Yeonjung Kim

Large-scale genome-wide association studies in east Asians identify new genetic loci influencing metabolic traits

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.

Stable overexpression of MEN1 suppresses tumorigenicity of RAS.

Although there is indirect genetic evidence that MEN1, the gene for multiple endocrine neoplasia type 1, is a tumor suppressor gene, little is known about the MEN1-encoded protein, menin. Menin was stably overexpressed in a well-characterized murine tumor cell line, (valine-12)-RAS-transformed NIH3T3 cells. Menin overexpression reverted the morphology of the RAS-transformed NIH3T3 cells towards the more flattened and more spread, fibroblastic shape of wild type NIH3T3 cells. The proliferation rate of the RAS-transformed cells in 0.5% calf serum was also slower with menin overexpression. Menin overexpression reduced the RAS-induced clonogenicity in soft agar. Menin also reduced tumor growth after injection of cells in nude mice. In conclusion, stable overexpression of MEN1 suppressed partially the RAS-mediated tumor phenotype in vitro and in vivo. Overexpressed menin protein had biological effects, directly supporting MEN1 gene function as a tumor suppressor.

Cohort Profile: The Korean Genome and Epidemiology Study (KoGES) Consortium

Worldwide globalization and Westernization in social and economic aspects have led to drastic changes in South Korea during the past several decades. These changes include individual health behaviours, which were reflected as increased prevalence of non-communicable chronic diseases (NCDs), such as type 2 diabetes mellitus (T2DM), hypertension, obesity and cardiovascular disease (CVD). These NCDs are known to be caused by both environmental risk factors and predisposing genetic factors. Population decline is another issue in South Korea; the recorded fertility rate was 1.3 births per woman, and 10% of the population were elderly individuals aged 65 years according to the Population and Housing Census results of 2005-2010. We have also been observing an increased influx and efflux of the population due to globalization. In particular, there has been a rising tendency in the marriage-based inflow of South Asian women during the last decade. To attempt to solve public health issues resulting from these population trends and prepare for personalized and preventive health care in the future, the Korean government (National Research Institute of Health (NIH), Centers for Disease Control and Prevention and the Ministry of Health and Welfare, Korea) initiated a large prospective cohort study with government funding, named the Korean genome and epidemiology study (KoGES). The study is a consortium project consisting of six prospective cohort studies that would be categorized into population-based and geneenvironment model studies (Figure 1). The aim of the KoGES was to establish a genome epidemiological study platform for the research community with a health database and biobank, to investigate the genetic and environmental aetiology of common complex diseases in Koreans (i.e. T2DM, hypertension, obesity, metabolic syndrome, osteoporosis, CVD,and cancer) and causes of death with longterm follow-up. The ultimate goal of the KoGES was to develop comprehensive and applicable health care guidelines for common complex diseases in Koreans, reduce the burden of chronic diseases and improve the quality of life.

Germline and somatic mutation of the gene for multiple endocrine neoplasia type 1 (MEN1)

Marx SJ, Agarwal SK, Kester MB, Heppner C, Kim YS, Emmert‐Buck MR, Debelenko LV, Lubensky IA, Zhuang Z, Guru SC, Manickam P, Olufemi SE, Skarulis MC, Doppman JL, Alexander RH, Liotta LA, Collins FS, Chandrasekharappa SC, Spiegel AM, Burns AL (National Institutes of Health, Bethesda, USA). Germline and somatic mutation of the gene for multiple endocrine neoplasia type 1 (MEN1) (Minisymposium: MEN & VHL). J Intern Med 1998; 243: 447–53.

Activation of Saccharomyces cerevisiae HIS3 Results in Gcn4p-Dependent, SWI/SNF-Dependent Mobilization of Nucleosomes over the Entire Gene

ABSTRACT The effects of transcriptional activation on the chromatin structure of the Saccharomyces cerevisiae HIS3 gene were addressed by mapping the precise positions of nucleosomes in uninduced and induced chromatin. In the absence of the Gcn4p activator, the HIS3 gene is organized into a predominant nucleosomal array. In wild-type chromatin, this array is disrupted, and several alternative overlapping nucleosomal arrays are formed. The disruption of the predominant array also requires the SWI/SNF remodeling machine, indicating that the SWI/SNF complex plays an important role in nucleosome mobilization over the entire HIS3 gene. The Isw1 remodeling complex plays a more subtle role in determining nucleosome positions on HIS3, favoring positions different from those preferred by the SWI/SNF complex. Both the SWI/SNF and Isw1 complexes are constitutively present in HIS3 chromatin, although Isw1 tends to be excluded from the HIS3 promoter. Despite the apparent disorder of HIS3 chromatin generated by the formation of multiple nucleosomal arrays, nucleosome density profiles indicate that some long-range order is always present. We propose that Gcn4p stimulates nucleosome mobilization over the entire HIS3 gene by the SWI/SNF complex. We suggest that the net effect of interplay among remodeling machines at HIS3 is to create a highly dynamic chromatin structure.

SWI/SNF-dependent long-range remodeling of yeast HIS3 chromatin.

