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Type 2 diabetes (T2D) is caused by genetic and environmental factors as well as gene-environment interactions. However, these interactions have not been systematically investigated. We analyzed these interactions for T2D and fasting glucose levels in three Korean cohorts, HEXA, KARE, and CAVAS, using the baseline data with a multiple regression model. Two polygenic risk scores for T2D (PRS

Introduction: Although many studies have investigated the association between smoking and obesity, very few have analyzed how obesity traits are affected by interactions between genetic factors and smoking. Here, we aimed to identify the loci that affect obesity traits via smoking status-related interactions in European samples. Methods: We performed stratified analysis based on the smoking status using both the UK Biobank (UKB) data (N = 334,808) and the Genetic Investigation of ANthropometric Traits (GIANT) data (N = 210,323) to identify gene-smoking interaction for obesity traits. We divided the UKB subjects into two groups, current smokers and nonsmokers, based on the smoking status, and performed genome-wide association study (GWAS) for body mass index (BMI), waist circumference adjusted for BMI (WCadjBMI), and waist-hip ratio adjusted for BMI (WHRadjBMI) in each group. And then we carried out the meta-analysis using both GWAS summary statistics of UKB and GIANT for BMI, WCadjBMI, and WHRadjBMI and computed the stratified p values (pstratified) based on the differences between meta-analyzed estimated beta coefficients with standard errors in each group. Results: We identified four genome-wide significant loci in interactions with the smoking status (pstratified < 5 × 10−8): rs336396 (INPP4B) and rs12899135 (near CHRNB4) for BMI, and rs998584 (near VEGFA) and rs6916318 (near RSPO3) for WHRadjBMI. Moreover, we annotated the biological functions of the SNPs using expression quantitative trait loci (eQTL) and GWAS databases, along with publications, which revealed possible mechanisms underlying the association between the smoking status-related genetic variants and obesity. Conclusions: Our findings suggest that obesity traits can be modified by the smoking status via interactions with genetic variants through various biological pathways.

Multiple environmental factors could interact with a single genetic factor to affect disease phenotypes. We used Struct-LMM to identify genetic variants that interacted with environmental factors related to body mass index (BMI) using data from the Korea Association Resource. The following factors were investigated: alcohol consumption, education, physical activity metabolic equivalent of task (PAMET), income, total calorie intake, protein intake, carbohydrate intake, and smoking status. Initial analysis identified 7 potential single nucleotide polymorphisms (SNPs) that interacted with the environmental factors (P value −6). Of the 8 environmental factors, PAMET score was excluded for further analysis since it had an average Bayes Factor (BF) value P value −6). Of these, rs2391331 had the most significant interaction (P value = 7.27 × 10−9) and was located within the intron of EFNB2 (Chr 13). In addition, the gene-based genome-wide association study verified EFNB2 gene significantly interacting with 7 environmental factors (P value = 5.03 × 10−10). BF analysis indicated that most environmental factors, except carbohydrate intake, contributed to the interaction of rs2391331 on BMI. Although the replication of the results in other cohorts is warranted, these findings proved the usefulness of Struct-LMM to identify the gene–environment interaction affecting disease.

Purpose Clinical rotations of medical students across the world have inevitably been affected due to the coronavirus disease 2019 (COVID-19) pandemic. The aims of this study were to explore medical students' perception on the school's response and management of clinical rotation during the COVID-19 pandemic and on how it had affected the quality of their education. Methods An online questionnaire was distributed to third year medical students at one institution whose clinical rotations re-started during the pandemic. The questions asked about the students' satisfaction with the school's policy and feelings of safety, and the impact of COVID-19 on clinical learning. Results The students' perception on the school's response to the pandemic was mixed. Re-commencement of the clinical rotations and procurement of personal protective equipment was positive but a third of students still felt unsafe. The decreased number of hospital patients did not seem to have impacted their overall clinical education with praise on the role of the supervising physicians. Seventy-six-point seven percent of students conferred the positive educational opportunities on medical professionalism presented to them only as the clinical rotation during the ongoing pandemic. Conclusion Our observations on the re-commencement of clerkship during this pandemic may help equip medical institutions on future public health crisis.

Hypertension is a common disease worldwide. Alcohol consumption is one of the risk factors for hypertension, however, it is unclear how alcohol consumption elevates blood pressure. Blood pressure could be affected by interactions between genetic variations and alcohol consumption. Thus, we performed a genome-wide interaction study (GWIS) to assess the effect of gene-alcohol consumption interaction on blood pressure among adults aged ≥40 years from the Ansan and Ansung cohort study (n = 6,176), a part of the Korean Genome Epidemiology Study (KoGES). As a result, rs1297184, single-nucleotide polymorphism (SNP) in locus LGR5 was significant (PGWIS = 8.78 × 10-9 ) in GWIS analysis on diastolic blood pressure, but not on systolic blood pressure. However, there was a heteroscedasticity of alcohol consumption. In the GWIS analysis, applying the inverse-variance weighting to correct the systematic inflation slightly attenuated the strength of interaction (PGWIS_IVW = 7.14 × 10-8 ). This interaction was replicated in the Health Examinees cohort (p = .026), a large-scale community-based cohort (n = 18,708). In conclusion, we identified a possible novel interaction between an SNP (rs1297184) and alcohol consumption on blood pressure.

Hypertension or hypotension prevails as a comorbidity in patients with heart failure (HF). Although blood pressure (BP) is an important factor in managing the mortality of HF, the molecular mechanisms of changes in BP have not been clearly understood in cases of HF. We and others have demonstrated that a loss in PRDM16 causes hypertrophic cardiomyopathy, leading to HF. We aimed to determine whether BP is altered in mice that experience cardiac loss of Prdm16 and identify the underlying mechanism of BP-associated changes. BP decreased significantly only in female mice with a cardiac-null mutation of Prdm16 compared with controls, by an invasive protocol under anesthesia and by telemetric method during conscious, unrestrained status. Mice with a cardiac loss of Prdm16 had higher heart-to-body weight ratios and upregulated atrial natriuretic peptide, suggesting cardiac hypertrophy. Plasma aldosterone-to-renin activity ratios and plasma sodium levels decreased in Prdm16-deficient mice versus control. By RNA-seq and in subsequent functional analyses, Prdm16-null hearts were enriched in factors that regulate BP, including Adra1a, Nos1, Nppa, and Nppb. The inhibition of nitric oxide synthase 1 (NOS1) reverted the decrease in BP in cardiac-specific Prdm16 knockout mice. Mice with cardiac deficiency of Prdm16 present with hypotension and cardiac hypertrophy. Further, our findings suggest that the increased expression of NOS1 causes hypotension in mice with a cardiac-null mutation of Prdm16. These results provide novel insights into the molecular mechanisms of hypotension in subjects with HF and contribute to our understanding of how hypotension develops in patients with HF.

