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The cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of the cytarabine (AraC) into a 1-β-D-arabinofuranosyluracil (AraU), an inactive metabolite that plays a crucial role in lowering the amount of AraC, a key chemotherapeutic drug, in the treatment of patients with acute myeloid leukemia (AML). In this study, we hypothesized that CDA polymorphisms were associated with the AraC metabolism for AML treatment and/or related clinical phenotypes. We analyzed 16 polymorphisms of CDA among 50 normal karyotype AML (NK-AML) patients, 45 abnormal karyotype AML (AK-AML) patients and 241 normal controls (NC). Several polymorphisms and haplotypes, rs532545, rs2072671, rs471760, rs4655226, rs818194 and CDA-ht3, were found to have a strong correlation with NK-AML compared with NC and these polymorphisms also revealed strong linkage disequilibrium with each other. Among them, rs2072671 (79A>C), which is located in a coding region and the resultant amino acid change K27Q, showed significant associations with NK-AML compared with NC (P=0.009 and odds ratio=2.44 in the dominant model). The AC and CC genotypes of rs2072671 (79A>C) were significantly correlated with shorter overall survival rates (P=0.03, hazard ratio=1.84) and first complete remission duration (P=0.007, hazard ratio=3.24) compared with the AA genotype in the NK-AML patients. Our results indicate that rs2072671 in CDA may be an important prognostic marker in NK-AML patients.

Among central nervous system (CNS) tumors, gliomas are the most prevalent type of tumor. Single nucleotide polymorphisms (SNPs) in telomerase reverse transcriptase ( TERT ) gene have been identified as risk loci for gliomas by previous genome-wide association studies (GWAS). We examined association between TERT variants and glioma risk in a Korean population. For a case-control study, a total of 32 TERT SNPs from 317 patients with glioma and 480 population-based controls were genotyped. Logistic regression was used for statistical analysis of the link between TERT SNPs and risk of glioma. In this study, eight TERT variants, including four glioma-associated variants reported in previous studies, showed significant association with the risk of glioma. Conditional and stepwise analyses were conducted to validate independent associations in the group of the eight variants. Both analyses identified an intronic variant ( rs56345976 ) as the causal variant among the eight variants. Glioma subgroup analyses indicate that rs56345976 variant is associated with the risk of WHO grade 4, glioblastoma, isocitrate dehydrogenase (IDH) wild-type, and 1p/19q non-codeletion glioma. This study presents a profound comprehension of the relationship between TERT variants and the risk of glioma. Further studies of this variant are required to investigate its effect on glioma susceptibility.

Gliomas are the most common primary tumors in the brain and spinal cord. In previous GWASs, SNPs in epidermal growth factor receptor ( EGFR ) have been reported as risk loci for gliomas. However, EGFR variants associated with gliomas in the Korean population remain unstudied. This study explored the association of EGFR SNPs with the risk of glioma. We genotyped 13 EGFR exon SNPs in a case–control study that included 324 Korean patients diagnosed with glioma and 480 population-based controls. Statistical analyses of the association between EGFR SNPs and glioma risk were conducted using logistic regression. Both stepwise analysis and conditional logistic analysis were performed to identify independent associations among genotyped variants. We confirmed that two SNPs ( rs2227983, rs1050171 ) were significantly associated with glioma ( rs2227983 : odds ratio = 1.42, P corr  = 0.009; rs1050171 : odds ratio = 1.68, P corr  = 0.005). Additionally, the stepwise analysis and conditional logistic analysis indicated that both SNPs created variants with independent genetic effects. This study is the first to show evidence that functional variants of EGFR , namely, rs2227983 (K521R) and rs1050171 (Q787Q), are associated with an increased risk of glioma in the Korean population. Future work should confirm the functional association between EGFR variants and glioma.

