susceptibility to lung cancer in Koreans.

EGFR, ERBB2, and KRAS mutations in Korean non-small cell lung cancer patients.

The epidermal growth factor receptor (EGFR), and its family members play an important role in the development and progression of lung cancers. It has been reported that somatic mutations in the tyrosine kinase domain of the EGFR or ERBB2 genes occur in a subset of patients with lung cancer. We searched for mutations of the EGFR, ERBB2, and KRAS genes in surgically resected non-small cell lung cancers (NSCLCs) to determine the prevalence of these mutations in Korean lung cancer patients. In addition, we examined the relationship between the mutations and clinicopathologic features of lung cancers. Mutations of the EGFR, ERBB2, and KRAS genes were determined by polymerase chain reaction-based direct sequencing in 115 surgically resected non-small cell lung cancers. EGFR mutations were present in 20 patients (17.4%). The EGFR mutations were found only in adenocarcinomas (20 of 55 adenocarcinomas, 36.4%). The ERBB2 mutation was found in 1 adenocarcinoma of the 115 NSCLCs (0.9% overall; 1.8% of the 55 adenocarcinomas). KRAS mutations were found in 6 (5.2%) of the 115 NSCLCs (2 of 60 squamous cell carcinomas, or 3.3%, and 4 of 55 adenocarcinomas, or 7.3%). EGFR mutations in adenocarcinomas were more frequent in women (P = 0.02) and in never-smokers (P = 0.004). EGFR mutations in adenocarcinomas were not associated with pathologic stage in never-smokers, but were more frequent in pathologic stage II-IV than in stage I in ever-smokers (P = 0.01). Of the 55 adenocarcinomas, 25 (45.5%) had mutations of one or another of the three genes; EGFR mutations were never found in adenocarcinomas together with ERBB2 or KRAS mutations. These findings suggest that the EGFR mutation is frequent in Korean lung cancer patients, and that the ERBB2 mutation is rare. Further studies are needed to investigate the role of EGFR mutations in the carcinogenesis of adenocarcinoma among smokers.

No association between dinucleotide repeat polymorphism in intron 1 of the epidermal growth factor receptor gene EGFR and risk of lung cancer.

The tyrosine kinase receptor EGFR pathway is one of the oncogenic signaling cascades involved in lung cancer, mediating the epidermal growth factor receptor gene EGFR. First-intron polymorphisms with greater numbers of CA dinucleotide repeats tend to downregulate EGFR expression, which suggests that this polymorphism may modulate susceptibility to lung cancer. The present hospital-based case-control study evaluated the possible association of CA repeat polymorphism in the EGFR gene with risk of lung cancer in a Korean population. A bimodal pattern appeared, with a frequency of 57.1% for 20 CA repeats and 18.6% for 16 CA repeats. There was, however, no significant difference in distribution of allele genotypes between all lung cancer cases and the controls, nor among histological types for the cases.

No association between p73 G4C14-to-A4T14 polymorphism and the risk of lung cancer in a Korean population.

A member of the p53 family, p73 may play an important role in the development of lung cancer. Variations in the DNA sequence in the p73 gene can lead to alterations in the production of p73 and/or activity, which can affect an individual's susceptibility to lung cancer. To test this hypothesis, this study examined the association between the G4C14-to-A4T14 polymorphism in the p73 gene and the risk of lung cancer in a Korean population. The p73 G4C14-to-A4T14 genotypes were determined in 582 lung cancer patients and 582 healthy age- and gender-matched control subjects. Compared with the GC/GC genotype, the GC/AT and the AT/AT genotypes were not significantly associated with the risk of lung cancer [adjusted odds ratio (OR) = 1.08, 95% confidence interval (CI) = 0.84-1.38; and adjusted OR = 1.37, 95% CI = 0.83-2.24, respectively]. In addition, the risk estimate for the combined variant genotype (GC/AT + AT/AT) was similar to that of the GC/GC genotype (a dominant model for the AT allele, adjusted OR = 1.12, 95% CI = 0.88-1.41). These results suggest that the p73 G4C14-to-A4T14 polymorphism does not significantly affect susceptibility to lung cancer in the Korean population.