Asthma is a complex disease that is reportedly associated with insomnia. However, the causal directionality of this association is still unclear. We used asthma and insomnia-associated single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) summary statistics to test the causal directionality between insomnia and asthma via Mendelian randomization (MR) analysis. We also performed a cross-trait meta-analysis using UK Biobank GWAS summary statistics and a gene–environment interaction study using data from UK Biobank. The interaction of genetic risk score for asthma (GRSasthma) with insomnia on asthma was tested by logistic regression. Insomnia was a risk factor for the incidence of asthma, as revealed by three different methods of MR analysis. However, asthma did not act as a risk factor for insomnia. The cross-trait meta-analysis identified 28 genetic loci shared between asthma and insomnia. In the gene–environment interaction study, GRSasthma interacted with insomnia to significantly affect the risk of asthma. The results of this study highlight the importance of insomnia as a risk factor of asthma, and warrant further analysis of the mechanism through which insomnia affects the risk of asthma.

Work-family conflict (WFC), an inter-role conflict between work and family, negatively affects mental health. Using a nationally representative systematic sample, this study aimed to investigate the association between WFC, depressive symptoms, and potential moderators in the association of adult female workers. Data of 4714 female workers (aged ≥19 years) were obtained cross-sectionally from the 2018 nationwide Korean Longitudinal Survey of Women and Families (KLoWF). WFC was assessed using a 7-item questionnaire, based on which scores were classified into high (75th percentile score) and low (≤75th percentile score) levels of WFC. Significant depressive symptoms were defined as a score of ≥10 on the 10-item version of the Center for Epidemiologic Studies for Depression Scale. Female workers with high WFC levels were more likely to have depressive symptoms than those with low WFC levels (odds ratio = 2.29, 95% confidence interval = 1.91-2.74). In stratified analyses, high WFC levels were associated with the highest odds of depressive symptoms in the following groups: young adults (19-39 years), those with a college degree or above or with high income, never-married individuals, those with a family size of three or a single child, nonstandard workers, and pink-collar workers. This study replicated and extended previous findings on the association between WFC and depressive symptoms. The association was moderated by age, education and income levels, marital status, family size, number of children, and job conditions.

Background/Aim Although alcohol consumption is known to affect the incidence of diabetes mellitus (DM), reports on the effects of moderate alcohol consumption on DM incidence have been inconsistent. This community-based prospective cohort study was performed to investigate the incidence of DM in male Korean moderate alcohol drinkers. Methods The Ansan and Ansung cohort was used for the analysis. The study population included a total of 3,492 men with no history of DM. The subjects were classified as mild (1–14 g/d), moderate (15–29 g/d), and heavy (≥30 g/d) drinkers based on their amount of alcohol consumption. The incidence rates of DM in the three groups were compared and analyzed over a 10 year follow-up period. Results The hazard ratios (HRs) for DM incidence were 25.12 (95% confidence interval [CI], 21.73–28.90) per 1,000 person years (PY) in mild drinkers, 31.13 (26.11–36.83) per 1,000 PY in moderate drinkers, and 31.68 (26.81–37.18) per 1,000 PY in heavy drinkers (p for trend, p = 0.043). Multivariate regression analysis showed that the HRs (95% CI) for DM were 1.25 (0.97–1.61, p = 0.086) in moderate drinkers and 1.30 (1.01–1.68, p = 0.045) in heavy drinkers compared to mild drinkers. The changes in pancreatic insulin secretion were more remarkable than those in insulin resistance in all three groups. Conclusions The incidence of DM in male Korean moderate drinkers did not increase significantly over the observation period. However, the incidence of DM tended to increase with increasing alcohol consumption. Pancreatic insulin secretion may play a more important role than insulin resistance in the relationship between alcohol and incidence of DM.

Hypertension is a complex disorder caused by genetic and environmental risk factors. Recently, genome-wide association studies (GWASs) identified more than 100 genetic variants for blood pressure traits and hypertension. However, the interactions between these genetic variants and environmental factors have not been systematically investigated. Therefore, we examined the interaction between genetic and environmental risk factors in blood pressure traits using the genetic risk score (GRS). Two Korean community-based cohorts, Cohort I (KARE; N = 8,840) and Cohort II (CAVAS; N = 9,599), were used for this study, and GRSs were calculated from 42 GWAS single-nucleotide polymorphisms (SNPs) that were validated for their association in these cohorts. We calculated GRSs in both ways by considering the effect sizes of each SNP (weighted GRS) and not considering the effect sizes (unweighted GRS). The unweighted GRS was strongly associated with systolic blood pressure, diastolic blood pressure, and hypertension (p = 9.03 × 10 -47 , p = 9.41 × 10 -48 , and p = 3.22 × 10 -55 by meta-analysis, respectively) and the weighted GRS showed the similar results. The environmental factors of body mass index, waist circumference, and drinking status were significantly associated with blood pressure traits, and the interaction between these factors and GRSs were examined. However, no interactions were found with either the GRS or the individual SNPs considered for the GRS. Our findings show that it is challenging to find GRS-environment interactions regarding blood pressure traits.

