Jason Yongha Kim

Identification of copy number variations and common deletion polymorphisms in cattle.

BackgroundRecently, 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.ResultsIn our study of cattle, we used Illumina BovineSNP50 BeadChip (54,001 markers) to obtain each markers 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.ConclusionsIn 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.

Melatonin receptor 1 B polymorphisms associated with the risk of gestational diabetes mellitus

BackgroundsTwo SNPs in melatonin receptor 1B gene, rs10830963 and rs1387153 showed significant associations with fasting plasma glucose levels and the risk of Type 2 Diabetes Mellitus (T2DM) in previous studies. Since T2DM and gestational diabetes mellitus (GDM) share similar characteristics, we suspected that the two genetic polymorphisms in MTNR1B may be associated with GDM, and conducted association studies between the polymorphisms and the disease. Furthermore, we also examined genetic effects of the two polymorphisms with various diabetes-related phenotypes.MethodsA total of 1,918 subjects (928 GDM patients and 990 controls) were used for the study. Two MTNR1B polymorphisms were genotyped using TaqMan assay. The allele distributions of SNPs were evaluated by x2 models calculating odds ratios (ORs), 95% confidence intervals (CIs), and corresponding P values. Multiple regressions were used for association analyses of GDM-related traits. Finally, conditional analyses were also performed.ResultsWe found significant associations between the two genetic variants and GDM, rs10830963, with a corrected P value of 0.0001, and rs1387153, with the corrected P value of 0.0008. In addition, we also found that the two SNPs were associated with various phenotypes such as homeostasis model assessment of beta-cell function and fasting glucose levels. Further conditional analyses results suggested that rs10830963 might be more likely functional in case/control analysis, although not clear in GDM-related phenotype analyses.ConclusionThere have been studies that found associations between genetic variants of other genes and GDM, this is the first study that found significant associations between SNPs of MTNR1B and GDM. The genetic effects of two SNPs identified in this study would be helpful in understanding the insight of GDM and other diabetes-related disorders.

Association of CACNG6 polymorphisms with aspirin-intolerance asthmatics in a Korean population.

BackgroundAspirin-intolerant asthma (AIA) occurs in the lower and upper airways through excessive production of leukotrienes upon administration of non-steroidal anti-inflammatory drugs (NSAIDs). One of the three symptoms of AIA is nasal polyposis, a chronic inflammatory disease that is related to the function of calcium ion in recruitment of immune cells during airway inflammation. It has been implicated that bronchodilation in the airway is related to Ca(2+) regulation. The calcium channel, voltage-dependent, gamma subunit 6 (CACNG6) gene encodes a protein that stabilizes the calcium channel.MethodsTo study the associations between AIA and polymorphisms in CACNG6 gene, eight variants were genotyped in 102 AIA cases and 429 aspirin-tolerant asthma (ATA) controls. Logistic analyses were used to evaluate the associations of CACNG6 polymorphisms with AIA.ResultsStatistical analyses revealed that a single nucleotide polymorphism (SNP; rs192808C > T; P = 0.0004, Pcorr = 0.0029, OR = 2.88 in co-dominant model; P = 0.0005, Pcorr = 0.0036, OR = 2.99 in dominant model) in intron and a haplotype unique to this variant (CACNG6_BL1_ht6; P = 0.003, Pcorr = 0.02, OR = 2.57 in co-dominant model, P = 0.001, Pcorr = 0.0087, OR = 2.81 in dominant model) were significantly associated with the risk of AIA.ConclusionsOur results suggest that the CACNG6 variants might be associated with the risk of AIA in a Korean population.

Association of KCNQ1 Polymorphisms with the Gestational Diabetes Mellitus in Korean Women

CONTEXT Similar genetic factors may play role in the pathogenesis of gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM). However, genetic studies on GDM are relatively scarce as compared with T2DM. OBJECTIVE A recent genome-wide association (GWA) study has proved that three KCNQ1 polymorphisms were significantly associated with the risk of T2DM in various ethnic groups. This study aimed to examine possible genetic effects of these KCNQ1 polymorphisms on the risk of GDM. DESIGN Three KCNQ1 polymorphisms (rs2074196, rs2237892, and rs2237895) were genotyped using TaqMan assay. The genotype distributions between GDM patients and normal controls were analyzed using logistic regression models. In addition, GDM-related phenotypes were analyzed using multiple regression models. SETTING All GDM patients recruited from Cheil General Hospital in Seoul, Korea, between 2003 and 2008. PARTICIPANTS PARTICIPANTS included 930 Korean females with GDM and the data of healthy controls from the previous GWA study. RESULTS KCNQ1 polymorphisms of rs2237892 and rs2237895 were significantly associated with the risk of GDM (P = 0.003 and 0.005, respectively). In the analyses of the GDM-related phenotype, only the risk allele of KCNQ1 rs2237895 was significantly associated with a high-level insulin sensitivity oral glucose tolerance test among patients with GDM (P = 0.0003, 0.004, and 0.05 for codominant, dominant, and recessive models, respectively). CONCLUSION KCNQ1 polymorphisms shown to be associated with increased risk for T2DM in the recent GWA study might also represent genetic factors contributing to the development of GDM in Koreans.