Current models for the role of the SWI/SNF chromatin remodeling complex in gene regulation are focused on promoters, where the most obvious changes in chromatin structure occur. Here we present evidence that the SWI/SNF complex is involved in the remodeling of the chromatin structure of an entire gene in vivo. We compared the native chromatin structures of a small yeast plasmid containing the HIS3 gene purified from uninduced and induced cells. Relative to uninduced chromatin, induced chromatin displayed a large reduction in negative supercoiling, a large reduction in sedimentation rate, and increased accessibility to restriction enzymes with sites located both near and far from the HIS3 promoter. These observations indicate that the entire plasmid was remodeled as a result of induction. Loss of supercoiling required the presence of the SWI/SNF remodeling complex and the activator Gcn4p in vivo. The TATA boxes were not required, suggesting that remodeling was not the result of transcription. The induction-dependent loss of negative supercoiling was not apparent in cells, indicating that the supercoils were lost preferentially from induced chromatin during purification. Thus, induced HIS3 chromatin has a highly labile structure that is revealed as a result of purification. It is concluded that induction of HIS3 creates a domain of labile chromatin structure that extends far beyond the promoter to include the entire gene. We propose that the SWI/SNF complex is recruited to the HIS3 promoter by Gcn4p and then directs remodeling of a chromatin domain, with important implications for transcription.

Differential proteome profiling using iTRAQ in microalbuminuric and normoalbuminuric type 2 diabetic patients.

Diabetic nephropathy (DN) is a long-term complication of diabetes mellitus that leads to end-stage renal disease. Microalbuminuria is used for the early detection of diabetic renal damage, but such levels do not reflect the state of incipient DN precisely in type 2 diabetic patients because microalbuminuria develops in other diseases, necessitating more accurate biomarkers that detect incipient DN. Isobaric tags for relative and absolute quantification (iTRAQ) were used to identify urinary proteins that were differentially excreted in normoalbuminuric and microalbuminuric patients with type 2 diabetes where 710 and 196 proteins were identified and quantified, respectively. Some candidates were confirmed by 2-DE analysis, or validated by Western blot and multiple reaction monitoring (MRM). Specifically, some differentially expressed proteins were verified by MRM in urine from normoalbuminuric and microalbuminuric patients with type 2 diabetes, wherein alpha-1-antitrypsin, alpha-1-acid glycoprotein 1, and prostate stem cell antigen had excellent AUC values (0.849, 0.873, and 0.825, resp.). Moreover, we performed a multiplex assay using these biomarker candidates, resulting in a merged AUC value of 0.921. Although the differentially expressed proteins in this iTRAQ study require further validation in larger and categorized sample groups, they constitute baseline data on preliminary biomarker candidates that can be used to discover novel biomarkers for incipient DN.

Prospective Study of Optimal Obesity Index Cutoffs for Predicting Development of Multiple Metabolic Risk Factors: The Korean Genome and Epidemiology Study

Background In this prospective cohort study, we estimated the risk of developing more than 1 metabolic risk factor, using different obesity indices. In addition, we investigated the relative usefulness of the obesity indices for predicting development of such risk factors and calculated optimal cutoffs for the obesity indices. Methods The cohort comprised 10 038 representative residents of a small city and a rural county who were recruited in 2001–2002. Follow-up examinations were conducted every 2 years. Among the 3857 participants without metabolic syndrome at baseline, 1102 new cases occurred during the 6-year follow-up. Receiver operating characteristic (ROC) curves for the obesity indices were plotted to compare the usefulness of the obesity indices. Results The numbers of new cases of multiple metabolic risk factors among people in the highest quintiles of body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and waist-height ratio at the baseline examination were 2 to 3 times those in the lowest quintiles. The area under the ROC curve for WHR was significantly higher than that for BMI. The optimal BMI cutoff was 24 kg/m2 in men and women, and the optimal WC cutoffs were 80 cm and 78 cm in men and women, respectively. Conclusions Both overall obesity and central obesity predicted risk of developing multiple metabolic risk factors, and WHR appeared to be a better discriminator than BMI. To prevent development of metabolic diseases among Koreans, it might be useful to lower the cutoff for abdominal obesity, as defined by WC.

A common intronic variant of CXCR3 is functionally associated with gene expression levels and the polymorphic immune cell responses to stimuli

BACKGROUND CXCR3 is a chemokine receptor that plays important roles in mediating chemotactic signals and modulating the activation of lymphocytes. We have previously conducted a case-control study by using a candidate gene approach to investigate the association of CXCR3 polymorphisms with the risk of asthma. Results from the epidemiologic study showed that a common nucleotide variant in the CXCR3 intron (rs2280964G>A) was associated with disease susceptibility (1006 cases and 384 control subjects; odds ratio, 0.81; 95% CI, 0.69-0.94; P = .007). OBJECTIVE The aim of our study was to evaluate the epidemiologic study and provide functional evidence for the association of rs2280964G>A with asthma by investigating the effects of intronic variant on chemokine-mediated phenotypes of human-derived T cells. METHODS We used cell line-based in vitro and human primary T cell-based ex vivo studies to examine the functional consequences of the intronic polymorphism, focusing on the regulation of gene expression, splicing, and immune responsiveness toward activating signals. RESULTS We present functional evidence indicating that the rs2280964A allele significantly correlates with decreased CXCR3 gene expression, which would lead to variation in immune cell responses to chemokine-cytokine signals in vitro and ex vivo that includes a decrease in chemotactic activity. CONCLUSION These findings, in conjunction with those of our previous epidemiologic studies, might implicate a functional link between a common nucleotide variant of a chemokine receptor gene, CXCR3, and a cause for a complex-trait disease, asthma.

Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population

Background Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population. Methods We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively. Results A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of β-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study. Conclusion Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.