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Background Several genetic variants are known to be associated with nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the longitudinal associations between genetic variants and NAFLD. Methods We performed a genome-wide association study (GWAS) in Korean individuals who underwent repeated health check-ups. NAFLD was defined by ultrasonography and exclusion of secondary causes. Results The subjects had a median age of 50.0 years, and 54.8% were male. The median follow-up duration was 39 months. Among the 3905 subjects without NAFLD at baseline, 874 (22.4%) subjects developed NAFLD, and among the 1818 subjects with NAFLD at baseline, NAFLD regressed in 336 (18.5%) subjects during the follow-up period. After adjusting for age, sex and body mass index, no single-nucleotide polymorphism (SNP) passed Bonferroni correction for genome-wide significance in the development or regression of NAFLD. Among the SNPs that passed the genome-wide suggestiveness threshold (p = 1E-04) in the discovery set in the GWAS, only 1 SNP (rs4906353) showed an association with the development of NAFLD, with marginal significance in the validation set (p-value, discovery set = 9.68E-5 and validation set = 0.00531). Conclusions This exploratory study suggests that longitudinal changes in NAFLD are not associated with genetic variants in the Korean population. These findings provide new insight into genetic mechanisms in the pathogenesis of NAFLD.

Diverticulosis results from complex interactions related to aging, environmental factors and genetic predisposition. Despite epidemiologic evidence of genetic risk factors, there has been no attempt to identify genes that confer susceptibility to colonic diverticulosis. We performed the first genome-wide association study (GWAS) on susceptibility to diverticulosis in a Korean population. A GWAS was carried out in 7,948 healthy individuals: 893 patients and 1,075 controls comprised the test set, and 346 patients and 305 controls comprised the replication set. Diverticulosis was diagnosed by colonoscopy during comprehensive medical check-ups, and single-nucleotide polymorphisms (SNPs) related to diverticulosis were detected with the Affymetrix Axiom KORV1.1-96 Array. In all, 9 SNPs were identified in three SNP aggregates in the test set (P −3, within 200 kb) after adjusting for sex. All the SNPs were replicated in the replication set (P −6, odds ratio = 1.415 (95% confidence interval: 1.223–1.637)]. These 9 novel SNP alleles associated with the WNT4, RHOU, and OAS1/3 genes are possibly involved in the underlying genetic susceptibility to right-sided diverticulosis. Our results provide basic knowledge about the development of diverticulosis in an Asian population.

Background and Purpose— Circulating bilirubin, a natural antioxidant, is associated with decreased risk of stroke. However, the nature of the relationship between the two remains unknown. We used a Mendelian randomization analysis to assess the causal effect of serum bilirubin on stroke risk in Koreans. Methods— The 14 single-nucleotide polymorphisms (SNP s ) (–7 ) including rs6742078 of uridine diphosphoglucuronyl-transferase were selected from genome-wide association study of bilirubin level in the KCPS-II (Korean Cancer Prevention Study-II) Biobank subcohort consisting of 4793 healthy Korean and 806 stroke cases. Weighted genetic risk score was calculated using 14 SNP s selected from the top SNP s . Results— Both rs6742078 (F statistics=138) and weighted genetic risk score with 14 SNP s (F statistics=187) were strongly associated with bilirubin levels. Simultaneously, serum bilirubin level was associated with decreased risk of stroke in an ordinary least-squares analysis. However, in 2-stage least-squares Mendelian randomization analysis, no causal relationship between serum bilirubin and stroke risk was found. Conclusions— There is no evidence that bilirubin level is causally associated with risk of stroke in Koreans. Therefore, bilirubin level is not a risk determinant of stroke.

Metabolic syndrome (MetS) which is caused by obesity and insulin resistance, is well known for its predictive capability for the risk of type 2 diabetes mellitus and cardiovascular disease. The development of MetS is associated with multiple genetic factors, environmental factors and lifestyle. We performed a genome-wide association study to identify single-nucleotide polymorphism (SNP) related to MetS in large Korean population based samples of 1,362 subjects with MetS and 6,061 controls using the Axiom® Korean Biobank Array 1.0. We replicated the data in another sample including 502 subjects with MetS and 1,751 controls. After adjusting for age and sex, rs662799 located in the APOA5 gene were significantly associated with MetS. 15 SNPs in GCKR, C2orf16, APOA5, ZPR1, and BUD13 were associated with high triglyceride (TG). 14 SNPs in APOA5, ALDH1A2, LIPC, HERPUD1, and CETP, and 2 SNPs in MTNR1B were associated with low high density lipoprotein cholesterol (HDL-C) and high fasting blood glucose respectively. Among these SNPs, 6 TG SNPs: rs1260326, rs1260333, rs1919127, rs964184, rs2075295 and rs1558861 and 11 HDL-C SNPs: rs4775041, rs10468017, rs1800588, rs72786786, rs173539, rs247616, rs247617, rs3764261, rs4783961, rs708272, and rs7499892 were first discovered in Koreans. Additional research is needed to confirm these 17 novel SNPs in Korean population.

Background: Bitter taste receptors (TAS2R) in human airway smooth muscle have recently been shown to have an important role in bronchodilation, together with β2-adrenergic receptors. Object: To evaluate the association between genetic variations in TAS2R and clinical features, including bronchodilator response and asthma control. Method: We analyzed the association between single nucleotide polymorphisms (SNPs) of TAS2R10 and TAS2R14 and variables such as demographic data, atopy, duration of disease, and asthma control status, including variables such as asthma control test (ACT) score, percent predicted value of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio, as well as bronchodilator response (BDR), in 721 asthma patients in Korea. Result: Three novel SNPs of 633G>A, 645C>A, and -79G>A in TAS2R10 and 3 known SNPs of -815T>C, -1267G>A, and -1897T>C in TAS2R14 were analyzed. Increased BDR was significantly associated with SNPs of -815T>C [OR (95% CI) = 1.88 (1.01-3.49), p = 0.04 ] [J Gen Physiol 2005;125:535-553; Am J Respir Cell Mol Biol 2010;42:373-3812], -1267A>G [OR (95% CI) = 2.07 (1.03-4.15), p = 0.04] and -1897T>C [OR (95% CI) = 3.05 (1.01-9.23), p = 0.04, in a dominant model, and OR = 1.91 (1.08−3.36), p = 0.02, in a codominant model] of the TAS2R14 gene. There was a significant association between -815T>C and a low mean ACT score [OR (95% CI) = 5.84 (1.94-17.61), p = 0.001]. In haplotype analysis, TAC, CAT, and TGT, or TG and CA haplotypes on TAS2R14 were significantly associated with increased BDR; CAT and CA haplotypes were significantly associated with a low ACT score. Conclusion: Genetic variations in TAS2Rs may be valuable genetic markers to predict therapeutic response and outcomes in asthma. Further research in an independent cohort is needed.

BackgroundAlthough genetic features vary across ethnicities, few genome-wide association studies (GWAS) have reported the genetic determinants of liver enzyme expression. This study was aimed to evaluate the associations of genome-wide single nuclear polymorphisms (SNPs) with the liver enzymes in a Korean population.MethodsWe performed a GWAS to identify genetic loci influencing liver function, as measured by concentrations of alkaline phosphatase (ALP), alanine transaminase (ALT), gamma-glutamyl transferase (GGT) and total bilirubin (BIL) in in Korean study participants.ResultsA total of 6,488 subjects (4,457 in the discovery and 2,031 in the validation set) were included. The mean subject age was 50.0±10.6 years (male, 53.7%). Among a total of 546,738 SNPs tested, rs651007 and rs579459 located in the ABO gene showed strong associations with ALP (P = 1.63×10-8 and 5.61×10-8, respectively [discovery set]; P = 4.08×10-15 and 9.92×10-16, respectively [validation set]). Additionally, rs5751901 and rs2006092, which are located in the GGT1 gene, showed strong associations with GGT (P = 6.44×10-15 and 1.26×10-15, respectively [discovery set]; P = 4.13×10-10 and 5.15×10-11, respectively [validation set]). Among the 13 SNPs that showed genome-wide significance with total bilirubin levels, rs10929302 and rs6742078 showed the most significant association (P = 3.08×10-64 and 2.05×10-62, respectively [discovery set]; P = 1.33×10-116 and 2.24×10-118, respectively [validation set]). No genome-wide significant associations was found for ALT.ConclusionsWe demonstrated that ABO, GGT1 and UGT1A family were associated with ALP, GGT and BIL, respectively in Korean population. These findings differ from reported results in GWAS in European populations in terms of associated genes and locations, suggesting different genetic mechanisms of liver enzyme regulation according to ethnicity.

