KyuBum Kwack

Association of the miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G polymorphisms with gastric cancer risk and survival in the korean population

We investigated whether four common microRNA polymorphisms (miR‐146aC>G [rs2910164], miR‐149T>C [rs2292832], miR‐196a2T>C [rs11614913], and miR‐499A>G [rs3746444]) are associated with the susceptibility and prognosis of gastric cancer in the Korean population. The four microRNA single‐nucleotide polymorphisms (SNPs) were identified in a case–control study (461 patients; 447 controls) by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis in the Korean population. When patients were stratified into diffuse and intestinal‐type gastric cancer groups, subjects with the miR‐499AG and AG + GG genotypes had reduced adjusted odds ratios (AORs) for diffuse‐type gastric cancer (AOR = 0.54 with 95% confidence interval [CI] = 0.31–0.97; AOR = 0.57 with 95% CI = 0.33–0.97). In the stratified analyses for gastric cancer risk, the miR‐146aGG and CG + GG genotypes were associated with increased risk of gastric cancers among the non‐smokers, whereas the miR‐149TC and TC + CC genotypes showed lower risk of gastric cancer in males. The miR‐196a2CC genotype was associated with elevated gastric cancer risk among females. For gastric cancer prognosis, intestinal‐type gastric cancer patients with miR‐146aCG + GG genotypes had significantly higher survival rates (log‐rank P = 0.030) than patients with the CC genotype, and patients with the miR‐499AA genotype had significantly increased survival rates compared to patients with the AG + GG genotypes (log‐rank P = 0.013). When miR‐146aCG + GG and miR‐499AA genotypes were combined, the survival rate of intestinal‐type gastric cancer patients was elevated (log‐rank P < 0.001). No association was found between gastric or diffuse‐type cancer prognosis and other miRNAs. Our data demonstrate that specific miRNA SNPs are associated with gastric cancer susceptibility (miR‐499A>G) and prognosis (miR‐146aC>G and miR‐499A>G) in the Korean population depending on gastric cancer type.

SNP–SNP interactions between DNA repair genes were associated with breast cancer risk in a Korean population

Single nucleotide polymorphisms (SNPs) in nucleotide excision repair (NER) pathway genes may modulate DNA repair capacity and increase susceptibility to breast cancer (BC). A case‐control study was conducted by evaluating genes involved in DNA repair to identify polymorphisms associated with BC.

Integrin alpha V polymorphisms and haplotypes in a Korean population are associated with susceptibility to chronic hepatitis and hepatocellular carcinoma.

Background/Aims: Integrins are cell surface receptors for extracellular matrix (ECM) proteins that initiate signalling pathways that modulate proliferation, survival, invasion or metastasis. Consequently, integrins are potential targets for the treatment of cancer. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in integrin αV (ITGAV) in a Korean population were associated with chronic hepatitis B virus (HBV) infection and HBV‐infected hepatocellular carcinoma (HCC).

Impact of genetic polymorphisms in base excision repair genes on the risk of breast cancer in a Korean population.

The contribution of single nucleotide polymorphisms (SNPs) in base excision repair (BER) genes to the risk of breast cancer (BC) was evaluated by focusing on two key genes: apurinic/apyrimidinic endonuclease 1 (APEX1) and 8-oxoguanine DNA glycosylase (OGG1). Genetic variations in the genes encoding these DNA repair enzymes may alter their functions and increase susceptibility to carcinogenesis. The aim of this study was to analyze polymorphisms in two BER genes, exploring their associations and particularly the combined effects of these variants on BC risk in a Korean population. Three SNPs of two BER genes were genotyped using the Illumina GoldenGate™ method. In total, 346 BC patients and 361 cancer-free controls were genotyped for these BER gene polymorphisms and analyzed for their correlation with BC risk in multiple logistic regression models. Multiple logistic regression models adjusted for age, family history of BC, and body mass index were used. The APEX1 Asp148Glu polymorphism was weakly associated with BC risk. The combined analysis among the BER genes, however, showed significant effects on BC risk. The APEX1 Asp148Glu carrier, in combination with OGG1 rs2072668 and OGG1 Ser326Cys, was strongly associated with an increased risk of BC. Moreover, the combination of the C-C haplotype of OGG1 with the APEX1 Asp148Glu genotype was also associated with an additive risk effect of BC [ORs=2.44, 2.87, and 3.50, respectively]. The combined effect of APEX1 Asp148Glu was found to be associated with an increased risk of BC. These results suggest that the combined effect of different SNPs within BER genes may be useful in predicting BC risk.