Elevated serum ferritin is associated with incident Type 2 diabetes (T2D), but the interactions between serum ferritin and genetic factors which may improve understanding underlying mechanism in the development of T2D are still unclear. We determined the gene-ferritin interactions on the development of T2D by genome-wide gene-ferritin interaction analyses.A total of 3405 participants from two prospective cohorts of community living residents were included, and the median follow-time was 3.99 years. Genome-wide gene-ferritin interactions were analyzed using the joint test with two degrees of freedom and the interaction test with one degree of freedom. There were 18 SNPs selected in the joint test. Finally, four independent variants [rs355140 (LINC00312), rs4075576 (nearby PDGFA), rs1332202 (PTPRD), and rs713157 (nearby LINC00900)] with low pairwise linkage disequilibrium (r20.2) and located at least 1000 kb from the index SNP showed interactions with serum ferritin level. In the association analyses between serum ferritin levels (tertiles of ferritin and ferritin status) and the incidence of T2D according to genotype, the Incidence Rate Ratios (IRRs) in the highest tertile of ferritin level (vs. the lowest tertile) were greater for participants with heterozygotes of risk alleles of each of the four SNP than IRRs for those with wild type. Compared with the normal group, the elevated ferritin group also had a higher risk of T2D for all genetic variants of risk alleles, particularly its homozygotes.Serum ferritin level interacts with genetic variants (rs355140, rs4075576, rs1332202, and rs713157) in the development of T2D.

Exosomes in blood play an important role in cell-to-cell signaling and are a novel source of biomarkers for the diagnosis and prognosis of diseases. Recently, evidence has accumulated that cytokines are released from encapsulated exosomes and are capable of eliciting biological effects upon contact with sensitive cells. However, there is currently limited information on exosome isolation methods for cytokine research. In this study, we evaluated three exosome isolation methods for their usability, yield, purity, and effectiveness in subsequent cytokine profiling. We found that ultracentrifugation (UC) and Exoquick (EQ), but not exoEasy, yielded appropriate exosome sizes, and EQ had higher exosome extraction efficiency than the other two methods. Although UC generated markedly fewer particles than EQ, it yielded a relatively high purity. Next, we performed a multiplex assay with the ProcartaPlex Immune Monitoring 65-Plex Panel to determine the feasibility of these methods for cytokine profiling. The results indicated significant differences among isolation methods when analyzing exosomal cytokine profiles. We further investigated the changes of exosomal cytokines according to breast cancer progression in triple-negative breast cancer. We found significantly decreased concentrations of MIP-3 alpha, IL-23, M-CSF, Eotaxin-3, BLC, SDF-1 alpha, IL-2R, MDC, FGF-2, IL-22, and IL-31 in exosomes from metastatic breast cancer (MBC) patients.

Introduction: Obesity results from an imbalance in the intake and expenditure of calories that leads to lifestyle-related diseases. Although genome-wide association studies (GWAS) have revealed many obesity-related genetic factors, the interactions of these factors and calorie intake remain unknown. This study aimed to investigate interactions between calorie intake and the polygenic risk score (PRS) of BMI. Methods: Three cohorts, i.e., from the Korea Association REsource (KARE; n = 8,736), CArdioVAscular Disease Association Study (CAVAS; n = 9,334), and Health EXAminee (HEXA; n = 28,445), were used for this study. BMI-related genetic loci were selected from previous GWAS. Two scores, PRS, and association (a)PRS, were used; the former was determined from 193 single-nucleotide polymorphisms (SNPs) from 5 GWAS datasets, and the latter from 62 SNPs (potentially associated) from 3 Korean cohorts (meta-analysis, p < 0.01). Results: PRS and aPRS were significantly associated with BMI in all 3 cohorts but did not exhibit a significant interaction with total calorie intake. Similar results were obtained for obesity. PRS and aPRS were significantly associated with obesity but did not show a significant interaction with total calorie intake. We further analyzed the interaction with protein, fat, and carbohydrate intake. The results were similar to those for total calorie intake, with PRS and aPRS found to not be associated with the interaction of any of the 3 nutrition components for either BMI or obesity. Discussion: The interaction of BMI PRS with calorie intake was investigated in 3 independent Korean cohorts (total n = 35,094) and no interactions were found between PRS and calorie intake for obesity.

Macrophage polarization plays an important role in tissue damage and repair. In this study, we show that Substance-P (SP) can directly induce M2 polarization of inflammatory macrophages. SP induced the differentiation of GM-CSF-differentiated pro-inflammatory macrophages into alternatively activated phagocytic M2 like macrophages (M2SP) through direct activation of the PI3K/Akt/mTOR/S6kinase pathway and induction of Arginase-1, CD163, and CD206, all of which were nullified by pretreatment with the neurokinin-1 receptor (NK-1R) antagonist RP67580 and specific signaling pathway inhibitors. M2SP were distinct from IL-4/IL-13-induced M2a and IL-10-induced M2c subtypes; they did not show STAT activation and exhibited high phagocytic and endothelial adhesive activity. Furthermore, SP had a dominant effect on M2 polarization over Interferon gamma (IFNγ), a potent M1-skewing cytokine, and effectively induced the M2 phenotype in monocytes and the human THP-1 cell line. Finally, adoptively transferred M2SP migrated to a spinal cord injury (SCI) lesion site and improved functional recovery. Collectively, our findings show that SP, a neuropeptide, plays a role as a novel cytokine by inducing tissue-repairing M2SP macrophages and thus may be developed for pharmacological intervention in diseases involving chronic inflammation and acute injury.

Research efforts towards developing near-infrared (NIR) therapeutics to activate the proliferation of human keratinocytes and collagen synthesis in the skin microenvironment have been minimal, and the subject has not been fully explored. Herein, we describe the novel synthesis Ag2S nanoparticles (NPs) by using a sonochemical method and reveal the effects of NIR irradiation on the enhancement of the production of collagen through NIR-emitting Ag2S NPs. We also synthesized Li-doped Ag2S NPs that exhibited significantly increased emission intensity because of their enhanced absorption ability in the UV–NIR region. Both Ag2S and Li-doped Ag2S NPs activated the proliferation of HaCaT (human keratinocyte) and HDF (human dermal fibroblast) cells with no effect on cell morphology. While Ag2S NPs upregulated TIMP1 by only twofold in HaCaT cells and TGF-β1 by only fourfold in HDF cells, Li-doped Ag2S NPs upregulated TGF-β1 by tenfold, TIMP1 by 26-fold, and COL1A1 by 18-fold in HaCaT cells and upregulated TGF-β1 by fivefold and COL1A1 by fourfold in HDF cells. Furthermore, Ag2S NPs activated TGF-β1 signaling by increasing the phosphorylation of Smad2 and Smad3. The degree of activation was notably higher in cells treated with Li-doped Ag2S NPs, mainly caused by the higher PL intensity from Li-doped Ag2S NPs. Ag2S NPs NIR activates cell proliferation and collagen synthesis in skin keratinocytes and HDF cells, which can be applied to clinical light therapy and the development of anti-wrinkle agents for cosmetics.