Epidemiologic evidence indicates that the prevalence and severity of coronary artery disease vary depending on ethnicity. In this study, a genome-wide association study for coronary artery calcification (CAC) was performed in a Korean population-based sample of 400 subjects without prior coronary artery disease and replicated in another of 1,288 subjects. CAC score, as assessed by multi-detector computed tomography, was evaluated in volunteers for screening purposes as part of a routine health examination. CAC score greater than the 90th percentile across the age in each sex group was considered severe CAC. Single nucleotide polymorphisms (SNPs) associated with severe CAC after adjusting for age, sex, hypertension, and diabetes were investigated using the additive model of logistic regression. One SNP (rs10757272 in the intronic region of the CDKN2B-AS1 gene in chromosome 9p21.3) met Bonferroni correction in the discovery set (p = 7.55E-08) and was also significant in the validation set by TaqMan assay (p = 0.036). Subjects with rs10757272 were found to have an increased odds ratio (OR) of having severe CAC in multivariate logistic regression analysis after adjusting for age, sex, hypertension, and diabetes (adjusted OR 3.24 and 95% CI 2.11-4.97). In conclusion, SNP rs10757272 in chromosome 9p21.3 was associated with severe CAC based on age and sex in an asymptomatic community-based Korean population. Therefore, it was associated with promotion of coronary artery calcification in subclinical state.

To investigate the association between genetic risk variants for age-related macular degeneration (AMD) and response to intravitreal ranibizumab in Korean patients with neovascular AMD.This prospective study included 273 treatment-naive patients (273 eyes) who underwent 5 monthly injections (Months 0, 1, 2, 3, and 4) of intravitreal ranibizumab for neovascular AMD. Patients were genotyped for 23 single-nucleotide polymorphisms within 12 AMD-relevant genes. For each polymorphism, genotypic association with good response at Month 5, predetermined as visual improvement of ≥ 8 Early Treatment Diabetic Retinopathy Study letters from baseline, was investigated with logistic regression analysis adjusted for age, gender, smoking, baseline Early Treatment Diabetic Retinopathy Study letter, central retinal thickness, lesion area, and type of choroidal neovascularization.At Month 5, visual acuity improved by 9.1 ± 17.6 letters from baseline, and 136 patients (49.8%) were classified as good responders. In logistic regression, no tested polymorphism showed statistically significant association with favorable visual outcome at Month 5. When unadjusted for multiple tests, AA genotype for VEGF rs699947 had an increased chance of good response compared with other genotypes (odds ratio, 3.61; 95% confidence interval, 1.42-9.18; P = 0.0071).In this Korean neovascular AMD cohort, there was no statistically significant effect of genotype on early visual outcome after ranibizumab treatment.

Single nucleotide polymorphisms (SNP) are inter-individual genetic variations that could explain inter-individual differences of response/survival to chemotherapy. The present study was performed to build up a risk model for survival in 247 patients with acute myeloid leukaemia (AML) with normal karyotype (AML-NK). Genome-wide Affymetrix SNP array 6.0 was used for genotyping in discovery set (n = 118). After identifying significant SNPs for overall survival (OS) in single SNP analysis, a risk model was constructed. Out of 632 957 autosomal SNPs analysed, finally four SNPs (rs2826063, rs12791420, rs11623492 and rs2575369) were introduced into the risk model. The model could stratify the patients according to their OS in discovery set (P = 1·053656 × 10−4). Replication was performed using Sequenom platform for genotyping in the validation cohort (n = 129). The model incorporated with clinical and four SNP risk score was successfully replicated in a validation set (P = 5·38206 × 10−3). The integration of four SNPs and clinical factors into the risk model showed higher area under the curve (AUC) reults than in the model incorporating only clinical or only four SNPs, suggesting improved prognostic stratification power by combination of four SNPs and clinical factors. In conclusion, a genome-wide SNP-based risk model in 247 patients with AML-NK can identify a group of high risk patients with poor survival.

Several recent genome-wide association studies (GWAS) identified susceptibility loci/genes for Behçet’s disease (BD). However, no study has specifically investigated the genetic susceptibility loci associated with intestinal involvement in BD. We aimed to identify distinctive genetic susceptibility loci/genes associated with intestinal involvement in BD and determine their roles in intestinal inflammation as well as their interactions with genes involved in inflammatory bowel disease (IBD). GWAS and validation studies showed intestinal BD-specific associations with an NAALADL2 gene locus (rs3914501, P = 3.8 × 10−4) and a YIPF7 gene locus (rs6838327, P = 3.5 × 10−4). Validation, haplotype, and pathway analyses showed distinct genetic architectures between intestinal BD and BD without intestinal involvement. Furthermore, network analysis revealed shared pathogenic pathways between intestinal BD and IBD. Gene functional analyses indicated that down-regulation of NAALADL2 and YIPF7 expression was associated with exacerbating intestinal inflammatory responses both in vitro and in vivo. Our results provide new insights into intestinal BD-specific genetic variations, which represents a distinct pathway from BD without intestinal involvement. Functional consequences of the intestinal BD-specific NAALADL2 and YIPF7 expression patterns proved a suggestive association with intestinal inflammation risk, which warrants further validation.

The identification of patients who are at high risk for irinotecan-related severe diarrhea and neutropenia is clinically important. We conducted the first genome-wide association study (GWAS) to search for novel susceptibility genes for irinotecan-related severe toxicities, such as diarrhea and neutropenia, in non-small-cell lung cancer (NSCLC) patients treated with irinotecan chemotherapy. The GWAS putatively identified 49 single-nucleotide polymorphisms (SNPs) associated with grade 3 diarrhea (G3D) and 32 SNPs associated with grade 4 neutropenia (G4N). In the replication series, the SNPs rs1517114 (C8orf34), rs1661167 (FLJ41856) and rs2745761 (PLCB1) were confirmed as being associated with G3D, whereas rs11128347 (PDZRN3) and rs11979430 and rs7779029 (SEMAC3) were confirmed as being associated with G4N. The final imputation analysis of our GWAS and replication study showed significant overlaps of association signals within these novel variants. This GWAS screen, along with subsequent validation and imputation analysis, identified novel SNPs associated with irinotecan-related severe toxicities.