GENOME-WIDE ASSOCIATION STUDIES AND EPISTASIS ANALYSES OF CANDIDATE GENES RELATED TO AGE AT MENARCHE AND AGE AT NATURAL MENOPAUSE IN A KOREAN POPULATION

ObjectiveThe aim of this study was to identify polymorphisms and gene-gene interactions that are significantly associated with age at menarche and age at menopause in a Korean population. MethodsA total of 3,452 and 1,827 women participated in studies of age at menarche and age at natural menopause, respectively. Linear regression analyses adjusted for residence area were used to perform genome-wide association studies (GWAS), candidate gene association studies, and interactions between the candidate genes for age at menarche and age at natural menopause. ResultsIn GWAS, four single nucleotide polymorphisms (SNPs; rs7528241, rs1324329, rs11597068, and rs6495785) were strongly associated with age at natural menopause (lowest P = 9.66 × 10−8). However, GWAS of age at menarche did not reveal any strong associations. In candidate gene association studies, SNPs with P < 0.01 were selected to test their synergistic interactions. For age at natural menopause, there was a significant interaction between intronic SNPs on ADAM metallopeptidase with thrombospondin type I motif 9 (ADAMTS9) and SMAD family member 3 (SMAD3) genes (P = 9.52 × 10−5). For age at menarche, there were three significant interactions between three intronic SNPs on follicle-stimulating hormone receptor (FSHR) gene and one SNP located at the 3′ flanking region of insulin-like growth factor 2 receptor (IGF2R) gene (lowest P = 1.95 × 10−5). ConclusionsNovel SNPs and synergistic interactions between candidate genes are significantly associated with age at menarche and age at natural menopause in a Korean population.

LAMC1 gene is associated with premature ovarian failure

OBJECTIVES Common variations with modest effect in complex and polygenic disease such as premature ovarian failure (POF) can be detected by a genome wide association study. We performed a genome wide association study to identify predisposing genes associated with an increased risk of POF. STUDY DESIGN In stage I, genome wide association study was performed using 24 POF patients and 24 matched controls. A strongly associated region was re-tested to confirm the association with POF in stage II using 98 patients and 218 matched controls. RESULTS In the stage I, we found a strongly associated region that was located on chromosome 1q31 and encoded the laminin gamma 1 (LAMC1) gene. All 22 single nucleotide polymorphisms (SNPs) in the LAMC1 formed a linkage disequilibrium block and two haplotypes were significantly associated with POF. In the stage II, 14 SNPs, the majority of which were SNPs located in coding region and tagging SNPs, were genotyped. Distributions of 9 SNPs of them including one nonsynonymous SNP (rs20558) and one haplotype (HT1, C-C-T-G-C-C-A-T-T-C) were significantly higher in POF patients than in control group (86.6% and 74.5%, respectively, OR=2.209, CI: 1.139-4.284, P=0.017). CONCLUSIONS We showed for the first time that LAMC1 is significantly associated with POF, and specifically, possession of at least one HT1 was associated with susceptibility to POF. This result means that HT1 may co-exist with causative variant for susceptibility to POF in linkage disequilibrium and that the LAMC1 may be involved in POF pathogenesis.

