OBJECTIVE: Genome-wide association studies (GWAS) of metabolic syndrome (MetS) have predominantly focused on non-Asian populations, with limited representation from East Asian cohorts. Moreover, previous GWAS analyses have primarily emphasized the significance of top single nucleotide polymorphisms (SNPs), poorly explaining other SNP signals in linkage disequilibrium. This study aimed to reveal the interaction between rs651821 and rs2266788, the principal variants of apolipoprotein A5 (APOA5), within the most significant loci identified through GWAS on MetS.
METHODS: GWAS on MetS and its components was conducted using the data from the Korean Genome and Epidemiology Study (KoGES) city cohort comprising 58,600 individuals with available biochemical, demographic, lifestyle factors, and the most significant APOA5 locus was analyzed further in depth.
RESULTS: According to GWAS of MetS and its diagnostic components, a significant association between the APOA5 SNPs rs651821/rs2266788 and MetS/triglycerides/high-density lipoprotein phenotypes was revealed. However, a conditional analysis employing rs651821 unveiled a reversal in the odds ratio for rs2266788. Therefore, rs651821 and rs2266788 emerged as independent and opposing signals in the extended GWAS analysis, i.e., the multilayered effects. Further gene-environment interaction analyses regarding lifestyle factors such as smoking, alcohol consumption, and physical activity underscored these multilayered effects.
CONCLUSIONS: This study unveils the intricate interplay between rs651821 and rs2266788 derived from MetS GWAS. Removing the influence of lead SNP reveals an independent protective signal associated with rs2266788, suggesting a multilayered effect between these SNPs. These findings underline the need for novel perspectives in future MetS GWAS.

UNASSIGNED: Addressing dietary factors to lower blood pressure can be a crucial strategy at the population level to mitigate the risk of hypertension. In a prior investigation, a tailored food score was used as a dietary index relevant to hypertension among Korean adults. This current study aims to assess the association between the overall quality of the diet, taking into account more precise food components, and evaluate the risk of developing hypertension.
UNASSIGNED: This prospective cohort study included 5,342 adults aged 40-70 without hypertension who participated in the Korean Genome and Epidemiology Study (KoGES) from 2001 to 2016. The improved Recommended Food Score for Hypertension (iRFSH) is a modified version of the Recommended Food Score to assess the consumption of foods recommended in the Dietary Approaches to Stop Hypertension (DASH) diet for Korean foods. A higher score reflects greater consumption of recommended foods, indicative of higher dietary quality. The maximum total score is 65. High blood pressure, which includes both hypertension and prehypertension, was analyzed using Cox proportional hazard regression models to examine its prospective relationship with iRFSH.
UNASSIGNED: Among 2,478 males and 2,864 females with 10.8 mean years of follow-up, a higher score of iRFSH was associated with a lower risk of hypertension in the highest quintile compared to the lowest quintile [total: hazard ratio (HR): 0.79; 95% confidence interval (CI): 0.72, 0.87; female: HR: 0.71; 95% CI: 0.62, 0.83].
UNASSIGNED: Higher iRFSH is associated with a lower incidence of hypertension. Our results suggest that the iRFSH may be a potential tool for assessing dietary quality and dietary patterns and predicting the risk of hypertension in Korean adults.

This study presents the nutrition survey methods and the updated food composition database for the Korean Genome and Epidemiology Study (KoGES). The KoGES, which is the largest and longest cohort study in Korea, aims to identify genetic and environmental factors associated with chronic diseases. This study has collected dietary data using a validated semi-quantitative food frequency questionnaire and/or the 24-hour recall method. However, these dietary survey methods use different food composition databases, and their nutritional values are out of date. Therefore, it became necessary to update the food composition database by revising nutrient analysis values to reflect improvements in the performance of food ingredient analysis equipment, revising international values to analysis values of Korean agricultural products, adjusting nutrient units, and adding newly reported nutrients related to chronic diseases. For this purpose, we integrated the different food composition databases used in each nutrition survey, updated 23 nutrients, and expanded 48 new nutrients for 3,648 food items using the latest reliable food composition databases published by national and international institutions. This revised food composition database may help to clarify the relationship between various nutrients and chronic diseases. It could serve as a valuable resource for nutritional, epidemiological, and genomic research and provide a basis for determining public health policies.