Comprehensive Variant Screening of the UGT Gene Family

Purpose UGT1A1, UGT2B7, and UGT2B15 are well-known pharmacogenes that belong to the uridine diphosphate glucuronyltransferase gene family. For personalized drug treatment, it is important to study differences in the frequency of core markers across various ethnic groups. Accordingly, we screened single nucleotide polymorphisms (SNPs) of these three genes and analyzed differences in their frequency among five ethnic groups, as well as attempted to predict the function of novel SNPs. Materials and Methods We directly sequenced 288 subjects consisting of 96 Korean, 48 Japanese, 48 Han Chinese, 48 African American, and 48 European American subjects. Subsequently, we analyzed genetic variability, linkage disequilibrium (LD) structures and ethnic differences for each gene. We also conducted in silico analysis to predict the function of novel SNPs. Results A total of 87 SNPs were detected, with seven pharmacogenetic core SNPs and 31 novel SNPs. We observed that the frequencies of UGT1A1 *6 (rs4148323), UGT1A1 *60 (rs4124874), UGT1A1 *93 (rs10929302), UGT2B7 *2 (rs7439366), a part of UGT2B7 *3 (rs12233719), and UGT2B15 *2 (rs1902023) were different between Asian and other ethnic groups. Additional in silico analysis results showed that two novel promoter SNPs of UGT1A1 -690G>A and -689A>C were found to potentially change transcription factor binding sites. Moreover, 673G>A (UGT2B7), 2552T>C, and 23269C>T (both SNPs from UGT2B15) changed amino acid properties, which could cause structural deformation. Conclusion Findings from the present study would be valuable for further studies on pharmacogenetic studies of personalized medicine and drug response.

CD58 polymorphisms associated with the risk of neuromyelitis optica in a Korean population

BackgroundNeuromyelitis optica (NMO) is a serious inflammatory demyelinating disease (IDD), characterized by the inflammation and demyelination of optic nerves and spinal cords, which subsequently leads to the loss of function. In a previous genome-wide association study, cluster of differentiation 58 (CD58) region was found to be susceptible for the risk of multiple sclerosis (MS) in Caucasian, and the association between CD58 variants and MS was replicated in Americans. However, no study has been conducted to explore the possible association between CD58 and NMO yet. Thus, this study aimed to investigate the association of CD58 polymorphisms with the risk of NMO in a Korean population.MethodsUsing TaqMan assay, 6 single nucleotide polymorphisms (SNPs) were genotyped in 98 NMO patients and 237 normal controls (N = 336). Logistic regression analysis was conducted to find a possible association between CD58 polymorphisms and NMO.ResultsThe analysis results showed that 6 variations (rs2300747, rs1335532, rs12044852, rs1016140, CD58_ht1, and CD58_ht3) showed significant associations (P = 0.002 ~ 0.008, Pcorr = 0.01 ~ 0.04).ConclusionThe genetic variations in CD58 may be associated with the susceptibility of NMO in a Korean population. Based on previous studies, we suspect that the A allele of rs2300747 may decrease CD58 RNA expression, thus increasing NMO risk. Also, we deduced that the G allele of rs1016140 caused an increase of T cell activity, which in turn eased the access of AQP4 antibody into central nervous system (CNS) and ultimately leading to NMO development.

The genetic effect of copy number variations on the risk of type 2 diabetes in a Korean population.

Background Unlike Caucasian populations, genetic factors contributing to the risk of type 2 diabetes mellitus (T2DM) are not well studied in Asian populations. In light of this, and the fact that copy number variation (CNV) is emerging as a new way to understand human genomic variation, the objective of this study was to identify type 2 diabetes–associated CNV in a Korean cohort. Methodology/Principal Findings Using the Illumina HumanHap300 BeadChip (317,503 markers), genome-wide genotyping was performed to obtain signal and allelic intensities from 275 patients with type 2 diabetes mellitus (T2DM) and 496 nondiabetic subjects (Total n = 771). To increase the sensitivity of CNV identification, we incorporated multiple factors using PennCNV, a program that is based on the hidden Markov model (HMM). To assess the genetic effect of CNV on T2DM, a multivariate logistic regression model controlling for age and gender was used. We identified a total of 7,478 CNVs (average of 9.7 CNVs per individual) and 2,554 CNV regions (CNVRs; 164 common CNVRs for frequency>1%) in this study. Although we failed to demonstrate robust associations between CNVs and the risk of T2DM, our results revealed a putative association between several CNVRs including chr15:45994758–45999227 (P = 8.6E-04, Pcorr = 0.01) and the risk of T2DM. The identified CNVs in this study were validated using overlapping analysis with the Database of Genomic Variants (DGV; 71.7% overlap), and quantitative PCR (qPCR). The identified variations, which encompassed functional genes, were significantly enriched in the cellular part, in the membrane-bound organelle, in the development process, in cell communication, in signal transduction, and in biological regulation. Conclusion/Significance We expect that the methods and findings in this study will contribute in particular to genome studies of Asian populations.