The molecular signature of in vitro senescence in human mesenchymal stem cells

We investigated the molecular characteristics of in vitro senescence in human bone marrow-derived mesenchymal stem cells. After prolonged in vitro expansion, MSCs underwent cellular senescence characterized by growth arrest and distinctive morphological alterations, such as an enlarged and flattened morphology, and SA β-gal activity. Slight reduction in telomere length was observed during 16 population doublings, however, telomere length was maintained much longer length than 4.5 kb, the critical size of the telomere. The expression of p16INK4a was increased during in vitro culture of MSCs and other cell cycle inhibitory proteins, such as p53, p21 and p14 were not increased in Western blot analysis. In whole-transcriptome oligonucleotide microarray analysis between highly proliferative MSCs at early passage and senescent MSCs at late passage, we identified 583 differentially expressed genes by more than two-fold change and paired T-test (P-value <0.05). Gene ontology analysis revealed that genes involved in vacuole, cell death and chromatin assembly were up-regulated in senescent MSCs, and genes involved in cell cycle, DNA repair, cytoskeletal part and DNA metabolism were down-regulated. This study will be valuable in understanding the in vitro senescence of mesenchymal stem cells.

Genome-Wide Profiling of Antigen-Induced Time Course Expression Using Murine Models for Acute and Chronic Asthma

Background: Asthma is a complex-trait disease caused by complicated interactions among multiple genetic and environmental risk factors. The clinical symptoms of asthma, such as periodic airway obstruction, hyperresponsiveness and mucus hypersecretion, are mediated by acute and chronic bronchial inflammation. Methods: To better understand the mechanisms by which allergen-induced acute inflammation leads to chronic asthma accompanied by irreversible airway remodeling, we analyzed time course transcriptional responses in the lungs of model mice that were exposed to aerosolized ovalbumin for up to 9 weeks after an initial sensitization. Results: We observed increased levels of total plasma IgE and histological changes in lung tissues from the ovalbumin-treated mice, which is consistent with the typical inflammatory phenotypes of asthma pathogenesis. Our oligonucleotide microarray analyses revealed a total of 776 differentially expressed genes induced by antigenic challenge (≧1.5-fold change, p < 0.05). Of these genes, most of the immune-responsive genes were transiently up-regulated in the early phase of the allergen treatment (within a week) with a concomitant up-regulation of genes involved in mucus production. These genes were not differentially regulated in the mice challenged for a longer period of time (up to 6 weeks). We also identified some of the genes implicated in extracellular matrix remodeling, for which the time course expression did not necessarily coincide with the expression patterns of immune-responsive genes. Conclusion: Our data suggest that there is a complex interregulatory genetic network associated with the structural changes that accompany the progression of the allergic inflammatory reaction in chronic asthma.

The effects of the catechol-O-methyltransferase val158met polymorphism on white matter connectivity in patients with panic disorder

BACKGROUND The catechol-O-methyltransferase (COMT) gene val158met polymorphism (rs4680) has been found to be associated with various psychiatric phenotypes including panic disorder. Considering the probable genetic influence of COMT on the pathogenesis of panic disorder and white matter connectivity, the present study investigated white matter connectivity using diffusion tensor imaging in relation to the COMT genotype in panic disorder. METHODS Twenty-six patients with panic disorder and twenty-six age- and gender-matched healthy controls participated in this study. Brain magnetic resonance scans and genotype analysis for COMT rs4680 were conducted. Panic Disorder Severity Scale, Albany Panic and Phobia Questionnaire, and Anxiety Sensitivity Inventory-Revised were assessed. Tract-based spatial statistics (TBSS) were used for image analysis. RESULTS There was no significant difference in white matter analysis between panic disorder and healthy controls. However, TBSS analysis showed increased fractional anisotropy (FA) in posterior thalamic radiation, posterior and superior corona radiata, superior longitudinal fasciculus, and sagittal stratum, all located in the right hemisphere in COMT AA/AG genotype group compared to GG genotype in panic disorder. Voxelwise correlational analysis revealed the symptom severity scores are correlated with the FA in white matter tracts that previously showed significant group differences between AA/AG and GG genotypes in COMT AA/AG genotype group, while no significant correlation was found in GG genotype group. LIMITATIONS The sample size in each group was small, hence, further studies with larger numbers of patients are needed to confirm our findings. CONCLUSIONS These data suggested that COMT rs4680 could affect the white matter connectivity in panic disorder.