BACKGROUND: Genome-wide association studies have successfully identified genetic variants associated with human disease. Various statistical approaches based on penalized and machine learning methods have recently been proposed for disease prediction. In this study, we evaluated the performance of several such methods for predicting asthma using the Korean Chip (KORV1.1) from the Korean Genome and Epidemiology Study (KoGES).
RESULTS: First, single-nucleotide polymorphisms were selected via single-variant tests using logistic regression with the adjustment of several epidemiological factors. Next, we evaluated the following methods for disease prediction: ridge, least absolute shrinkage and selection operator, elastic net, smoothly clipped absolute deviation, support vector machine, random forest, boosting, bagging, naïve Bayes, and k-nearest neighbor. Finally, we compared their predictive performance based on the area under the curve of the receiver operating characteristic curves, precision, recall, F1-score, Cohen\'s Kappa, balanced accuracy, error rate, Matthews correlation coefficient, and area under the precision-recall curve. Additionally, three oversampling algorithms are used to deal with imbalance problems.
CONCLUSIONS: Our results show that penalized methods exhibit better predictive performance for asthma than that achieved via machine learning methods. On the other hand, in the oversampling study, randomforest and boosting methods overall showed better prediction performance than penalized methods.

UNASSIGNED: Pro-oxidant/antioxidant imbalances leading to chronic inflammation and insulin resistance can contribute to the development of metabolic syndrome (MetS). Oxidative Balance Score (OBS), a comprehensive measure of exposure to pro- and anti-oxidants, represents an individual\'s total oxidative balance. This study aimed to evaluate the association between OBS and MetS using two large datasets.
UNASSIGNED: We analyzed data from 2,735 adults older than 19 years from the 2021 Korean National Health and Nutritional Examination Survey (KNHANES) and 5,807 adults aged 40-69 years from the Korean Genome and Epidemiology Study (KoGES). In each dataset, OBS was categorized into sex-specific tertiles (T).
UNASSIGNED: In KNHANES, the odds ratios and 95% confidence intervals for prevalent MetS in T3, compared to T1, were 0.44 (0.29-0.65) in men and 0.34 (0.23-0.50) in women after adjusting for confounders. In KoGES, the hazard ratios and 95% confidence intervals for incident MetS in T3, compared to T1, were 0.56 (0.48-0.65) in men and 0.63 (0.55-0.73) in women after adjusting for confounders.
UNASSIGNED: OBS appears to be inversely related to MetS, which suggests that adopting lifestyle behaviors that decrease oxidative stress could be an important preventive strategy for MetS.

Asthma is a complex heterogeneous disease caused by gene-environment interactions. Although numerous genome-wide association studies have been conducted, these interactions have not been systemically investigated. We sought to identify genetic factors associated with the asthma phenotype in 66,857 subjects from the Health Examination Study, Cardiovascular Disease Association Study, and Korea Association Resource Study cohorts. We investigated asthma-associated gene-environment (smoking status) interactions at the level of single nucleotide polymorphisms, genes, and gene sets. We identified two potentially novel (SETDB1 and ZNF8) and five previously reported (DM4C, DOCK8, MMP20, MYL7, and ADCY9) genes associated with increased asthma risk. Numerous gene ontology processes, including regulation of T cell differentiation in the thymus (GO:0033081), were significantly enriched for asthma risk. Functional annotation analysis confirmed the causal relationship between five genes (two potentially novel and three previously reported genes) and asthma through genome-wide functional prediction scores (combined annotation-dependent depletion, deleterious annotation of genetic variants using neural networks, and RegulomeDB). Our findings elucidate the genetic architecture of asthma and improve the understanding of its biological mechanisms. However, further studies are necessary for developing preventive treatments based on environmental factors and understanding the immune system mechanisms that contribute to the etiology of asthma.