The aim of this study was to determine whether tagging polymorphisms (tSNPs) of deoxycytidine kinase (DCK) have an effect on toxicity or prognosis in patients with non-small-cell lung cancer (NSCLC) treated with gemcitabine plus cisplatin. Three tSNPs (-201 C>T, rs2306744; IVS2+9846 G>A, rs12648166; IVS6+1392 T>C, rs4694362) were chosen using the international HapMap Project and Japanese Single-Nucleotide Polymorphisms. We evaluated the associations of the tSNPs with hematologic toxicity or overall survival of 139 NSCLC patients at stages IIIA/IIIB (59) and IV (80). Hematologic toxicity such as neutropenia, thrombocytopenia, and anemia were not different by the three tSNPs or haplotypes (CGT, CAT, and CAC) of DCK. The genetic variations did not affect survival of the patients (log-rank p: 0.248 for -201 C>T, 0.571 for IVS2+9846 G>A, 0.686 for IVS6+1392 T>C, 0.556 for CGT, 0.453 for CAT, and 0.845 for CAC). In a Cox model, these tSNPs and haplotypes did not reveal prognostic relevance (aHR and 95% CI: 0.954 and 0.611 to 1.489 for -201 C>T; 1.193 and 0.719 to 1.979 for IVS2+9846 G>A; 1.072 and 0.674 to 1.706 for IVS6+1392 T>C, 0,668 and 0.205 to 2.175 for CGT, 1.043 and 0.713 to 1.525 for CAT, and 1.043 and 0.701 to 1.550 for CAC). This is the first study to focus on the association of tSNPs and their haplotypes of DCK with toxicity and survival in NSCLC patients. This suggests that genetic variations of DCK have no effect on the outcomes in the patients treated with gemcitabine-based chemotherapy.

Kawasaki disease (KD) is an acute self-limited vasculitis of infants and children that manifests as fever and signs of mucocutaneous inflammation. Coronary artery aneurysms develop in approximately 15-25% of untreated children. Although the etiology of KD is largely unknown, epidemiologic data suggest the importance of genetic factors in the susceptibility to KD. In order to identify genetic variants that influence KD susceptibility, we performed a genome-wide association study (GWAS) using Affymetrix SNP array 6.0 in 186 Korean KD patients and 600 healthy controls; 18 and 26 genomic regions with one or more sequence variants were associated with KD and KD with coronary artery lesions (CALs), respectively (p

Adiponectin is associated with obesity and insulin resistance. To date, there has been no genome-wide association study (GWAS) of adiponectin levels in Asians. Here we present a GWAS of a cohort of Korean volunteers. A total of 4,001 subjects were genotyped by using a genome-wide marker panel in a two-stage design (979 subjects initially and 3,022 in a second stage). Another 2,304 subjects were used for follow-up replication studies with selected markers. In the discovery phase, the top SNP associated with mean log adiponectin was rs3865188 in CDH13 on chromosome 16 (p = 1.69 × 10(-15) in the initial sample, p = 6.58 × 10(-39) in the second genome-wide sample, and p = 2.12 × 10(-32) in the replication sample). The meta-analysis p value for rs3865188 in all 6,305 individuals was 2.82 × 10(-83). The association of rs3865188 with high-molecular-weight adiponectin (p = 7.36 × 10(-58)) was even stronger in the third sample. A reporter assay that evaluated the effects of a CDH13 promoter SNP in complete linkage disequilibrium with rs3865188 revealed that the major allele increased expression 2.2-fold. This study clearly shows that genetic variants in CDH13 influence adiponectin levels in Korean adults.

Aims The STAT4 gene encodes a transcription factor which plays an important role in the development of inflammation of many immune-mediated diseases. We investigated the relationship between STAT4 single nucleotide polymorphisms (SNPs) and susceptibility to ulcerative colitis (UC) and Crohn's disease (CD) and disease phenotypes in the Korean population. Main methods We performed a case–control association study in individuals with UC (N = 246), CD (N = 182), and healthy controls (N = 229). Key findings We genotyped 8 STAT4 SNPs (rs11889341, rs7574865, rs8179673, rs6752770, rs925847, rs10168266, rs10181656, and rs11685878) in the STAT4 gene in patients and controls. SNP rs925847 in the STAT4 gene was significantly associated with susceptibility to UC (P = 0.025; OR = 0.63) in dominant genotype analysis, though none of these SNPs were associated with CD susceptibility. Moreover, a significant association was identified between SNP rs11889341 and joint involvement (P = 0.040; OR = 3.79), and between SNP rs925847 and eye involvement (P = 0.030; OR = 2.42) in UC patients. For CD, rs925847 genetic variant was associated with joint (P = 0.029; OR = 3.93) and perianal lesions (P = 0.033; OR = 2.27). Significance Our data demonstrated that the STAT4 genetic variants could predispose an individual to IBD and its extra-intestinal ailments in Koreans, suggesting the common pathogenesis of IBD (especially, extra-intestinal manifestations) and other autoimmune diseases.

To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study.A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population.The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA-DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P=8.16x10(-13)). Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (P=7.61x10(-8)) and DPB1*0901 (P=2.55x10(-5)) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (P=7.58x10(-17)/4.84x10(-16)) or anticentromere autoantibodies (P=1.12x10(-3)/3.2x10(-5)), respectively.The results of our genome-wide association study in Korean subjects indicate that the region of HLA-DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA-DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti-DNA topoisomerase I or anticentromere autoantibodies.

Objective The pathogenesis of osteonecrosis of the femoral head (ONFH) probably reflects multiple etiologies. Recent studies have explored associations between genetic mutations and/or polymorphisms and ONFH. Annexins ( ANX s) have been implicated in many physiological functions, including blood coagulation, inflammation, apoptosis, as well as Ca 2+ homeostasis in bone cells, all of which may be associated with ONFH. The aim of this study was to evaluate the possible association of AnnexinA ( ANXA ) family gene polymorphisms with ONFH. Methods 52 SNPs from three genes of the ANXA family were selected from public databases and genotyped in 443 ONFH patients and 273 control subjects using the Affymetrix Targeted Genotyping 3 K Chip array. The association analysis of genotyped SNPs and haplotypes was performed with ONFH. Results Among the polymorphisms tested of the ANXA family gene, the rs9324679, rs9324677, rs10037814, and rs11960458 SNPs of the ANXA6 gene were significantly associated with the risk of ONFH in all alternative analysis models ( p range; 0.0007–0.049, odds ratio (OR); 0.63–1.72). Further analysis stratified by pathological etiology showed that these SNPs were also associated with the risk of ONFH in at least one subgroup ( p range; 0.0017–0.049). Haplotype association analysis showed that several haplotypes were significantly associated with a risk of ONFH, with p values ranging between 0.0005 and 0.049 (OR range; 0.44–1.76). Conclusions These findings indicate that the polymorphisms of ANXA6 are associated with ONFH. Thus, these polymorphisms may be useful genetic markers to identify high-risk individuals.

Clopidogrel is a prodrug that has to be converted to an active metabolite by hepatic cytochrome P450 (CYP) isoenzymes to inhibit platelet aggregation. Individual variability of platelet inhibition by clopidogrel suggests a possibility for genetic factors having a significant influence on clopidogrel responsiveness. In this study, we sought to determine the relation of genetic polymorphisms of CYP genes to clopidogrel resistance in Koreans. Four hundred fifty patients who underwent successful percutaneous coronary intervention with drug-eluting stents were randomly assigned to treatment with dual antiplatelet regimen (aspirin plus clopidogrel) or triple antiplatelet regimen (aspirin plus clopidogrel plus cilostazol). Clopidogrel resistance using VerifyNow P2Y12 assay and genetic analysis were performed in 387 patients. Clopidogrel resistance was found in 112 patients (28.9%). In the clopidogrel-responsive group, there was a significantly higher proportion of cilostazol use. Because cilostazol showed a significant influence on clopidogrel resistance, we examined the association of single-nucleotide polymorphisms and clopidogrel resistance in the dual and triple antiplatelet therapy groups, respectively. In all subjects, the CYP2C19*3A allele was significantly more prevalent in the clopidogrel-resistant group compared with the clopidogrel-responsive group. Multiple logistic regression analysis demonstrated that CYP2C19*3 is an independent predictor of clopidogrel resistance. In conclusion, CYP2C19*3 single-nucleotide polymorphisms is an independent risk factor of clopidogrel resistance in Korean subjects with coronary artery disease.