Background Default mode network (DMN) functional connectivity is one of the neuroimaging candidate biomarkers of Alzheimer disease. However, no studies have investigated DMN connectivity at different stages of mild cognitive impairment (MCI). The aim of this study was to investigate patterns of DMN connectivity and its breakdown among cognitively normal (CN), early MCI (EMCI), and late MCI (LMCI) subjects. Methods Magnetic resonance imaging data and neuropsychological test scores from 130 subjects (CN=43, EMCI=47, LMCI=40) were obtained from the Alzheimer's Disease Neuroimaging Initiative. DMN functional connectivity was extracted using independent components analysis and compared between groups. Results Functional connectivity in the precuneus, bilateral medial frontal, parahippocampal, middle temporal, right superior temporal, and left angular gyri was decreased in EMCI subjects compared with CN subjects. When the 2 MCI groups were directly compared, LMCI subjects exhibited decreased functional connectivity in the precuneus, bilateral medial frontal gyri, and left angular gyrus. There was no significant difference in gray matter volume among the 3 groups. Amyloid-positive EMCI subjects revealed more widespread breakdown of DMN connectivity than amyloid-negative EMCI subjects. A quantitative index of DMN connectivity correlated well with measures of cognitive performance. Conclusions Our results suggest that the breakdown of DMN connectivity may occur in the early stage of MCI.

Prediabetic subjects represent a vulnerable population, requiring special care to reduce the risk of diabetes onset. We developed and validated a diabetes risk score for prediabetic subjects using the Korea National Diabetes Program (KNDP) cohort. Subjects included in the multicenter and prospective cohort (n = 1162) had high diabetes risk at baseline (2005) and were followed until 2012. Survival analysis was performed to analyze the prospective cohort over time, and the bootstrap method was used to validate our model. We confirmed our findings in an external cohort. A diabetes risk score was calculated and the cut-off defined using a receiver operating characteristic curve. Age, body mass index, total cholesterol, and family history of diabetes were associated with diabetes. The model performed well after correction for optimism (Cadj = 0.735). A risk score was defined with a cut-off of ≥5 that maximized sensitivity (72%) and specificity (62%), with an area under the curve of 0.73. Prediabetic subjects with a family history of diabetes had a higher probability of diabetes (risk score = 5) irrespective of other variables; this result was confirmed in the external cohort. Hence, prediabetic subjects with a family history of diabetes have a higher probability of developing diabetes, regardless of other clinical factors.

Background Face morphology is strongly determined by genetic factors. However, only a small number of genes related to face morphology have been identified to date. Here, we performed a two-stage genome-wide association study (GWAS) of 85 face morphological traits in 7569 Koreans (5643 in the discovery set and 1926 in the replication set). Results In this study, we analyzed 85 facial traits, including facial angles. After discovery GWAS, 128 single nucleotide polymorphisms (SNPs) showing an association of P

PR interval is the period from the onset of P wave to the start of the QRS complex on electrocardiograms. A recent genomewide association study (GWAS) suggested that GAREM1 was linked to the PR interval on electrocardiograms. This study was designed to validate this correlation using additional subjects and examined the function of Garem1 in a mouse model. We analyzed the association of rs17744182, a variant in the GAREM1 locus, with the PR interval in 5646 subjects who were recruited from 2 Korean replication sets, Yangpyeong (n = 2471) and Yonsei (n = 3175), and noted a significant genomewide association by meta-analysis (P = 2.39 × 10−8). To confirm the function of Garem1 in mice, Garem1 siRNA was injected into mouse tail veins to reduce the expression of Garem1. Garem1 transcript levels declined by 53% in the atrium of the heart (P = 0.029), and Garem1-siRNA injected mice experienced a significant decrease in PR interval (43.27 ms vs. 44.89 ms in control, P = 0.007). We analyzed the expression pattern of Garem1 in the heart by immunohistology and observed specific expression of Garem1 in intracardiac ganglia. Garem1 was expressed in most neurons of the ganglion, including cholinergic and adrenergic cells. We have provided evidence that GAREM1 is involved in the PR interval of ECGs. These findings increase our understanding of the regulatory signals of heart rhythm through intracardiac ganglia of the autonomic nervous system and can be used to guide the development of a therapeutic target for heart conditions, such as atrial fibrillation.

The objective of this study is to find single nucleotide polymorphisms (SNPs) associated with a risk of Type 2 diabetes (T2D) in Korean adults and to investigate the longitudinal association between these SNPs and T2D and the interaction effects of iron intake and average hemoglobin level. Data from the KoGES_ Ansan and Ansung Study were used. Gene-iron interaction analysis was conducted using a two-step approach. To select candidate SNPs associated with T2D, a total of 7,935 adults at baseline were included in genome-wide association analysis (step one). After excluding T2D prevalent cases, prospective analyses were conducted with 7,024 adults aged 40-69 (step two). The association of selected SNPs and iron status with T2D and their interaction were determined using a Cox proportional hazard model. A total of 3 SNPs [rs9465871 (CDKAL1), rs10761745 (JMJD1C), and rs163177 (KCNQ1)] were selected as candidate SNPs related to T2D. Among them, rs10761745 (JMJD1C) and rs163177 (KCNQ1) were prospectively associated with T2D. High iron intake was also prospectively associated with the risk of T2D after adjusting for covariates. Average hemoglobin level was positively associated with T2D after adjusting for covariates in women. We also found significant interaction effects between rs10761745 (JMJD1C) and average hemoglobin levels on the risk of T2D among women with normal inflammation and without anemia at baseline. In conclusion, KCNQ1 and JMJD1C may prospectively contribute to the risk of T2D incidence among adults over the age of 40 and JMJD1C, but CDKAL1 may not, and iron status may interactively contribute to T2D incidence in women.

p53 is an important tumor-suppressor protein deactivation of which by mdm2 results in cancers. A SUMO-specific protease 4 (SUSP4) was shown to rescue p53 from mdm2-mediated deactivation, but the mechanism is unknown. The discovery by NMR spectroscopy of a "p53 rescue motif" in SUSP4 that disrupts p53-mdm2 binding is presented. This 29-residue motif is pre-populated with two transient helices connected by a hydrophobic linker. The helix at the C-terminus binds to the well-known p53-binding pocket in mdm2 whereas the N-terminal helix serves as an affinity enhancer. The hydrophobic linker binds to a previously unidentified hydrophobic crevice in mdm2. Overall, SUSP4 appears to use two synergizing modules, the p53 rescue motif described here and a globular-structured SUMO-binding catalytic domain, to stabilize p53. A p53 rescue motif peptide exhibits an anti-tumor activity in cancer cell lines expressing wild-type p53. A pre-structures motif in the intrinsically disordered proteins is thus important for target recognition.