Association analysis of UBE3C polymorphisms in Korean aspirin-intolerant asthmatic patients

BACKGROUND Aspirin-intolerant asthma (AIA), as an asthma phenotype that involves the upper or lower airways, occurs from excessive leukotriene production on administration of nonsteroidal anti-inflammatory drugs. The UBE3C gene on chromosome 7 is a member of the E3 ligase enzymes and is implicated in the ubiquitin-proteasome pathway. This pathway is involved in immune responses to inflammation, including asthma. OBJECTIVE To investigate whether the UBE3C polymorphisms are associated with the risk of AIA. METHODS Twenty-four nonmonomorphic genetic variants of UBE3C were genotyped in 163 patients with AIA and 429 controls with aspirin-tolerant asthma. After genotyping, logistic analyses were performed and haplotypes of each individual were inferred using the PHASE algorithm. RESULTS Logistic analyses revealed that 2 polymorphisms (rs3802122 and rs6979947) in the intron showed significant associations with risk of AIA (P < .001 and P(corr) = .002 in both single nucleotide polymorphisms; odds ratios, 0.61 and 0.60, respectively). In associations with haplotypes, haplotype 2, which contains all the significantly associated single nucleotide polymorphisms and was infrequent in AIA compared with aspirin-tolerant asthma, was associated with aspirin hypersensitivity in asthmatic patients (P = .003 and P(corr) = .03; odds ratio, 0.64; 95% confidence interval, 0.47-0.86). CONCLUSIONS The rs3802122 and rs6979947 polymorphisms were significantly associated with the risk of AIA. However, further studies are required to establish the underlying mechanism by which UBE3C and its polymorphisms affect the risk of AIA.

Positive Association between Aspirin-Intolerant Asthma and Genetic Polymorphisms of FSIP1: a Case-Case Study

BackgroundAspirin-intolerant asthma (AIA), which is caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, causes lung inflammation and reversal bronchi reduction, leading to difficulty in breathing. Aspirin is known to affect various parts inside human body, ranging from lung to spermatogenesis. FSIP1, also known as HDS10, is a recently discovered gene that encodes fibrous sheath interacting protein 1, and is regulated by amyloid beta precursor protein (APP). Recently, it has been reported that a peptide derived from APP is cleaved by α disintegrin and metalloproteinase 33 (ADAM33), which is an asthma susceptibility gene. It has also been known that the FSIP1 gene is expressed in airway epithelium.ObjectivesAim of this study is to find out whether FSIP1 polymorphisms affect the onset of AIA in Korean population, since it is known that AIA is genetically affected by various genes.MethodsWe conducted association study between 66 single nucleotide polymorphisms (SNPs) of the FSIP1 gene and AIA in total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of FSIP1 and AIA were analyzed with sex, smoking status, atopy, and body mass index (BMI) as covariates.ResultsInitially, 18 SNPs and 4 haplotypes showed associations with AIA. However, after correcting the data for multiple testing, only one SNP showed an association with AIA (corrected P-value = 0.03, OR = 1.63, 95% CI = 1.23-2.16), showing increased susceptibility to AIA compared with that of ATA cases. Our findings suggest that FSIP1 gene might be a susceptibility gene for aspirin intolerance in asthmatics.ConclusionAlthough our findings did not suggest that SNPs of FSIP1 had an effect on the reversibility of lung function abnormalities in AIA patients, they did show significant evidence of association between the variants in FSIP1 and AIA occurrence among asthmatics in a Korean population.

Genetic association analysis of ERBB4 polymorphisms with the risk of schizophrenia and SPEM abnormality in a Korean population.

The human receptor tyrosine-protein kinase erbB-4 (ERBB4) gene mediates neuregulin 1 (NRG1) signaling, and is involved in neuronal migration and differentiation. Despite the potential significance of ERBB4 in the development of schizophrenia, relatively few genetic studies for the association of ERBB4 with schizophrenia were performed in the populations including Ashkenazi Jews, Americans including Caucasians and African Americans, and Han Chinese. In this study, differences in ERBB4 variations were investigated to determine association with schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Seven polymorphisms in ERBB4 gene were genotyped in 435 schizophrenia cases and 390 unrelated healthy controls. In order to investigate the relationship between ERBB4 and the risk of schizophrenia and SPEM abnormality, differences in SNP and haplotype distribution were analyzed using logistic and multiple regression analyses. However, we failed to replicate the associations reported by previous studies in other populations. Although statistically not significant, the tendency towards associations between ERBB4 polymorphisms and the risk of schizophrenia and SPEM abnormality in this study from a Korean population would be helpful for further genetic etiology studies in schizophrenia.