Background Atopic dermatitis (AD) patients have been recognized to have an increased susceptibility to cutaneous colonization and infection by bacteria, fungi and viruses. Objective We wanted to evaluate the associations of single nucleotide polymorphism (SNP) and the haplotype in the defensin (DEFA) and defensin (DEFB) genes, and so we performed genotyping for the SNPs in these genes in both AD patients and normal controls. Method We genotyped 27 SNPs from the DEFA 4, 5 and 6 genes and the DEFB1 gene for 1089 case–control samples (631 AD patients and 458 normal controls). We analyzed the SNPs and haplotypes in each gene. Result We identified that two SNPs and the haplotype CT in the DEFB1 gene are associated with AD in Koreans. The rs5743399 (−2266T/C) SNP is associated with AD, and especially with the high IgE, extrinsic type, and the rs5743409 (−1241T/G) SNP is associated with AD. On the haplotype analysis of these two SNPs, the haplotype CT is associated with AD, and especially with the allergic, extrinsic type of AD. However, we could not find any significant associations between the SNPs in the three DEFA genes and AD. Conclusion We found that the rs5743399 SNP, the rs5743409 SNP and the CT haplotype in the DEFB1 gene were significantly associated with the susceptibility to AD. We also found that rs5743399 polymorphism and the haplotype CT in this gene showed a strong association with the allergic, extrinsic type of AD. These results suggest that the DEFB1 gene has a main effect on the skin inflammation and/or skin responsiveness to any kind of allergic reaction.

Purpose To determine whether germ-line variations in BRCA1 affect outcome in non–small-cell lung cancer (NSCLC) patients treated with platinum combination chemotherapy. Patients and Methods We evaluated the associations of four tagging BRCA1 polymorphisms and their haplotypes with treatment outcome in 300 NSCLC patients at stages IIIA (16%), IIIB (31%), and IV (53%). Results The median age was 63 years (range, 28 to 89 years). Histologically, 139 (46.3%) of the patients had squamous cell carcinomas and 137 (45.7%) had adenocarcinomas. Patient median survival time (MST) was 13.0 months. We observed no significant association between any of the tagging polymorphisms [S1613G, IVS13-1893 (A>C), IVS12-1207 (C>T), and IVS12+112 (C>A)] and overall survival. Of the five haplotypes evaluated (AACC, AACA, GCTC, GATC, and AATC), the survival of patients with two copies of the AACC (wild-type) haplotype was significantly shorter than that of patients with zero to one copies (MST, 8.47 v 14.57 months; log-rank P = .0066), even after adjustment for body weight loss, performance status, stage, second-line treatment, and radiation therapy (hazard ratio = 2.097; 95% CI, 1.339 to 3.284). The survival of patients with squamous cell carcinoma and two copies was significantly shorter than that of other patients with squamous cell carcinoma (MST, 6.8 v 15.3 months; log-rank P = 3.6 × 10−5), whereas differences in survival between the two adenocarcinoma groups was not significant (log-rank P = .677). Conclusion These findings suggest that the AACC haplotype of the BRCA1 gene is an important prognostic marker in NSCLC patients treated with platinum combination chemotherapy.

Summary 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.

Context.—Chronic hepatitis B infection is the leading cause of cirrhosis and hepatocellular carcinoma. Human leukocyte antigen may be involved in the chronicity of hepatitis B virus (HBV) infection. Objective.—To analyze the association between HBV chronicity and human leukocyte antigen alleles and haplotypes of 636 organ donors and recipients. Design.—Subjects were categorized into 2 groups according to their clinical and serologic profiles, specifically, an HBV natural convalescent group and an HBV chronic carrier (CC) group. Results.—Hepatitis B chronicity was positively associated with A33 (P = .004, odds ratio [OR] = 1.59) and DR7 (P < .001, OR = 2.58), and negatively associated with HLA-DR13 (P < .001, OR = 0.40). Coexpression of A33 and DR7 was significantly higher in the CC group (OR = 3.63), compared with that of either allele alone (OR = 1.76 in A33; OR = 2.53 in DR7). The statistically significant haplotypes were B44-DR7 (P < .001, OR = 5.44), A33-DR7 (P < .001, OR = 4.47), and A33-B44-DR7 (P < .001, OR = 7.31) in the CC group. Conclusions.—Our results indicate that alleles of A33, DR7, and haplotypes containing DR7 are associated with HBV chronicity among Koreans. Moreover, the 2 antigens had an additive effect on chronicity. These findings support the theory that human leukocyte antigen class I–restricted cytotoxic T cells and human leukocyte antigen class II– restricted helper T cells play an important role in HBV chronicity.

Background: Chronic cough is associated with increased sensitivity to inhaled capsaicin, and both tachykinins and their receptors play important roles in the cough reflex. However, associations between polymorphisms of the tachykinin receptor genes and cough sensitivity in patients with non-productive chronic cough have not been reported. Methods: Direct sequencing was used to identify single nucleotide polymorphisms (SNPs) in the genes for the neurokinin-1 and neurokinin-2 receptors (NK-1R and NK-2R, respectively). Informative non-synonymous SNPs were scored using the single base extension method for 312 patients with chronic cough and for 100 age matched healthy controls. The cough response to capsaicin was recorded for 312 patients with chronic cough, and the potential genetic association between cough sensitivity to capsaicin and the NK-1R and NK-2R genotypes was evaluated. Results: Two informative SNPs were identified in NK-2R (Gly231Glu and Arg375His), whereas no informative SNP was found in NK-1R . After adjusting for atopy, sex, age, and smoking, the prevalence of enhanced cough sensitivity to capsaicin was higher in the chronic cough patients with the 231Glu allele (p = 0.004; OR 1.69 (95% CI 1.18 to 2.42)) and the 231Glu_375Arg haplotype (p = 0.003; OR 1.71 (95% CI 1.20 to 2.24)]. Moreover, the lowest capsaicin concentration to cause five consecutive coughs (C5) was significantly lower in patients with 231Glu (mean (SD) 44.1 (53.2) v 60.9 (55.8) μM/l, p = 0.04) and those with 231Glu_375Arg (43.2 (52.7) v 69.6 (52.0) μM/l, p = 0.03). Conclusions: The results of this study suggest that NK-2R gene polymorphisms are involved in the enhanced cough sensitivity to capsaicin of patients with chronic cough.

Interleukin (IL)-13, which is essential for IgE synthesis, mediates its effects by binding with a receptor composed of IL-4Ralpha and IL-13Ralpha1. We investigated the effects of IL-13 and IL-13Ralpha1 polymorphisms in Korean children with asthma, and whether these have been associated with IgE production. We enrolled 358 atopic asthmatic, 111 non-atopic asthmatic, and 146 non-atopic healthy children. IL-13 and IL-13Ralpha1 genotypes were identified using the PCR-RFLP method. There was an association between the asthma susceptibility and homozygosity for risk allele of IL-13 G+2044A. In children with atopic asthma, risk alleles in IL-13 (A-1512C and C-1112T) and IL-13Ralpha1 (A+1398G) showed increased total IgE (P=0.012, 0.015 and 0.017, respectively). Three-loci haplotype analysis for IL-13 showed that the haplotype composed of -1512C, -1112T and +2044A was associated with higher total IgE than other tested haplotypes in children with atopic asthma (P=0.003). The gene-gene interaction between risk alleles of each IL-13 promoter polymorphism and IL-13Ralpha1 polymorphism was associated with higher total IgE in children with atopic asthma (P=0.002, 0.010). These findings indicate that the IL-13 G+2044A is associated with asthma development and the IL-13 and IL-13Ralpha1 polymorphisms may interact to enhance IgE production.