Polymorphisms in the caspase-8 gene and the risk of lung cancer.

Caspase-8 (CASP-8) is an initiator CASP in the cell death receptor-mediated apoptotic pathway, and plays an important role in the development of cancer. Polymorphisms and their haplotypes in the CASP-8 gene can result in alterations in CASP-8 expression and/or activity, thereby modulating the susceptibility to lung cancer. To test this hypothesis, we examined the association of -678_-673delAGTAAG (-678del) and IVS12-19G-->A polymorphisms and their haplotypes with the risk of lung cancer in a Korean population. The CASP-8 genotypes were determined in 432 lung cancer patients and 432 healthy age- and gender-matched control subjects. The distributions of the CASP-8 -678del and IVS12-19G-->A genotypes were not significantly different between the overall lung cancer cases and the controls. When the cases were categorized by tumor histology, however, the IVS12-19 AA genotype and the combined IVS12-19 GA + AA genotype were associated with a significantly decreased risk of small cell carcinoma (SmCC) compared with the IVS12-19 GG genotype [adjusted odds ratio (OR) = 0.14, 95% confidence interval (CI) = 0.03-0.64, P = 0.01; and adjusted OR = 0.56, 95% CI = 0.33-0.96, P = 0.03, respectively]. Consistent with the genotyping analyses, the -678del-/IVS12-19A haplotype containing 94% of the IVS12-19A allele in the study population was associated with a significantly decreased risk of SmCC compared with the -678del-/IVS12-19G (adjusted OR = 0.58, 95% CI = 0.36-0.93, P = 0.023, and Pc = 0.046). These findings suggest that the CASP-8 gene may contribute to an inherited predisposition to SmCC of the lung.

Polymorphisms in the hMSH2 gene and the risk of primary lung cancer.

Polymorphisms in the DNA repair genes may be associated with differences in the capacity to repair DNA damage, and so this can influence an individual's susceptibility to lung cancer. To test this hypothesis, we investigated the association of hMSH2 -118T>C, IVS1+9G>C, IVS10+12A>G, and IVS12-6T>C genotypes and their haplotypes with the risk of lung cancer in a Korean population. The hMSH2 genotypes were determined in 432 lung cancer patients and in 432 healthy controls who were frequency matched for age and gender. The hMSH2 haplotypes were estimated based on a Bayesian algorithm using the Phase program. The presence of at least one IVS10+12G allele was associated with a significantly decreased risk of adenocarcinoma, as compared with the IVS10+12AA genotype [adjusted odds ratio (OR), 0.59; 95% confidence interval (95% CI), 0.40-0.88; P = 0.01], and the presence of at least one IVS12-6C allele was associated with a significantly increased risk of adenocarcinoma, as compared with the IVS12-6TT genotype (adjusted OR, 1.52; 95% CI, 1.02-2.27; P = 0.04). Consistent with the results of the genotyping analysis, the TGGT haplotype with no risk allele was associated with a significantly decreased risk of adenocarcinoma, as compared with the TCAC haplotype with two risk allele [i.e., IVS10+12A and IVS12-6C allele; adjusted OR, 0.49; 95% CI, 0.30-0.78; P = 0.003 and P(c) (Bonferroni corrected P value) = 0.012]. The effect of the hMSH2 haplotypes on the risk of adenocarcinoma was statistically significant in the never smokers and younger individuals (adjusted OR, 0.45; 95% CI, 0.27-0.75; P = 0.002 and P(c) = 0.004; and adjusted OR, 0.44; 95% CI, 0.23-0.85; P = 0.014 and P(c) = 0.028, respectively) but not in the ever-smokers and older individuals. These results suggest that the hMSH2 polymorphisms and their haplotypes may be an important genetic determinant of adenocarcinoma of the lung, particularly in never smokers.