Epistasis between IGF2R and ADAMTS19 polymorphisms associates with premature ovarian failure

STUDY QUESTION Do single nucleotide polymorphisms (SNPs) or synergistic interactions between SNPs and diplotypes within the insulin-like growth factor 2 receptor (IGF2R) and ADAM metallopeptidase with thrombospondin type 1 motif, 19 (ADAMTS19), contribute to premature ovarian failure (POF)? SUMMARY ANSWER Synergistic interactions were detected between SNPs, including a non-synonymous SNP, and diplotypes within IGF2R and ADAMTS19 which may contribute to POF; however, there was no correlation with POF in a single SNP model after Bonferroni correction. WHAT IS KNOWN ALREADY IGF2R regulates free IGF2 level, which is involved in steroidogenesis in bovine granulosa cells. ADAMTS19 expression is higher in the murine embryonic ovary than in the embryonic testis during sexual differentiation, and an ADAMTS19 SNP (rs246246) showed a possible association with POF in a genome-wide association study in Caucasian women. STUDY DESIGN, SIZE, DURATION This study analyzed interactions between SNPs and diplotypes within IGF2R and ADAMTS19 as well as SNPs within the two genes. In Stage I, a total of 120 patients with POF and 152 female controls were recruited. All patients were diagnosed with POF at the CHA hospital in Seoul, Korea, and were recruited between 1994 and 2004. The 152 controls were recruited from Chungju, Korea, as part of another study that was conducted from April 2002 to March 2004. For Stage II, we obtained genotype data for an additional 1641 female controls, recruited in Ansung and Ansan from 2001 to 2008, from the Korean Genome Epidemiology Study (KoGES). PARTICIPANTS/MATERIALS, SETTING, METHODS In Stage I, the GoldenGate assay with VeraCode technology was used to genotype SNPs in IGF2R and ADAMTS19. In Stage II, we obtained genotype data for IGF2R and ADAMTS19 using Affymetrix Genome-Wide Human SNP array 5.0 and imputed data by the IMPUTE program from the KoGES. To identify POF-associated SNPs, logistic regression analysis in an additive model was performed using the PLINK tool. Synergistic interactions between SNPs and diplotypes within IGF2R and ADAMTS19 were analyzed by logistic regression analysis in three alternative models. MAIN RESULTS AND THE ROLE OF CHANCE In Stage I, 13 combinations of SNPs showed significant synergistic interactions after Bonferroni correction [the strongest association had odds ratio (OR) = 5.77, 95% confidence interval (CI): 2.26-14.75, P = 0.00025]. In Stage II and combined analyses, two and four combinations, respectively, of the significant results in Stage I showed significant synergistic interactions after Bonferroni correction. For interactions between diplotypes in block 2 of IGF2R and block 3 of ADAMTS19 in Stage I, we found 17 synergistic interactions with P < 0.0001, but there was no significant interaction after Bonferroni correction. In Stage II and combined analyses, we found that three and seven combinations in the same blocks, respectively, showed significant synergistic interactions after Bonferroni correction (strongest association: OR = 4.12, 95% CI: 2.22-7.62, P = 6.74E-06). LIMITATIONS, REASONS FOR CAUTION The sample size for patients with POF in this study was small but, compared with recent reports describing associations between SNPs and POF and considering the low prevalence of POF (1%), the sample size is considered to be reasonable. These results should be confirmed in large-scale studies involving different ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS Our results may ultimately provide predictive markers for women at a high risk of POF. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2009-0093821, 2011-0010637). There are no competing interests.