Background Vascular endothelial growth factor (VEGF) has been suggested to be a key mediator in the development of atopy and T H 2 inflammation. Objective We sought to evaluate the effects of variations in the gene coding VEGF receptor (VEGFR) 2 on intermediate phenotypes of asthma in the Korean population. Methods A cohort of 2055 children and adolescents responded to a questionnaire concerning asthma symptoms and risk factors and underwent methacholine bronchial challenge and skin tests. The VEGFR2 gene, including the promoter area, was sequenced on 24 healthy subjects to discover informative single nucleotide polymorphisms (SNPs; minor allele frequency >2%). After haplotype reconstruction, 4 tagging SNPs (IVS6+54A>G, +889G>A, +1416T>A, and IVS25-92G>A) were scored. These SNPs were also scored in 480 adult asthmatic patients to verify the above genetic association study. Results The prevalence of atopy was associated with a single SNP (+889G>A) of VEGFR2 with borderline significance ( P = .048; relative risk, 1.13; 95% CI, 1.00-1.28). However, haplotype analysis showed that the atopy prevalence was strongly associated with a haplotype (AGAG) of VEGFR2 ( P = .002; relative risk, 1.25; 95% CI, 1.09-1.42). As for airway hyperresponsiveness, neither individual SNPs nor haplotypes were found to be associated. Interestingly, the significant association was also found between atopy and the AGAG haplotype among adult asthmatic patients ( P = .008; odds ratio, 1.66; 95% CI, 1.14-2.44). Conclusions The present study demonstrated that genetic variations of VEGFR2 are significantly associated with atopy in the Korean population.

Purpose: A single-nucleotide polymorphism (SNP) in codon 655 of HER-2 has been extensively studied with inconclusive results. The purpose of this study was to investigate the association between common variants of HER-2 and breast cancer risk, HER-2 expression, and survival using a haplotype-based stepwise approach. Experimental Design: Twenty-nine SNPs listed in the National Center for Biotechnology Information database were screened to identify novel polymorphisms of HER-2 gene in 90 healthy Korean women. Six of 29 SNPs were polymorphic and had greater than 10% of minor allele frequencies. Using these six SNPs, linkage disequilibrium and haplotype patterns were characterized. We tested association between the haplotypes and breast cancer in a large case–control study (n = 1,039 cases and 995 controls). Six-hundred two breast cancer patients with follow-up at least 24 months were analyzed for outcome in relation to haplotype. Expression of HER-2 protein was determined by immunohistochemistry in 1,094 cases of invasive breast cancer. Results: All six SNPs showed a strong linkage disequilibrium pattern and were considered to belong to one haplotype block. Two haplotype-tagging SNPs (I655V and P1170A) for three common haplotypes (>5%) were genotyped in cases and controls. The haplotypes and individual SNPs were not associated with breast cancer risk. In patients with at least one copy of haplotype I (the most common haplotype), HER-2 expression was 1.5 times higher (P = 0.009) and the prognosis was worse (P = 0.032) compared with patients without having that haplotype. Conclusions: Our results suggest that the currently identified genetic polymorphisms of HER-2 are not associated with an increased risk of breast cancer in Korean women, whereas one haplotype does affect protein expression of the tumor and disease outcome.

GOAL AND BACKGROUND Host genetic diversity may play roles in development of HCC. This study was conducted to validate the effects of tumor necrosis factor-alpha (TNF-α) gene polymorphism on development of hepatocellular carcinoma (HCC) in patients chronically infected with hepatitis B virus (HBV). STUDY The study cohort comprised 224 patients with HBV-associated HCC and 206 with HBV-associated liver cirrhosis (LC). Using chromosomal DNA, TNF-α promoter gene polymorphisms were determined at 3 common single-nucleotide polymorphism (SNP) sites (TNF-α-1031 T>C, TNF-α-857 C>T, and TNF-α-308 G>A) using a single base extension method. The genotype distributions were compared between the 2 groups. All the HBV-associated LC patients were followed up regularly every 6 to 12 months for surveillance of HCC development. RESULTS In the cross-sectional analysis, the frequency of TNF-α-857 T allele was much higher in patients with HCC compared with those with LC (42% vs. 31%, P

Context: Osteoporotic fracture risk is highly heritable, but genome-wide association studies have explained only a small proportion of the heritability to date. Genetic data may improve prediction of fracture risk in osteopenic subjects and assist early intervention and management. Objective: To detect common and rare variants in coding and regulatory regions related to osteoporosis-related traits, and to investigate whether genetic profiling improves the prediction of fracture risk. Design and Setting: This cross-sectional study was conducted in three clinical units in Korea. Participants: Postmenopausal women with extreme phenotypes (n = 982) were used for the discovery set, and 3895 participants were used for the replication set. Main Outcome Measure: We performed targeted resequencing of 198 genes. Genetic risk scores from common variants (GRS-C) and from common and rare variants (GRS-T) were calculated. Results: Nineteen common variants in 17 genes (of the discovered 34 functional variants in 26 genes) and 31 rare variants in five genes (of the discovered 87 functional variants in 15 genes) were associated with one or more osteoporosis-related traits. Accuracy of fracture risk classification was improved in the osteopenic patients by adding GRS-C to fracture risk assessment models (6.8%; P < .001) and was further improved by adding GRS-T (9.6%; P < .001). GRS-C improved classification accuracy for vertebral and nonvertebral fractures by 7.3% (P = .005) and 3.0% (P = .091), and GRS-T further improved accuracy by 10.2% (P < .001) and 4.9% (P = .008), respectively. Conclusions: Our results suggest that both common and rare functional variants may contribute to osteoporotic fracture and that adding genetic profiling data to current models could improve the prediction of fracture risk in an osteopenic individual.

BackgroundTwo common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin-exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population.MethodsA comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n = 264), NC (n = 238) and disease-control (aspirin tolerant asthma; ATA, n = 387) groups.ResultsThe minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (P = 0.001, P = 0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (P = 0.039, 0.037, and 0.004, respectively).ConclusionsThis implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype.

Background and Aim Recent genomic studies have identified genetic variants in the IL12B gene, which encodes the p40 subunit shared by interleukin 12 and interleukin 23, as susceptibility loci for inflammatory bowel disease (IBD). The study aimed to identify additional novel genetic variants in IL12B and investigated whether variants confer susceptibility to the development of Crohn's disease (CD) or ulcerative colitis (UC) in the Korean population. Methods To detect single nucleotide polymorphisms (SNPs) in IL12B, direct sequencing of all coding exons, exon-intron boundaries, promoter region, and 5′ untranslated region was performed in 24 randomly selected samples. Selected haplotype-tagging SNPs were subsequently genotyped in 493 IBD patients (245 patients with CD and 248 with UC) and 504 healthy controls. Results Two haplotype-tagging SNPs (rs2288831 and rs919766) were selected through direct sequencing and were genotyped. Of them, SNP rs2288831 in the IL12B gene was significantly associated with CD susceptibility in allelic association analysis (odds ratio = 1.30; 95% confidence interval 1.04–1.62; P = 0.019). This significant association with CD was also observed for a haplotype consisting of SNP rs919766 and rs2288831 (odds ratio = 1.29; 95% confidence interval 1.03–1.60; P = 0.025). However, none of IL12B SNPs were associated with UC susceptibility. Finally, no specific associations between genetic variants and disease phenotype of CD were identified. Conclusions This study is first to identify SNP rs2288831 in the IL12B gene as a susceptible variation for CD. Further studies in other ethnic groups are warranted to validate the association of this genetic variant with IBD.