Relationship between cyclooxygenase 8473T>C polymorphism and the risk of lung cancer: a case-control study.

BACKGROUND: Cyclooxygenase-2 (COX-2) plays an important role in the development of lung cancer. DNA sequence variations in the COX-2 gene may lead to altered COX-2 production and/or activity, and so they cause inter-individual differences in the susceptibility to lung cancer. To test this hypothesis, we investigated the association between the 8473T>C polymorphism in the 3'-untranslated region of the COX-2 gene and the risk of lung cancer in a Korean population. METHODS: The COX-2 genotypes were determined using PCR-based primer-introduced restriction analysis in 582 lung cancer patients and in 582 healthy controls that were frequency-matched for age and gender. RESULTS: The distribution of the COX-2 8473T>C genotypes was not significantly different between the overall lung cancer cases and the controls. However, when the cases were categorized by the tumor histology, the combined 8473 TC + CC genotype was associated with a significantly decreased risk of adenocarcinoma as compared with the 8473 TT genotype (adjusted OR = 0.64; 95% CI = 0.46-0.90, P = 0.01). On the stratification analysis, the protective effect of the combined 8473 TC + CC genotype against adenocarcinoma was statistically significant in the males, older individuals and ever-smokers (adjusted OR = 0.59; 95% CI = 0.39-0.91, P = 0.02; adjusted OR = 0.55; 95% CI = 0.33-0.93, P = 0.03; and adjusted OR = 0.57; 95% CI = 0.37-0.87, P = 0.01, respectively). CONCLUSION: These findings suggest that the COX-2 8473T>C polymorphism could be used as a marker for the genetic susceptibility to adenocarcinoma of the lung.

Polymorphisms in TGF-beta1 gene and the risk of lung cancer.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) functions as a suppressor of tumor initiation by inhibiting cellular proliferation or by promoting cellular differentiation or apoptosis in the early phase of cancer development. Variations in the DNA sequence in the TGF-beta1 gene may lead to altered TGF-beta1 production and/or activity, and so this can modulate an individual's susceptibility to lung cancer. To test this hypothesis, we investigated the association of the TGF-beta1 -509C > T and 869T > C (L10P) polymorphisms and their haplotypes with the risk of lung cancer in a Korean population. METHODS: The TGF-beta1 genotypes were determined in 432 lung cancer patients and in 432 healthy control subjects who were frequency-matched for age and gender. The TGF-beta1 haplotypes were predicted using a Bayesian algorithm in the Phase program. RESULTS: Individuals with at least one -509T allele were at a significantly decreased risk of adenocarcinoma (AC) and small cell carcinoma (SM), as compared with carriers with the -509CC genotype [adjusted odds ratio (OR), 0.63; 95% confidence interval (CI), 0.42-0.96; P = 0.04; and adjusted OR, 0.45; 95% CI, 0.27-0.76; P = 0.002; respectively]. For the 869T > C polymorphism, the combined TC + CC genotype was associated with a significantly decreased risk of SM compared with the TT genotype (adjusted OR, 0.52; 95% CI, 0.31-0.88; P = 0.01). Consistent with the results of the genotyping analyses, the -509T/869C haplotype was associated with a significantly decreased risk of AC and SM as compared with the -509C/869T haplotype (adjusted OR, 0.75; 95% CI, 0.57-0.98; P = 0.04; and adjusted OR, 0.67; 95% CI, 0.47-0.96; P = 0.02; respectively). CONCLUSION: The TGF-beta1 -509C > T and 869T > C polymorphisms and their haplotypes may contribute to genetic susceptibility to AC and SM of the lung.

O6-alkylguanine-DNA alkyltransferase gene polymorphisms and the risk of primary lung cancer.