Previously, genetic polymorphisms of C12orf51 (HECTD4) (rs2074356 and/or rs11066280) have been shown to be related to alcohol consumption and type 2 diabetes (T2D). This study aimed to prospectively examine whether C12orf51 had an interaction with or independent effect on alcohol consumption and the risk of T2D. The present study included 3,244 men and 3,629 women aged 40 to 69 years who participated in the Korean Genome and Epidemiology Study (KoGES)_Ansan and Ansung Study. Cox proportional hazards models were used to estimate HRs and 95% CIs for T2D. rs2074356 and rs11066280 were associated with the risk of T2D after adjusting for alcohol consumption (rs2074356 for AA: HR = 0.39 and 95% CI = 0.17-0.87 in men, and HR = 0.36 and 95% CI = 0.13-0.96 in women; rs11066280 for AA: HR = 0.44 and 95% CI = 0.23-0.86 in men, and HR = 0.39 and 95% CI = 0.16-0.94 in women). We identified that the association of each variant (rs2074356 and rs11065756) in C12orf51 was nearly unchanged after adjusted for alcohol consumption. Therefore, the association of 2 SNPs in C12orf51 with diabetes may not be mediated by alcohol use. There was no interaction effect between alcohol consumption and the SNPs with T2D. However, even in never-drinkers, minor allele homozygote strongly influenced T2D risk reduction (rs2074356 for AA: HR = 0.35, 95% CI = 0.14-0.90, and p-trend = 0.0035 in men and HR = 0.34, 95% CI = 0.13-0.93, and p-trend = 0.2348 in women; rs11066280 for AA: HR = 0.36, 95% CI = 0.16-0.82, and p-trend = 0.0014 in men and HR = 0.39, 95% CI = 0.16-0.95, and p-trend = 0.3790 in women), while alcohol consumption did not influence the risk of T2D within each genotype. rs2074356 and rs11066280 in or near C12orf51, which is related to alcohol drinking behavior, may longitudinally decrease the risk of T2D, but not through regulation of alcohol consumption.

High blood pressure contributes to more than 10 million deaths per year worldwide through stroke and ischemic heart disease. Yet, genome-wide association studies (GWASs) have identified a small fraction of its underlying genetic factors. To identify biologically important single-nucleotide polymorphisms (SNPs) that regulate variations in blood pressure, we analyzed SNPs in a genome-wide association study. Genome-wide genotype data (original study n = 7551, SNP = 352,228; replication study n = 3703, SNP = 20) were obtained from the Korea National Institute of Health, wherein 29,921 of 352,228 SNPs lay within 5 kbp upstream of genes. Linear regression analysis was performed for systolic and diastolic blood pressure (DBP) by controlling for cohort, age, sex and body mass index. For the 20 SNPs that were associated with both blood pressure values, a replication study was performed in an independent population. A total of 20 SNPs were significantly associated with both blood pressure values in the original study, 13 of which lay in a conserved transcription factor-binding site. One SNP (rs11638762), in the GATA-3 binding site upstream of the AKAP13 gene, was significantly replicated in another cohort (P-value of the meta-analysis = 1.4 × 10(-5) for systolic blood pressure and 6.3 × 10(-4) for DBP). A functional GWAS was performed using upstream SNPs, and a novel genetic factor (AKAP13), which is essential for cardiac myocyte development in mice, was identified as a regulator of blood pressure.

Essential hypertension causes high rates of morbidity and mortality, primarily due to its complications, and its development is regulated by genetic risk and environmental factors. However, until recent genomewide association studies (GWASs) were reported, the genetic factors were unknown. Two GWASs on systolic blood pressure (SBP), diastolic blood pressure (DBP) and hypertension in Caucasians-Global Blood Pressure Genetics (Global BPgen) and Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE)-reported 51 single-nucleotide polymorphisms (SNPs) in 12 loci at P4 x 10(-7). Because the prevalence, age of onset and severity of complications of hypertension vary between ethnic groups, we wanted to investigate these results in other ethnic groups. We examined the association of 27 of the 51 SNPs in 8512 unrelated individuals from Korean Association REsource (KARE), a GWAS that was based on epidemiological cohorts in Korea. Four loci-ATP2B1 (ATPase, Ca(++) transporting, plasma membrane 1), CSK (c-src tyrosine kinase), CYP17A1 (cytochrome P450 17A1) and PLEKHA7 (pleckstrin homology domain-containing family A member 7)-were associated with blood pressure and hypertension in the Korean population.

Blood pressure, one of the important vital signs, is affected by multiple genetic and environmental factors. Recently, several genome-wide association (GWA) studies have successfully identified genetic factors that influence blood pressure and hypertension risk. In this study, we report results of the Korean Association REsource (KARE, 8842 subjects) GWA study on blood pressure and hypertension risk. In all, 10 single-nucleotide polymorphisms (SNPs) that showed significant association with hypertension were further analysed for replication associations in the Health2 project (7861 subjects). Among these 10 SNPs, 3 were replicated in the Health2 cohort for an association with systolic or diastolic blood pressure. The most significant SNP (rs17249754 located in ATPase, Ca(++) transporting, plasma membrane 1 (ATP2B1)) has been previously reported, and the other two SNPs are rs1378942 in the c-src tyrosine kinase (CSK) gene and rs12945290 in the arylsulphatase G (ARSG) gene. An additional hypertension case-control study confirmed that rs17249754 (in ATP2B1) increases hypertension risk in both the KARE and Health2 (meta-analysis, P-value=4.25 x 10(-9)) cohorts. One more SNP, rs995322, located in the CUB and Sushi multiple domains 1 (CSMD1), is also associated with increased risk of hypertension (meta-analysis, P-value=1.00 x 10(-4)). Despite the difficulty of obtaining replication results for a complex trait genetic association between blood pressure and hypertension, we were able to identify consistent genetic factors in both the Korean cohorts in ATP2B1, CSK, ARSG and CSMD1 genes.