Background Recently, the discovery of copy number variation (CNV) led researchers to think that there are more variations of genomic DNA than initially believed. Moreover, a certain CNV region has been found to be associated with the onset of diseases. Therefore, CNV is now known as an important genomic variation in biological mechanisms. However, most CNV studies have only involved the human genome. The study of CNV involving other animals, including cattle, is severely lacking. Results In our study of cattle, we used Illumina BovineSNP50 BeadChip (54,001 markers) to obtain each marker's signal intensity (Log R ratio) and allelic intensity (B allele frequency), which led to our discovery of 855 bovine CNVs from 265 cows. For these animals, the average number of CNVs was 3.2, average size was 149.8 kb, and median size was 171.5 kb. Taking into consideration some overlapping regions among the identified bovine CNVs, 368 unique CNV regions were detected. Among them, there were 76 common CNVRs with > 1% CNV frequency. Together, these CNVRs contained 538 genes. Heritability errors of 156 bovine pedigrees and comparative pairwise analyses were analyzed to detect 448 common deletion polymorphisms. Identified variations in this study were successfully validated using visual examination of the genoplot image, Mendelian inconsistency, another CNV identification program, and quantitative PCR. Conclusions In this study, we describe a map of bovine CNVs and provide important resources for future bovine genome research. This result will contribute to animal breeding and protection from diseases with the aid of genomic information.

Previous studies have identified multiple loci for inherited susceptibility to glioma development, including the regulator of telomere elongation helicase 1 (RTEL1). However, the association between RTEL1 variants and risk of glioma has not been well understood. Therefore, we sought to comprehensively examine the genetic interaction between RTEL1 variants and risk of glioma with respect to defined histological and molecular subtypes. We employed a case-control study involving 250 adult glioma patients with previous molecular alterations and 375 population-based controls within Korean populations. Statistical analyses on the association between RTEL1 single nucleotide polymorphisms (SNPs) and glioma risk were conducted using unconditional logistic regression. Additional conditional and stepwise analyses were performed on significant RTEL1 SNPs. We detected significant associations (Bonferroni P < .05) between six SNPs (rs6089953, rs3848669, rs6010620, rs3787089, rs6062302, and rs115303435) and risk of glioma in the Korean subjects. The two coding variants, rs6062302 (D664D) and rs115303435 (A1059T), were plausibly causal variants and were independent among the significantly associated RTEL1 variants. The glioma subgroup analyses showed that the causal variants (rs6062302 and rs115303435) may be associated with increased risk of glioma regardless of histological grades and molecular alterations. This study provides a deeper understanding of relationships between RTEL1 variants and risk of glioma. Further studies are required to ascertain the impact of those variants on glioma susceptibility.

A growing list of membrane-spanning proteins involved in the transport of a large variety of drugs has been recognized and characterized to include peptide and organic anion/cation transporters. Given such an important role of transporter genes in drug disposition process, the role of single-nucleotide polymorphisms (SNPs) in such transporters as potential determinants of interindividual variability in drug disposition and pharmacological response has been investigated. To define the distribution of transporter gene SNPs across ethnic groups, we screened 450 DNAs in cohorts of 250 Korean, 50 Han Chinese, 50 Japanese, 50 African-American and 50 European-American ancestries for 64 SNPs in four transporter genes encoding proteins of the solute carrier family ( SLC15A2 , SLC22A1 , SLC22A2 and SLC22A6 ). Of the 64 SNPs, 19 were core pharmacogenetic variants and 45 were HapMap tagging SNPs. Polymorphisms were genotyped using the golden gate genotyping assay. After genetic variability, haplotype structures and ethnic diversity were analyzed, we observed that the distributions of SNPs in a Korean population were similar to other Asian groups (Chinese and Japanese), and significantly different from African-American and European-American cohorts. Findings from this study would be valuable for further researches, including pharmacogenetic studies for drug responses.