BACKGROUND: Glutamate is a major neurotransmitter, although it causes cytotoxicity and inflammation in nonneuronal organs. This study aimed to investigate the metabolic disorders in which glutamate, associated with type 2 diabetes onset, is induced in the liver.
METHODS: An analysis of Korean community-based Ansan-Ansung cohort study data as well as functional research using in vitro and mouse models were performed.
RESULTS: Groups with high plasma glutamate levels (T2, T3) had a significantly increased risk of diabetes incidence after 8 years, compared to the group with relatively low glutamate levels (T1). Analysis of the effect of glutamate on diabetes onset in vitro showed that glutamate induces insulin resistance by increasing glucose-related protein 78 (GRP78) and phosphoenolpyruvate carboxykinase (PEPCK) expression in SK-Hep-1 human liver cells. In addition, three different genes, FRMB4B, PLG, and PARD3, were significantly associated with glutamate and were identified via genome-wide association studies. Among glutamate-related genes, plasminogen (PLG) levels were most significantly increased in several environments in which insulin resistance was induced, and was also upregulated by glutamate. Glutamate-induced increase in PLG in liver cells was caused by metabotropic glutamate receptor 5 activation, and PLG levels were also upregulated after extracellular secretion. Moreover, glutamate increased the expression of plasminogen activator inhibitor-1 (PAI-1). Thus, extracellular secreted PLG cannot be converted to plasmin (fibrinolytic enzyme) by increased PAI-1.
CONCLUSIONS: Increased glutamate is closely associated with the development of diabetes, and it may cause metabolic disorders by inhibiting the fibrinolytic system, which plays an important role in determining blood clots, a hallmark of diabetes.
背景:谷氨酸是一种主要的神经递质, 尽管它在非神经元器官中引起细胞毒性和炎症。本研究旨在探讨与2型糖尿病发病相关的谷氨酸在肝脏中诱导的代谢紊乱。 方法:对韩国基于社区的Ansan-Ansung队列研究数据进行分析, 并利用体外和小鼠模型进行功能研究。 结果:与谷氨酸水平相对较低组(T1)相比, 高谷氨酸水平组(T2, T3)8年后糖尿病发病风险显著增加。谷氨酸对糖尿病发病影响的体外研究显示, 谷氨酸通过增加人肝细胞SK-Hep-1中葡萄糖相关蛋白78 (GRP78)和磷酸烯醇式丙酮酸羧激酶(PEPCK)的表达诱导胰岛素抵抗。此外, 三个不同的基因FRMB4B, PLG和PARD3, 通过全基因组关联研究被鉴定出与谷氨酸显著相关。在与谷氨酸相关的基因中, 纤溶酶原(PLG)水平在几种诱导胰岛素抵抗的环境中显著升高, 并且调节谷氨酸。谷氨酸诱导的肝细胞PLG增加是由代谢型谷氨酸受体5激活引起的, 细胞外分泌后PLG水平也上调。此外,谷氨酸还增加纤溶酶原激活物抑制剂-1 (PAI-1)的表达。因此, 细胞外分泌的PLG不能被升高的PAI-1转化为纤溶酶。.

The COBLL1 gene is associated with leptin, a hormone important for appetite and weight maintenance. Dietary fat is a significant factor in obesity. This study aimed to determine the association between COBLL1 gene, dietary fat, and incidence of obesity. Data from the Korean Genome and Epidemiology Study were used, and 3055 Korean adults aged ≥ 40 years were included. Obesity was defined as a body mass index ≥ 25 kg/m2. Patients with obesity at baseline were excluded. The effects of the COBLL1 rs6717858 genotypes and dietary fat on incidence of obesity were evaluated using multivariable Cox proportional hazard models. During an average follow-up period of 9.2 years, 627 obesity cases were documented. In men, the hazard ratio (HR) for obesity was higher in CT, CC carriers (minor allele carriers) in the highest tertile of dietary fat intake than for men with TT carriers in the lowest tertile of dietary fat intake (Model 1: HR: 1.66, 95% confidence interval [CI]: 1.07-2.58; Model 2: HR: 1.63, 95% CI: 1.04-2.56). In women, the HR for obesity was higher in TT carriers in the highest tertile of dietary fat intake than for women with TT carriers in the lowest tertile of dietary fat intake (Model 1: HR: 1.49, 95% CI: 1.08-2.06; Model 2: HR: 1.53, 95% CI: 1.10-2.13). COBLL1 genetic variants and dietary fat intake had different sex-dependent effects in obesity. These results imply that a low-fat diet may protect against the effects of COBLL1 genetic variants on future obesity risk.