Purpose: The aim of this study was to evaluate the changes of the regulatory T cell subset in peripheral blood caused by gestational age and premature rupture of membranes (PROM) with or without labor to verify the role of regulatory T cells in pregnancy. Patients and Methods: We investigated regulatory T cell distribution in the peripheral blood of pregnancies during the first trimester (group I, n = 2), the second trimester (group II, n = 12), and the third trimester without PROM and labor (group III, n= 15). In addition, we evaluated pregnancies in the third trimester complicated by PROM (group IV, n = 4) and labor with no complication by PROM (Group V, n = 5). Comparisons were made with non-pregnant controls (group VI, n = 4) using flow cytometry. Results: During uncomplicated pregnancy, the CD4 + CD25 bright regulatory T cell population decreased with advancing gestational age (group I = 3.35 ± 0.47, group II = 2.91 ± 1.44, group III = 2.81 ± 1.36, group VI = 2.52 ± 0.71, p = NS). When we compared group IV with group III and V to evaluate the changes of the regulatory T cells with PROM, the CD4 + CD25 bright regulatory T cell population was significantly decreased in group IV compared to group III (p= 0.001) and group V (p = 0.026). Conclusion: The present results revealed that the regulatory T cell population increased in early pregnancy but decreased in pregnancies complicated by PROM, indicating that regulatory T cells might be related to the maintenance of pregnancy.

To investigate the mechanism of vascular endothelial growth factor (VEGF)-induced endothelin-1 production in human umbilical vein endothelial cells (HUVECs).Endothelin-1 levels were measured in conditioned medium of women with preeclampsia HUVECs were treated with different concentrations of VEGF(165) and at various time intervals. Next, we measured endothelin-1 levels after HUVECs were also incubated with VEGF and endothelin-converting enzyme-1 (ECE-1) inhibitor or tissue inhibitors of matrix metalloproteinase-2 (TIMP-2). Additionally, the circulating levels of total and free VEGF, matrix metalloproteinase-2 (MMP-2), and endothelin-1 were measured in 20 preeclamptic patients and 20 healthy pregnant controls.HUVECs treated with VEGF increased their endothelin-1 production in a concentration and time-dependent manner. The production of endothelin-1 was inhibited by TIMP-2, but not by the ECE-1 inhibitor. Total VEGF, MMP-2, and endothelin-1 concentrations were higher in preeclampsia and showed significant positive correlations between them.These findings suggest that VEGF-induced endothelin-1 production might be mediated by MMP-2 rather than by ECE-1 upregulation.

The eIF4E-binding protein 1 (4EBP1) has long been known to be completely unstructured without any secondary structures, which contributed significantly to the proposal of the induced fit mechanism for target binding of intrinsically disordered proteins. We show here that 4EBP1 is not completely unstructured, but contains a pre-structured helix.

Objective Recent genome-wide association studies have identified 33 human genetic loci that influence blood pressure. The 15q24 locus is one such locus that has been confirmed in Asians and Europeans. There are 21 genes in the locus within a 1-Mb boundary, but a functional link of these genes to blood pressure has not been reported. We aimed to identify a causative gene for blood pressure change in the 15q24 locus. Methods and Results CSK and ULK3 were selected as candidate genes based on eQTL analysis studies that showed the association between gene transcript levels and the lead SNP (rs1378942). Injection of siRNAs for mouse homologs Csk, Ulk3, and Cyp1a2 (negative control) showed reduced target gene mRNA levels in vivo. However, Csk siRNA only increased blood pressure while Ulk3 and Cyp1a2 siRNA did not change it. Further, blood pressure in Csk(+/-) heterozygotes was higher than in wild-type, consistent with what we observed in Csk siRNAinjected mice. We confirmed that haploinsufficiency of Csk increased the active form of Src in Csk(+/-) mice aorta. We also showed that inhibition of Src by PP2, a Src inhibitor decreased high blood pressure in Csk(+/-) mice and the active Src in Csk(+/-) mice aorta and in Csk knockdown vascular smooth muscle cells, suggesting blood pressure regulation by Csk through Src. Conclusions Our study demonstrates that Csk is a causative gene in the 15q24 locus and regulates blood pressure through Src, and these findings provide a novel therapeutic target for the treatment of hypertension.

Recent evidence suggests that brain-derived neurotrophic factor (BDNF) regulates food intake and the control of body weight. A common polymorphism in human BDNF, Val66Met (single-nucleotide polymorphism database (dbSNP) no. rs6265), impairs intracellular trafficking, resulting in the reduced secretion of BDNF. Several European studies have indicated that Val66Met is associated with BMI. In this study, we examined the association of the Val66Met polymorphism with BMI in Koreans (n = 20,270) from three independent epidemiological cohorts. All three studies observed a consistent association of this polymorphism with BMI, and their combined analysis demonstrated a robust correlation (β = −0.17 ± 0.03 and P = 5.6 × 10 −8 ). We also examined the effect of smoking on the link between Val66Met and BMI. The association of Val66Met with BMI was statistically significant only in the smoking group, reflecting a possible interaction between smoking and the BDNF polymorphism for BMI. Thus, we have confirmed BDNF as a genetic risk factor for BMI in an Asian population and hypothesize that the Val66Met mutation influences individual differences in BMI. In addition, smoking might interact with BDNF Val66Met to modulate BMI.