O6-alkylguanine-DNA alkyltransferase (AGT) plays an important role in the repair of O6-alkylguanine adducts, which are major mutagenic lesions produced by environmental carcinogens. Polymorphisms in the AGT gene may affect the capacity to repair DNA damage and thereby have influence on individual's susceptibility to smoking-related cancer. To test this hypothesis, we investigated the potential association of AGT polymorphisms (485C > A, Leu53Leu (C > T) and Leu84Phe] with the risk of lung cancer in a Korean population. The AGT genotypes were determined in 432 lung cancer patients and in 432 healthy controls who were frequency-matched for age and gender. The 485 AA genotype was associated with a significantly increased risk for overall lung cancer as compared with the 485 CC genotype and the combined 485 CC + CA genotype, respectively (adjusted odds ratio (OR) = 1.83, 95% confidence interval (CI) = 1.12-2.99, P = 0.02, and Bonferroni corrected P-value (Pc) = 0.04; and adjusted OR = 1.67, 95% CI = 1.05-2.66, P = 0.03, respectively). When the lung cancer cases were categorized by the tumor histology, the 485 AA genotype was associated with a significantly increased risk of adenocarcinoma (AC) and small cell carcinoma (SmCC), respectively, as compared with the combined 485 CC + CA genotype (adjusted OR = 2.54, 95% CI = 1.39-4.66, P = 0.003; and adjusted OR = 2.19, 95% CI = 1.06-4.55, P = 0.04, respectively). However, the genotype distributions of the Leu53Leu and Leu84Phe polymorphisms were not significantly different between the lung cancer cases and the controls. On a promoter assay, the 485C > A polymorphism did not have an effect on the promoter activity of the AGT gene. These results suggest that the effect of the AGT 485C > A polymorphism on the risk of lung cancer may be secondary to linkage disequilibrium (LD) with either another AGT variant or with a true susceptibility gene, and that the AGT 485C > A polymorphism could be used as a marker for the genetic susceptibility to lung cancer.

XPC polymorphisms and lung cancer risk.

Polymorphisms in DNA repair genes may be associated with differences in the capacity to repair DNA damage and thereby influence an individual's susceptibility to smoking-related cancer. To test this hypothesis, we investigated the potential association of 7 XPC polymorphisms (-449G-->C, -371G-->A, -27G-->C, Val499Arg, PAT-/+, IVS11-5C-->A and Lys939Gln) and their haplotypes with lung cancer risk in a Korean population. XPC genotypes were determined in 432 lung cancer patients and 432 healthy controls frequency-matched for age and sex. XPC haplotypes were predicted using a Bayesian algorithm in the Phase program. The combined -27CG+CC genotype was associated with a significantly increased risk for overall lung cancer compared to the -27GG genotype (adjusted OR = 1.97, 95% CI 1.22-3.17, p = 0.005). The other 6 polymorphisms were not significantly associated with overall risk of lung cancer. When lung cancer cases were categorized by tumor histology, the -371AA genotype was associated with a significantly increased risk of squamous cell carcinoma compared to the combined -371GG and GA genotype (adjusted OR = 2.08, 95% CI 1.09-4.00, p = 0.03). The PAT-/+, IVS11-5C-->A and Lys939Gln polymorphisms were associated with a significantly decreased risk of small cell carcinoma (SM) under a dominant model for the polymorphic allele (adjusted OR = 0.49, 95% CI 0.29-0.82, p = 0.006; adjusted OR = 0.60, 95% CI 0.36-1.00, p = 0.05; and adjusted OR = 0.58, 95% CI 0.35-0.97, p = 0.04, respectively). Consistent with genotyping analyses, haplotype 4 (1112222) containing the PAT+/IVS11-5A/939Gln alleles was associated with a significantly decreased risk of SM (adjusted OR = 0.56, 95% CI 0.37-0.85, p = 0.007 and Bonferroni-corrected p = 0.049), whereas haplotype 5 (1122111) containing the -27C allele was associated with a significantly increased risk of SM (adjusted OR = 2.88, 95% CI 1.41-5.87, p = 0.004 and Bonferroni-corrected p = 0.028). These results suggest that XPC polymorphisms/haplotypes may contribute to genetic susceptibility for lung cancer.