Subarachnoid aneurysmal hemorrhage (SAH) due to cerebral aneurysm rupture is a very serious disease resulting in high mortality rate. It has been known that genetic factors are involved in the risk of SAH. A recent breakthrough in genomic variation called copy number variation (CNV) has been revealed to be involved in risks of human diseases. In this study, we hypothesized that CNVs can predict the risk of SAH. We used the Illumina HumanHap300 BeadChip (317 503 markers) to genotype 497 individuals in a Japanese population. Furthermore, individual CNVs were identified using signal and allelic intensities. The genetic effect of CNV on the risk of SAH was evaluated using multivariate logistic regression controlling for age and gender in 187 common CNV regions (frequency >1%). From a total of 4574 individual CNVs identified in this study (9.7 CNVs per individual), we were able to discover 1644 unique CNV regions containing 1232 genes. The identified variations were validated using visual examination of the genoplot image, overlapping analysis with the Database of Genomic Variants (73.2%), CNVpartition (72.4%) and quantitative PCR. Interestingly, two CNV regions, chr4:153210505–153212191 (deletion, 4q31.3, P =0.0005, P corr (corrected P -value)=0.04) and chr10:6265006–6267388 (duplication, 10p15.1, P =0.0006, P corr =0.05), were significantly associated with the risk of SAH after multiple testing corrections. Our results suggest that the newly identified CNV regions may contribute to SAH disease susceptibility.

Background Hepatitis B is known to cause several forms of liver diseases including chronic hepatitis B (CHB), and hepatocellular carcinoma. Previous genome-wide association study of CHB risk has demonstrated that rs12614 of complement factor B ( CFB) was significantly associated with CHB risk. In this study, fine-mapping study of previously reported GWAS single nucleotide polymorphism (SNP; CFB rs12614 ) was performed to validate genetic effect of rs12614 on CHB susceptibility and identify possible additional causal variants around rs12614 in a Korean population. This association study was conducted in order to identify genetic effects of CFB single nucleotide polymorphisms (SNPs) and to identify additional independent CHB susceptible causal markers within a Korean population. Methods A total of 10 CFB genetic polymorphisms were selected and genotyped in 1716 study subjects comprised of 955 CHB patients and 761 population controls. Results A non-synonymous variant, rs12614 (Arg32Trp) in exon2 of CFB, had significant associations with risk of CHB (odds ratio = 0.43, P  = 5.91 × 10 − 10 ). Additional linkage disequilibrium and conditional analysis confirmed that rs12614 had independent genetic effect on CHB susceptibility with previously identified CHB markers. The genetic risk scores (GRSs) were calculated and the CHB patients had higher GRSs than the population controls. Moreover, OR was found to increase significantly with cumulative GRS. Conclusions rs12614 showed significant genetic effect on CHB risk within the Korean population. As such rs12614 may be used as a possible causal genetic variant for CHB susceptibility.

Aspirin-exacerbated respiratory disease (AERD) is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC) for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA), and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (210-1) were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p = 3.40×10-8) in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954) showed the best AUC of 0.75 (asymptotic p-value of 7.94×10-21), with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be \"probably damaging\" to the structure and function of the protein, with a high score of '1'. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.

Interleukin-6 (IL6) has many roles essential to the regulation of the immune response, hematopoiesis, and bone resorption. Three single-nucleotide polymorphisms (SNP) in the IL6 promoter region were genotyped by the single-base extension method. The frequencies of each SNP were 0.002 ( IL6−597 G → A ), 0.27 ( IL6−572 G → C ), and 0.002 ( IL6−174 G → C ) in a Korean population ( n =1,082). IL6−597 G → A and IL6−174 G → C were totally linked together ( d 2 =1) and showed very low allele frequencies (0.002), which are common in Caucasians. On the other hand, the frequency of the IL6−572 G → C*C allele was much higher (0.27) than that in Caucasian populations (<0.07). One of the IL6 promoter SNPs, viz., IL6−572 G → C , showed significant associations with bone mineral density (BMD), i.e., the C allele was associated with increased BMD ( P =0.02, co-dominant model; P =0.007, dominant model). The mean BMD was highest in homozygous C individuals (0.67±0.15), lowest in homozygous G individuals (0.58±0.19), and intermediate in heterozygotes (0.64±0.21). In the present study, we describe a variant in the IL6 promoter region that shows positive association with higher BMD in a gene-dose-dependent manner in pre-menopausal women.