The aim of this study was to estimate the national rates of induced abortion in South Korea, where no quantitative national studies of abortion exist because the procedure is illegal.A survey of 25 hospitals and 176 private clinics that provide induced abortions was conducted in 2005. The data were analyzed to estimate the nationwide rate of induced abortion. Indirect estimation methodology was used to calculate the number of annual induced abortions.In 2005, an estimated 342 433 induced abortions were performed in South Korea at a rate of 29.8 per 1000 women aged 15-44years. We observed that the abortion rate was higher in single women (31.6 per 1000 women) than in married women (28.6 per 1000 women).A significant number of induced abortions occur in both cohorts of married and unmarried women. To prevent serious physical harm to patients, the government should reconsider the practicality of the current statutes that prohibit women from seeking abortions from a qualified provider.

Aims To identify the genetic risk factors that influence the development of electrocardiographic (ECG) left ventricular hypertrophy (LVH), a major risk factor for cardiovascular (CV) morbidity and mortality. Methods and results We performed a genomewide association study (GWAS) of ECG-LVH, in which the community-based Korea Association REsource (KARE) study (8432 controls and 398 cases) was analysed by Affymetrix SNP array 5.0. The GWAS results were validated in hospital-based samples (597 controls and 207 cases). Fourteen single-nucleotide polymorphisms (SNPs) in eight genetic loci (5q35.1, 6p22.3-22.1, 8q24.2, 11p15, 11q21-22.1, 14q12, 17q11.2, and 19q13.1) were associated with ECG-LVH in the original GWAS study ( P < 1 × 10−5). Of these SNPs, 12 were genotyped in the hospital sample. There was consistent association with the 19q13.1 region which contains RYR1 gene. The most significant SNP in the region was rs10500279, which had genomewide significance in the combined GWAS/replication sample [odds ratio = 1.58 (confidence interval: 1.35–1.85), P = 1.0 × 10−8]. Mutations in RYR1 , which encodes a major Ca2+ channel in the skeletal muscle, have been reported to correlate with CV diseases. Conclusion We performed the first GWAS for ECG-LVH, implicating the skeletal muscle Ca2+ channel protein RYR1 as a genetic risk factor. These results might increase our understanding of the development of ECG-LVH.

AIMS. Blood pressure control is influenced by various genetic and environmental factors, and genetic susceptibility is important in the development of essential hypertension. Because the renin-angiotensin-aldosterone system (RAAS) has a key role in vasoconstriction, vasodilation, and sodium and electrolyte balance, it is central in blood pressure control and so is an appropriate target in hypertension treatments. The present study assessed the association of RAAS-related genes with blood pressure and hypertension in a Korean population. Single nucleotide polymorphisms (SNPs, n = 114) in nine RAAS-related genes (AGT, REN, ACE, ACE2, AGTR1, CYP11B2, NR3C2, MAS1, and CMA1) were assessed for their correlation with blood pressure and hypertension using genotype data of 8842 individuals from the Korea Association Resource subject pool. MAJOR FINDINGS. Linear regression analysis revealed a statistically significant association with blood pressure of 10 SNPs in six genes (ACE, ACE2, CYP11B2, NR3C2, MAS1, and CMA1). An additional hypertension case-control study identified 10 SNPs in NR3C2 and ACE that were linked to hypertension. PRINCIPAL CONCLUSION. Three SNPs (rs11737660, rs6810951, and rs10519963) in NR3C2 correlate with both blood pressure and hypertension. Genetic polymorphisms in RAAS-related genes appear to be associated with hypertension in a Korean population.

Background The prevalence of type 2 diabetes has reached epidemic proportions worldwide, and the incidence of life-threatening complications of diabetes through continued exposure of tissues to high glucose levels is increasing. Advances in genotyping technology have increased the scale and accuracy of the genotype data so that an association genetic study has expanded enormously. Consequently, it is difficult to search the published association data efficiently, and several databases on the association results have been constructed, but these databases have their limitations to researchers: some providing only genome-wide association data, some not focused on the association but more on the integrative data, and some are not user-friendly. In this study, a user-friend database of type 2 diabetes genetic association of manually curated information was constructed. Description The list of publications used in this study was collected from the HuGE Navigator, which is an online database of published genome epidemiology literature. Because type 2 diabetes genetic association database (T2DGADB) aims to provide specialized information on the genetic risk factors involved in the development of type 2 diabetes, 701 of the 1,771 publications in the type 2 Diabetes case-control study for the development of the disease were extracted. Conclusions In the database, the association results were grouped as either positive or negative. The gene and SNP names were replaced with gene symbols and rsSNP numbers, the association p-values were determined manually, and the results are displayed by graphs and tables. In addition, the study design in publications, such as the population type and size are described. This database can be used for research purposes, such as an association and functional study of type 2 diabetes related genes, and as a primary genetic resource to construct a diabetes risk test in the preparation of personalized medicine in the future.

Recently, genome-wide association studies have identified a strong association between the ZBTB38 locus and human height. In a functional study, we detected two RT-PCR products of ZBTB38, amplified with primers in exons 7 and 8 from a chondrocyte cell line, C-28/I2. Sequencing revealed that the longer product contained an Alu segment in intron 7 of ZBTB38, which contained a potential splicing acceptor site that likely was used to generate the alternative transcript. Insertion of the Alu segment changed the consensus Kozak sequence of the ZBTB38 transcript, potentially altering translational efficiency. We performed RT-PCR using 16 tissue samples from humans and 8 tissue samples from primates to determine any tissue specificity or evolutionary conservation of the alternative splicing. Although we failed to identify any difference among the tissues, all primate samples expressed only the shorter Alu segment (lacking the transcript), suggesting that the alternative splicing event is hominid primate-specific.

In humans, the kidneys regulate blood pressure by balancing sodium concentrations. Fine-tuning of renal sodium reabsorption and excretion depends on the epithelial sodium channel protein (ENaC: protein complex of SCNN1A, SCNN1B, and SCNN1G). The surface expression of ENaC components is directed by the ubiquitination of ENaC by NEDD4L, an ENaC-specific E3 ubiquitin ligase, and is regulated by the deubiquitination of ENaC by USP2. The activity of NEDD4L in turn is regulated by phosphorylation by SGK1 and also through interaction with NDFIP2.We analyzed 91 SNPs in 7 genes using the genotype data of 8,842 individuals from the Korea Association REsource subject pool for their correlation with blood pressure and hypertension.25 SNPs in the SCNN1A, SCNN1B, SCNN1G, NEDD4L, NDFIP2, and USP2 loci were found to be associated with blood pressure. An additional hypertension case-control study identified 13 SNPs in SCNN1B, SCNN1G, and NEDD4L that were linked to hypertension.These results support our hypothesis that individual variations in blood pressure are attributed to variants of the genes that regulate renal sodium reabsorption and excretion. Our data also suggest that it would be meaningful to investigate the role of NEDD4L-mediated ubiquitination in the pathogenesis of hypertension.