Background The histology of atopic dermatitis includes dilated, tortuous vessels within the papillary dermis and perivascular edema. Method This study included 1120 case-control samples (646 AD patients and 474 normal controls), for which we genotyped 34 SNPs from four VEGF family genes and the FLT4 gene. For the rs11607007 SNP in the VEGFB gene and three SNPs (rs10085109, rs3736062, and rs11949194) in the FLT4 gene, which had significant p -values in the initial stage, were further investigated using 1132 independent samples (440 AD patients and 692 normal controls). Result Of the four SNPs, rs10085109 in the FLT4 gene was only significantly associated with the AD phenotype in both initial and replication samples. Although no SNPs in the VEGFA gene were significantly associated with AD, the rs2010963 SNP had a marginally significant effect on log-eosinophil counts. Conclusion The rs10085109 SNP in the FLT4 gene were associated with susceptibility to AD.

Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand-foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib-induced HFSR and genetic polymorphisms in Korean patients with HCC.For this prospective cohort study, the authors enrolled 59 consecutive patients with intermediate stage HCC from 5 centers in Korea. All patients received sorafenib 400 mg twice daily in combination with transarterial chemoembolization (TACE). Genotyping was performed on a total of 49 single nucleotide polymorphisms (SNPs) in 8 candidate genes (minor allelic frequency ≥5%). Serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were measured using enzyme-linked immunosorbent assays before therapy and 1 month after therapy.During a median treatment period of 18 months, 55 patients (93%) developed sorafenib-induced HFSR, including grade 1 reactions in 15 patients, grade 2 reactions in 27 patients, and grade 3 reaction in 13 patients. The SNPs TNF-α -308GG, VEGF -94GG, VEGF 1991CC, VEGF IVS3-28CC, and uridine diphosphate glucuronosyltransferase 1 family-polypeptide A9 (UGT1A9) IVS1-37431AA were associated significantly with the development of high-grade (grade 2 or 3) HFSR in univariate analysis (P.05). In multivariate analysis, the SNPs VEGF 1991CC (odds ratio, 45.7), TNF-α -308GG (odds ratio, 44.1), and UGT1A9 IVS1-37431AA (odds ratio, 18.7) were identified as independent risk factors for the development of high-grade HFSR (P = .01, P = .02, and P = .02, respectively). He serum TNF-α level measured 1 month after sorafenib therapy was correlated significantly with the development of high-grade HFSR (odds ratio, 3.56; P = .026).Differences in the incidence of HFSR may have been caused by ethnic differences in genetic polymorphisms of the TNF-α, VEGF, and UGT1A9 genes, especially in relation to the expression of serum TNF-α after sorafenib therapy.

Background & Aims We aimed at determining whether single nucleotide polymorphisms (SNPs) of DNA repair genes influence the development and clinical outcomes of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Methods We evaluated 14 SNPs of eight DNA repair genes in 708 patients with HCC and 388 HBsAg positive controls without HCC. The Kaplan–Meier methods with log-rank test and Cox regression models were used to compare survival of HCC patients according to the genotype. Results The SNP of XRCC4 rs1805377 was significantly associated with decreased risk of HCC development (OR, 0.592; p =0.028) and improved overall survival of patients with HCC (median survival time (MST) of 48, 72, and 89months for the AA, AG, and GG genotypes, respectively; p =0.044). In addition, SNP of OGG1 rs1053133 was significantly associated with postoperative recurrence (OR, 0.604; p =0.049), tumor differentiation (OR, 0.571; p =0.041), and improved survival of resected HCC (MST of 55 and 108months for the GG and GC/CC genotypes, p =0.001). The multivariate analysis showed that OGG1 rs1052133, XRCC1 rs25487, ERCC5 rs2018836, ERCC5 rs3818356, and XRCC4 rs1805377 had a significant effect on survival. Moreover, a strong dose-dependent association was observed between the number of putative high-risk genotypes of OGG1 , XRCC1 , ERCC5 , and XRCC4 with the overall survival. The MST of HCC with ⩽2 putative high-risk genotypes was significantly prolonged compared to those with ⩾3 high-risk genotypes (76 vs. 46months, respectively, p= 0.002). Conclusions Polymorphisms of DNA repair genes play a potential role in the development, progression, and survival of Korean HCC patients with chronic HBV infection.

Th2-dominated immune responses are believed to contribute to the pathogenesis of atopic dermatitis (AD). IL-4 and IL-13 are typical pleiotropic Th2 cytokines that play a central role in IgE-dependent inflammatory reactions. Single-nucleotide polymorphisms (SNPs) in IL-4 and IL-13 have been reported in patients with allergic disease from numerous countries. Gene-gene interactions among genes have been identified in patients with asthma, although negative results have been reported. To investigate the associations of SNPs in these genes and the interactions between these genes in AD, we genotyped 23 SNPs of the IL-4, IL-13, IL-4R, IL-13Rα1 and IL-13Rα2 genes for 1089 case-control samples (631 AD patients and 458 controls) and analysed the SNPs and haplotypes in these genes. We also searched for gene-gene interactions among these five genes. Our data identified an association between rs3091307 and rs20541 in the IL-13 gene and between rs2265753 and rs2254672 in the IL-13Rα1 gene and the AD phenotype. In particular, three of the four SNPs were especially predictive of the allergic type of AD (ADe), and the haplotype TCGG in the IL-13Rα1 gene showed significant association with AD, especially ADe. Furthermore, the combination of rs3091307 GG/ rs2265753 GG (IL-13/IL-13Rα1) conveyed a significantly higher risk for developing ADe. However, we did not identify any SNPs in the IL-4, IL-4R and IL-13Rα2 genes that were associated with AD. As IL-13Rα1 is most likely expressed in Th17 cells rather than in Th2 cells, these data suggest diversity in the classification of Th cells that needs to be verified in future studies.

Backgrounds/Aims Metastatic tumour antigen 1 (MTA1) promotes angiogenesis by stabilizing hypoxia-inducible factor-1α (HIF-1α), which is closely associated with frequent postoperative recurrence and poor survival in patients with HCC. In this study, we determined single nucleotide polymorphisms (SNPs) in angiogenesis-related genes that are associated with MTA1 overexpression in HCC tissues. Methods A total of 376 patients with HCC who had received curative surgical resection or liver transplantation were enrolled (312/21/43; HBV/HCV/NBNC). MTA1 expression was determined via immunohistochemistry. Thirty-three common SNPs sites (frequency ≥5%) in the angiogenic protein gene that are closely connected to one another were selected, including MTA1, VEGF, HIF-1α, FGF-2, and IGF-II. Results Expression of MTA1 was detected in 120 HCC tissues (31%). An A allele at position IVS4-81G/A of the MTA1 gene (P = 0.016) and the TT genotype at position +12916C of the VEGF gene (P = 0.023) were significantly associated with MTA1 overexpression. However, the TT genotype at position −13021C (P = 0.011) and the haplotypes CT-CT (−11228C; −13021C) of the IGF-II gene (Pcor = 0.033) were more common in patients with MTA1-negative HCC. Using multivariate analysis, the A allele at IVS4-81G/A in MTA1 gene (P = 0.015) and a T allele (TT+CT genotype) at −13021C in IGF-II (P = 0.002) were independent risk factors in HCC recurrence after curative surgical resection. Conclusions The genetic polymorphisms IVS4-81G/A in MTA1 and +12916C in VEGF genes were correlated with MTA1 overexpression. The SNPs in MTA1 and IGF-II genes may be important risk factors for the recurrence of HCC.