BACKGROUND: Sarcopenia is commonly found in the elderly due to a decline in muscle mass. Many researchers have performed genome-wide association studies (GWAS) to find genetic risk factors of sarcopenia. Although many studies have discovered sarcopenia associated single nucleotide polymorphisms (SNPs), most of them are studies targeting Caucasians. The purpose of this study was to evaluate genetic correlation according to muscle mass in middle aged Koreans using data of the Korean Genome and Epidemiology Study (KOGES), a large population-based genomic cohort study.
METHODS: Baseline participants were 10,030 subjects aged 40 to 69 years who were from Ansan or Anseong in Gyeonggi-do, South Korea. Among them, 9,351 subjects with laboratory data available were included in this study. To identify sarcopenia associated variants, those in the top 30% and bottom 30% of muscle mass index (MMI) were compared. A total of 7,452 people with an MMI of 30-70% were excluded. A total of 1,004 people were also excluded due to missing data. Finally, 895 people were selected for this study. The Korea Biobank Array generated 500,568 SNPs for this dataset.
RESULTS: When subjects were divided into top 30% and bottom 30% of MMI, the top 30% had 169 men and 308 women and the bottom 30% had 220 men and 198 women. In men, age, body mass index (BMI), waist and hip were significantly (P < 0.005) different between top 30% and bottom 30% MMI groups. In women, age, BMI, waist, hip, and hypertension history were significantly different between the two MMI groups. There were 13 significant SNPs in men and 14 significant SNPs in women. Genes associated with variants in men based on the single-nucleotide polymorphism database (dbSNP) were LRP1B containing rs11679458 and RGS6 containing rs11848300. A gene associated with variants in women was Pi4K2A, which contained rs1189312 as a variant. In addition, rs11189312 was associated with expression quantitative trait loci (eQTL) of ZFYVE27 in skeletal muscles and other SNPs of ZFYVE27 (rs10882883, rs17108378, rs35077384) known to be associated with spastic paraplegia. The eQTL analysis revealed that rs11189312 was a variant associated with SNPs of ZFYVE27.
CONCLUSIONS: In the demographic study, significant results were found in BMI, waist, hip, history of hyperlipidemia, and sedentary life status in male group, and significant results were found in BMI, waist, hip, and hypertension history in female group. Variant rs11189312 was found to be a novel variant affecting ZFYVE27 expressed in skeletal muscles, suggesting that rs11189312 might be related to sarcopenia as a novel discovery of this study. Further study is needed to determine the association between sarcopenia and ZFYVE27 known to be associated with spastic paraplegia.

UNASSIGNED: Despite accumulating evidence on the benefits of dietary fiber in the general population, there is a lack of representative data on mortality in patients with chronic kidney disease (CKD). This study examined the role of dietary fiber intake on all-cause and cardiovascular mortality in patients with CKD using representative Korean cohort data.
UNASSIGNED: The study included 3,892 participants with estimated glomerular filtration rates <60 mL/min/1.73 m2 from the Korean Genome and Epidemiology Study. Mortality status was followed by data linkage with national data sources. Nutritional status was assessed using a validated food frequency questionnaire. Dietary fiber was categorized into quintiles (Q). A multivariable Cox proportional hazards regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cardiovascular mortality.
UNASSIGNED: The average daily fiber intake of patients with CKD was 5.1 g/day. During the 10.1-year follow-up period, 602 (149 cardiovascular) deaths were documented. The HR (95% CI) for all-cause mortality in the highest quintile compared with that in the lowest quintile was 0.63 (0.46-0.87) after adjusting for age, sex, BMI, smoking, alcohol intake, exercise, total calorie intake, hypertension, diabetes, and dyslipidemia (P = 0.005). The HR (95% CI) for cardiovascular mortality in the highest quintile compared with that in the lowest quintile was 0.56 (0.29-1.08) after adjusting for same confounders (P = 0.082).
UNASSIGNED: In conclusion, we observed an inverse association between dietary fiber intake and all-cause mortality in CKD patients. Small increments in fiber intake reduced the risk of all-cause mortality by 37%. This finding highlights the need for inexpensive but important dietary modification strategies for encouraging fiber intake in the Korean CKD population.