Under the activation of insulin receptors, glucose transporter 4 (Glut4) translocation is regulated by two signal transduction pathways. These pathways are the PI 3-kinase-dependent pathway and the CAP/TC10 pathway. The adaptor protein Rap guanine exchange factor 1 (RAPGEF1) also known as C3G is a component of the CAP/TC10 pathway. Defects in the RAPGEF1 protein may contribute to insulin resistance and type 2 diabetes. Recently, the RAPGEF1 gene was suggested to be involved in the development of type 2 diabetes by FUSION study. To investigate this association in the Korean population, we sequenced the RAPGEF1 gene in 24 unrelated individuals and identified 39 sequence variants. Eleven single nucleotide polymorphisms (SNPs) were selected and genotyped in 1122 Korean patients with type 2 diabetes. There were 1138 non-diabetic controls. Using a logistic regression analysis, a significant association was found between SNP rs11243444 in the RAPGEF1 gene and type 2 diabetes [OR=0.490 (95% CI 0.296–0.813), p =0.006] in the recessive model, leading the protective effect of the GG genotype on the disease development. The present study examines genetic polymorphisms in the RAPGEF1 gene, and the positive association between one polymorphism and type 2 diabetes in the Korean population.

Preeclampsia is a disease associated with the maternal inflammatory response. YKL-40 and interleukin-18 (IL-18) are inflammatory markers involved in inflammatory states and vascular processes. The aim of this study was to evaluate serum levels of YKL-40 and IL-18 in preeclampsia. Twenty-four patients with preeclampsia and 13 healthy pregnant women were included in this study. Serum levels of YKL-40 and IL-18 were measured using an enzyme-linked immunosorbent assay (ELISA). Serum YKL-40 levels were significantly higher in patients with preeclampsia (median 75.0 ng/mL; range 45.8-125.4 ng/mL) than in normal pregnant women (median 29.3 ng/mL; range 16.2-39.5 ng/mL; p=0.000). Serum IL-18 levels were also significantly higher in patients with preeclampsia (median 159.9 pg/mL; range 125.6-193.5 pg/mL) than in normal pregnant women (median 120.2 pg/mL; range 102.2-157.9 pg/mL; p=0.018). Notably, higher serum YKL-40 levels were observed in patients with more severe proteinuria (>or=3+ by dipstick) than in patients with milder proteinuria (

The purpose of this study was to compare the posterior superior iliac spine (PSIS) and the iliac crest as accurate anatomical landmarks for identifying spinal level.This study was conducted in 2 stages. First, 4 examiners examined 60 patients and blindly identified iliac crest and PSIS levels, and the interexaminer reliability of PSIS and iliac crest palpation were then analyzed. Second, 4 examiners attached a radio opaque marker at presumed PSIS and iliac crest levels in 72 patients, and posteroanterior lumbar radiographs were then taken. Four examiners then confirmed PSIS and iliac crest levels after radiographically identifying the marker levels and checked the spinal level at which the spinous process or interspace was crossed by drawing a horizontal line drawn between radio opaque markers.The interexaminer reliability of palpation was significantly greater for PSIS level than for the iliac crest (P.05). Spinal levels of estimated PSISs identified by palpation ranged from the L5-S1 interspace to the S2 spinous process, and the spinal levels of estimated iliac crest ranged from the L2-3 interspace to the L5 spinous process.Although PSIS palpation showed statistically higher interexaminer reliability than iliac crest level, clinicians should be cautious when applying this method as a measurement tool because estimated spinal level by palpation can be influenced inadvertently by examiner skill and anatomical variations.

The aim of this study was to explain possible relationships in cases of ectopic pregnancy between sonographic endometrial features and treatment outcome following methotrexate (MTX) injection. A total of 157 cases of unruptured tubal pregnancy were diagnosed and treated systemically with MTX. The sonographic endometrial pattern, endometrial thickness and treatment outcome were retrospectively analyzed. There were four types of endometrial patterns: these were trilaminar, homogeneous, heterogeneous and pseudosac. Success rates following MTX treatment were different for each group: these were 64.7%, 78.4%, 50.0% and 46.2%, respectively (p = 0.0129). And the risk of treatment failure was increased 3.64 times (95% CI 1.56 to 8.49) in heterogeneous thick pattern and 4.24 times (95% CI 1.18 to 15.23) in pseudosac pattern. In conclusion, when tubal pregnancy was seen in a pseudogestational sac pattern or a heterogeneous pattern, the failure rate of medical treatment was increased. This can serve as a reference for considering the decision about medical treatment in women with unruptured tubal pregnancy. (E-mail: haijkim@korea.ac.kr )

To evaluate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of preeclampsia, we measured total VEGF, free VEGF and soluble Flt-1 (sFlt-1) concentrations and determined their relationships. Maternal serum samples were collected from 20 patients with preeclampsia and 20 normotensive women with uncomplicated pregnancies matched with the patients with preeclampsia for gestational age and parity. The serum concentrations of total VEGF (2.39+/-0.75 vs. 0.28+/-0.14) and sFlt-1 (934.5+/-235.5 vs. 298.0+/-161.2) were significantly increased in the patients with preeclampsia compared to the women with uncomplicated pregnancies. However the serum concentration of free VEGF (21.5+/-6.3 vs. 134.0+/-16.3) was lower in patients with preeclampsia. There was a positive correlation between the serum concentrations of total VEGF and sFlt-1 with systolic and diastolic blood pressure, respectively. There was a negative correlation between the serum concentration of free VEGF and systolic and diastolic blood pressure. There was a strong negative correlation between free VEGF and sFlt-1 concentrations. In conclusion, we found VEGF and sFlt-1 were related to the pathogenesis of preeclampsia. Although reduced concentrations of free VEGF might interfere with endothelial cell function and survival, further studies are required to clarify its specific role in the pathogenesis of preeclampsia.