Clinical studies, including twin studies, support the concept that the risk of atopic dermatitis (AD) may be mediated through skin-specific genes, rather than simply through systemic immune or atopy risk genes. The SPINK5 gene is expressed on epithelial surfaces and may provide protection against other allergenic serine proteases. Mutations in the SPINK5 gene result in Netherton syndrome, a disorder characterised by AD, ichthyosis, and elevated serum IgE levels. We genotyped 21 single nucleotide polymorphisms (SNPs) from the SPINK5 gene for 1090 case-control samples (631 patients with AD and 459 normal controls) and analysed the SNPs and haplotypes in this gene and also searched for gene-gene interactions between SPINK5 and the DEFB1 gene that we previously reported. Six SNPs [rs17718511 (P = 0.026), rs17860502 (P = 0.024), KN0001820 (P = 0.045), rs60978485 (P = 0.007), rs17718737 (P = 0.02), and rs1422985 (P = 0.038)] and the haplotype TAA (rs60978485, rs6892205, rs2303064; P = 0.023) in the SPINK5 gene showed significant different allelic or genotypic distributions between the AD group and the control group. We also found that four SNPs [rs17718511 (P = 0.033), rs17860502 (P = 0.031), rs60978485 (P = 0.005), rs17718737 (P = 0.023)] and the haplotype TAA (P = 0.02) in the SPINK5 gene showed associations with the susceptibility of the allergic type of AD (ADe). In addition to this finding, we speculate that the SNPs from DEFB1 and SPINK5 affect the individual susceptibility to development of ADe in an additive manner. This study provides evidence for a significant interaction between allergens and the SPINK5 gene that may contribute to ADe susceptibility.

Single-nucleotide polymorphisms (SNPs) in genes of the axon guidance pathway have been reported to be a possible susceptibility factor for Parkinson's disease (PD). This study investigated whether the genetic variability in the axon guidance pathway is a susceptibility factor in PD patients in the Korean population. A total of 373 patients and 384 healthy subjects were included. A set of 22 SNPs was analyzed, and the risk of PD was evaluated using odds ratios in an unconditional and conditional logistic regression models of age- and gender-matched subsets. A multidimensionality reduction (MDR) analysis was performed to explore potential gene-gene interactions. SNPs in the DCC, CHP, RRAS2 and EPHB1 genes of the axon guidance pathway showed significant associations with PD. The DCC rs17468382 and EPHB1 rs2030737 SNPs may be associated with increased PD risk, and the CHP rs6492998 and RRAS2 rs2970332 SNPs may be associated with reduced PD risk. However, no significant interactions for PD risk were found in the MDR analysis and logistic regression analysis using SNP interaction terms. This study supports that only four of the selected 22 SNPs are regulating factors associated with PD in the Korean population. However, no interactions were found among the SNPs, suggesting that the effect for the pathway as a whole is not greater than that for single genes in the Korean population. Further investigations involving populations of various ethnicities and other genetic markers and models are warranted.

Background The genes encoding IL-9 and IL-9R have recently been implicated in the genetic basis of asthma and allergy. Although studies performed on transgenic and knockout mice have shown conflicting results, no evidence of skin changes has ever been reported in these animals. Objective To find association of the SNPs in IL-9 and IL-9R genes and interaction of these genes in atopic dermatitis. Method We genotyped 5 SNPs from the IL-9 and IL-9R genes of 1090 subject samples (631 AD patients and 459 normal controls). A luciferase assay was then performed for the rs31563 (−4091G/A) SNP located in the IL-9 gene promoter region. Result The rs31563 (−4091G/A) SNP in the IL-9 gene was significantly associated with the AD phenotype, especially allergic-type AD. In the luciferase assay, the rs31563 G construct was observed to have 1.54 times higher activity than the rs31563 A construct. Although no association was found between SNPs in IL-9R gene and AD, the rs3093467 SNP showed association with non-allergic AD. In the gene–gene interaction analysis, we found that IL-9/IL-9R genotype rs31563 GG/rs3093467 TT conveyed a greater risk for AD phenotype development. Conclusion Significant evidence exists to suggest that the rs31563 SNP (−4091G/A) located in the IL-9 gene is associated with an increased susceptibility to AD. Similarly, the rs3093467 SNP in IL-9R gene seems to be associated with an increased risk for developing non-allergic AD. In a subsequent gene–gene interaction analysis, the rs31563 GG/rs3093467 TT genotype combination (IL-9/IL-9R) was found to exert a synergistic effect in the development of the AD phenotype. As the classes of helper T cells are diverse and the function of IL-9 cytokine has not been fully described, the cutaneous function of IL-9 needs to be further explored in future studies.

Transforming growth factor-beta (TGF-β) and its receptors have been suggested to play key roles in the pathogenesis of asthma. The aim of this study was to evaluate the effects of genetic variations in the TGF-β receptor type III (TGFBR3) on asthma and on its related phenotypes in the general population. A cohort of 2,118 subjects aged from 10 to 18 years responded to a questionnaire concerning asthma symptoms and risk factors. Methacholine airway hyperresponsiveness (AHR), skin test responses to common aeroallergens, and serum total IgE levels were evaluated in the cohort. A total of 19 SNPs for TGFBR3 were found using direct re-sequencing in 24 healthy adults. Of these, informative SNPs [+44T>C (S15F) and +2753G>A at 3'UTR] were selected and scored using the high throughput single base extension method. Atopy was identified in subjects with 44T>C allele [P = 0.04, OR (95% CI) = 0.79 (0.62-0.99)] and in subjects with Ht1 (CG) more frequently than in subjects with other haplotypes [P = 0.04, OR (95% CI) = 1.27 (1.01-1.59)]. The A allele in 2753G>A was more common in subjects with non-atopic asthma [OR (95% CI) = 1.76 (1.01-3.05)]. A significant association was found between non-atopic asthma and 44T_2753A [OR (95% CI) = 2.16 (1.22-3.82)]. Genetic variations in TGFBR3 appear to be associated with a genetic predisposition to development of asthma and to phenotypes of asthma. Also, the minor allele 2753G and the haplotype TA in the TGFBR3 gene were associated with a pathogenesis of non-atopic asthma.

Background The acute skin lesions of atopic dermatitis (AD) are associated with Th2 cells; however, the chronic skin lesions of AD are associated with Th1 cells via the action of IL-12. Objective We evaluated the associations of single nucleotide polymorphisms (SNPs) and haplotype in the IL-12 and IL-12 receptor genes, and determined the gene–gene interactions between the SNPs of these genes and the SNPs of the IL-18 gene that we previously reported. Method We genotyped 24 SNPs from 4 IL-12/IL-12R genes for 1089 case–control samples (631 AD patients and 458 normal controls). We measured the serum IL-12 concentrations in 89 individuals (79 AD patients and 10 controls) by ELISA. We analyzed the SNPs and haplotypes in each gene and also searched for the gene–gene interactions. Result The rs582504 (IVS − 798A/T) SNP and the haplotype TA (rs582054 and rs2243151) in the IL-12A gene, and the rs438421 (IVS12 + 1266T/C) SNP and the haplotype CCA (rs375947, rs438421, and rs1870063) in the IL-12RB1 gene were significantly associated with the AD phenotype. We showed that the rs438421 polymorphism in the IL-12RB1 (TT) gene and the rs2066446 polymorphism in the IL-12RB2 (AA) gene had a significant interaction to develop the ADe phenotype (allergic type of AD), and those individuals with the risk alleles, TT/AA/CC (IL-12RB1/IL-12RB2/IL-18), have more than a 10-fold increased risk to develop ADe. Conclusion This study provides evidence for a significant interaction between the IL-12RB1 and IL-12RB2 genes that contribute to a 4-fold increased risk for developing ADe. In addition to the IL-12R interaction, we suggest that the IL-18 gene can significantly interact with the IL-12R gene to develop ADe. In addition to the interaction, the SNPs and haplotypes in the IL-12A and IL-12RB1 genes are independently and significantly associated with the AD phenotype, and especially with the ADe phenotype. This data may contribute to our understanding of AD genetic interactions and account for the additional risk of certain patients to develop AD.

The G2385R (SNP accession no. rs34778348) and R1628P (rs33949390) variants of leucine-rich repeat kinase 2 (LRRK2, PARK8) are emerging as an important risk factor for Parkinson's disease (PD) in the ethnic Chinese and Japanese populations. The purpose of this study was to investigate whether these variants are a genetic risk factor in sporadic PD patients in the Korean population. A total of 923 patients and 422 healthy subjects were included. The variants were screened by a SNaPshot assay. The LRRK2 G2385R variant was detected in 82 PD patients (8.9%, two homozygous and 80 heterozygous) and in 21 normal controls (5.0%, all heterozygous). The frequency of the LRRK2 G2385R variant in PD was significantly higher than in normal controls (adjusted odds ratio 1.83, p = 0.0170, 95% confidence interval 1.11-3.00). There were no differences in the mean age at onset or gender between the G2385R carriers and the non-carriers in PD patients. The LRRK2 R1628P variant was very rare (0.78% in patients versus 0.26% in controls) in the tested 384 patient-control pairs, and was not a significant risk factor. This study supports that the LRRK2 G2385R variant may be a genetic risk factor for sporadic PD in the Korean population.

Cyclin-dependent kinase 5 (CDK5), a proline-directed serine/threonine kinase, which was originally known for its regulatory role in neuronal activities, has recently been suggested to play a role in extraneuronal activities. For example, a recent study detected overexpression of the CDK5 gene in non-small-cell lung cancer. Therefore, in order to explore the association of the CDK5 gene with lung cancer risk in a Korean population, the genotypes of the CDK5 promoter region were determined in 407 lung cancer patients and 402 normal participants. The result showed that the −904 G>A genotype affected susceptibility to lung cancer risk (odd ratios (OR)=1.53, 95% confidence interval (CI)=1.02–2.32). Furthermore, subsequent haplotype analysis of three single-nucleotide polymorphism (SNP) regions suggested that the A–G–C haplotype was associated with a higher overall risk of lung cancer (OR=1.59, 95% CI=1.16–2.18). These results suggest that CDK5 promoter polymorphisms contribute to the genetic susceptibility to lung cancer in the Korean population.

To investigate the genetic association between ankylosing spondylitis (AS) and single nucleotide polymorphisms (SNP) of collagen 6A1 gene (COL6A1), the candidate gene for ossification of the posterior longitudinal ligament.One-hundred thirty Korean patients with AS (M: 116, F: 14, age: 29.0 +/- 4.6) and 130 age- and sex-matched healthy subjects were recruited. The SNP of G365G, IVS15+39 C/T, IVS21+18 A/C by Snap shot assay and the SNP of IVS32-29T/C, IVS33+15G/A, IVS33+20A/G, and IVS33+55A/G by direct sequencing were genotyped and analyzed. Bonferroni correction was applied to multiple comparisons.The observed allelic frequencies for these SNP met Hardy-Weinberg equilibrium in all AS and controls. We also found an additional 2 SNP (R783Q and IVS33+88C/T) during direct sequencing. Therefore, a total of 9 SNP were analyzed in this study. There were no significant associations of allelic and genotype variations between AS and controls. The presence of uveitis was marginally associated with a haplotype (CC in G365G + IVS15+39 C/T). The variation of allele or haplotype of COL6A1 is not significantly associated with "more ossified disease."Because the genetic variations of COL6A1 could not be correlated with the occurrence of AS in Koreans, we conclude that despite common clinical features, AS and ossification of posterior longitudinal ligament are not genetically related, and the hyperostotic condition seen in the 2 diseases might be regulated differently. Further SNP of COL6A1 were not related to radiographic progression of AS. However, we found that the occurrence of uveitis might be related to the genetic variations of COL6A1 in patients with AS.

IgE-dependent activation of mast cells and basophils through the high-affinity IgE receptor (Fc(epsilon)R1) is involved in the pathogenesis of allergen-induced immune responsiveness in atopic disease including bronchial asthma.We genotyped 650 children for allelic determinants at two polymorphic sites, -109T/C and E237G, in the Fc(epsilon)R1beta gene by SNP-IT assays using the SNP stream 25K system.Distributions of the genotype and allele frequencies of Fc(epsilon)R1beta -109T/C and E237G polymorphisms were significantly associated with atopy (P0.05) and elevated serum IgE levels. However, differences in the E237G polymorphism did not reach statistical significance after adjustment for multiple comparisons. The genotypes TC or CC at -109T/C were associated with decreased forced expiratory flow(25-75%) in children with asthma (P0.05), but this did not reach statistical significance after correction for multiple comparisons. In addition, haplotype 1 (T-A) was associated with atopy susceptibility (P = 0.0069). Analysis of genotype distributions of haplotypes demonstrated a significantly lower PC(20) for homozygous -/- diploids compared with homozygous Ht1/Ht1 (P = 0.0261).Polymorphisms in the Fc(epsilon)R1beta gene confer susceptibility to atopy in Korean children and may have a disease-modifying effect on airways of asthmatic patients.

Summary The RASSF1 gene, a putative tumor suppressor gene located on human chromosome 3p21, has attracted a great deal of attention because of frequent allelic loss and gene silencing via promoter hypermethylation in a variety of human malignancies. To evaluate the role of RASSF1A gene in lung cancer risk, genotypes of the RASSF1A promoter region (−710 C > T and −392 T > C) were determined in 410 lung cancer patients and 410 normal subjects. Furthermore, to examine potential effects of the common haplotypes (C–C, T–T and C–T haplotypes) on RASSF1A transcription, luciferase reporter assays were performed in H2009 and H358 non-small cell lung cancer (NSCLC) cell lines. We found that ht2 C–T haplotype was associated with susceptibility to the risk of lung cancer in dominant (odds ratio (OR): 0.69; 95% CI: 0.46–0.99) model. In particular, we found that C–T haplotype showed a decreased risk of lung cancer in males (codominant OR: 0.59; 95% CI: 0.38–0.93 and dominant OR: 0.58; 95% CI: 0.35–0.96) and in smokers (codominant OR: 0.58; 95% CI: 0.36–0.93 and dominant OR: 0.56; 95% CI: 0.33–0.96). Interestingly, C–T haplotype induced transcriptional activity by 50–60% compared with other haplotypes in NSCLC cell lines. These results suggest that RASSF1A promoter polymorphisms affect RASSF1A expression, further contributing to the genetic susceptibility to lung cancer.

BACKGROUND. The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS. Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (−24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. RESULTS. Among 8 polymorphisms, 3435TT and 2677TT were associated with AUCSN-38G and CLSN-38G. When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUCSN-38G (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUCSN-38 (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1st cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 −24TT and 3972TT genotypes were associated with higher response rates (P = .031 and .046, respectively) and longer progression-free survival (P = .035 and .038, respectively), which was sustained in haplotype analysis. CONCLUSIONS. Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC. Cancer 2007. © 2007 American Cancer Society.

Summary To investigate whether the OATP1B1 polymorphisms affect irinotecan-pharmacokinetics and subsequent toxicity and tumor response of patients with advanced NSCLC. A total of 81 Korean NSCLC patients enrolled in a phase II study of irinotecan and cisplatin chemotherapy were genotyped for OATP1B1 −11187G>A, 388A>G and 521T>C variants. The 521TC or CC and −11187AA genotypes were associated with higher AUC SN-38 ( p =0.016 and 0.030, respectively). When haplotypes were assigned, patients with *15 haplotype showed significantly higher AUC SN-38 than *1a or *1b haplotypes ( p =0.006). Grade 4 neutropenia was associated with the 521TC or CC genotypes, whereas, grade 3 diarrhea was associated with 388GG genotype ( p =0.046). Of the 81 patients enrolled, 77 were assessable for response and 36 (47%) patients achieved partial responses (PR). However, no statistical significance was observed between genotype and response. These findings suggest that OATP1B1 variants are involved in SN-38 disposition and highly predictive for severe toxicity of NSCLC patients treated with irinotecan-based chemotherapy.