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Background@#Genome-wide association studies (GWAS) on type 2 diabetes mellitus (T2DM) have identified more than 400 distinct genetic loci associated with diabetes and nearly 120 loci for fasting plasma glucose (FPG) and fasting insulin level to date. However, genetic risk factors for the longitudinal deterioration of FPG have not been thoroughly evaluated. We aimed to identify genetic variants associated with longitudinal change of FPG over time. @*Methods@#We used two prospective cohorts in Korean population, which included a total of 10,528 individuals without T2DM. GWAS of repeated measure of FPG using linear mixed model was performed to investigate the interaction of genetic variants and time, and meta-analysis was conducted. Genome-wide complex trait analysis was used for heritability calculation. In addition, expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression project. @*Results@#A small portion (4%) of the genome-wide single nucleotide polymorphism (SNP) interaction with time explained the total phenotypic variance of longitudinal change in FPG. A total of four known genetic variants of FPG were associated with repeated measure of FPG levels. One SNP (rs11187850) showed a genome-wide significant association for genetic interaction with time. The variant is an eQTL for NOC3 like DNA replication regulator (NOC3L) gene in pancreas and adipose tissue. Furthermore, NOC3L is also differentially expressed in pancreatic β-cells between subjects with or without T2DM. However, this variant was not associated with increased risk of T2DM nor elevated FPG level. @*Conclusion@#We identified rs11187850, which is an eQTL of NOC3L, to be associated with longitudinal change of FPG in Korean population.
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Background@#Nonsteroidal anti-inflammatory drugs (NSAID) are currently among the most prescribed medications worldwide to relieve pain and reduce inflammation, especially in patients suffering osteoarthritis (OA). However, NSAIDs are known to have adverse effects on the gastrointestinal system. If a gastric ulcer occurs, planned OA treatment needs to be changed, incurring additional treatment costs and causing discomfort for both patients and clinicians. Therefore, it is necessary to create a gastric ulcer prediction model that can reflect the detailed health status of each individual and to use it when making treatment plans. @*Methods@#Using sample cohort data from 2008 to 2013 from the National Health Insurance Service in South Korea, we developed a prediction model for NSAID-induced gastric ulcers using machine-learning algorithms and investigated new risk factors associated with medication and comorbidities. @*Results@#The population of the study consisted of 30,808 patients with OA who were treated with NSAIDs between 2008 and 2013. After a 2-year follow-up, these patients were divided into two groups: without gastric ulcer (n=29,579) and with gastric ulcer (n=1,229). Five machine-learning algorithms were used to develop the prediction model, and a gradient boosting machine (GBM) was selected as the model with the best performance (area under the curve, 0.896; 95% confidence interval, 0.883–0.909). The GBM identified 5 medications (loxoprofen, aceclofenac, talniflumate, meloxicam, and dexibuprofen) and 2 comorbidities (acute upper respiratory tract infection [AURI] and gastroesophageal reflux disease) as important features. AURI did not have a dose-response relationship, so it could not be interpreted as a significant risk factor even though it was initially detected as an important feature and improved the prediction performance. @*Conclusions@#We obtained a prediction model for NSAID-induced gastric ulcers using the GBM method. Since personal prescription period and the severity of comorbidities were considered numerically, individual patients’ risk could be well reflected. The prediction model showed high performance and interpretability, so it is meaningful to both clinicians and NSAID users.
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Background@#As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. @*Results@#In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. @*Conclusions@#This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.
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Asthma is a heterogeneous disease whose development is shaped by a variety of environmental and genetic factors. While several recent studies suggest that microbial dysbiosis in the gut may promote asthma, little is known about the relationship between the recently discovered lung microbiome and asthma. Innate lymphoid cells (ILCs) have also been shown recently to participate in asthma. To investigate the relationship between the lung microbiome, ILCs, and asthma, we recruited 23 healthy controls (HC), 42 patients with non-severe asthma, and 32 patients with severe asthma. Flow cytometry analysis showed severe asthma associated with fewer natural cytotoxicity receptor (NCR) + ILC3s in the lung.Similar changes in other ILC subsets, macrophages, and monocytes were not observed. The asthma patients did not differ from the HC in terms of the alpha and beta-diversity of the lung and gut microbiomes. However, lung function correlated positively with both NCR + ILC3 frequencies and microbial diversity in the lung. Sputum NCR + ILC3 frequencies correlated positively with lung microbiome diversity in the HC, but this relationship was inversed in severe asthma. Together, these data suggest that airway NCR + ILC3s may contribute to a healthy commensal diversity and normal lung function.
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Background@#Epidemiological data have shown that vitamin D deficiency is highly prevalent in Korea. Genetic factors influencing vitamin D deficiency in humans have been studied in Europe but are less known in East Asian countries, including Korea. We aimed to investigate the genetic factors related to vitamin D levels in Korean people using a genome-wide association study (GWAS). @*Methods@#We included 12,642 subjects from three different genetic cohorts consisting of Korean participants. The GWAS was performed on 7,590 individuals using linear or logistic regression meta- and mega-analyses. After identifying significant single nucleotide polymorphisms (SNPs), we calculated heritability and performed replication and rare variant analyses. In addition, expression quantitative trait locus (eQTL) analysis for significant SNPs was performed. @*Results@#rs12803256, in the actin epsilon 1, pseudogene (ACTE1P) gene, was identified as a novel polymorphism associated with vitamin D deficiency. SNPs, such as rs11723621 and rs7041, in the group-specific component gene (GC) and rs11023332 in the phosphodiesterase 3B (PDE3B) gene were significantly associated with vitamin D deficiency in both meta- and mega-analyses. The SNP heritability of the vitamin D concentration was estimated to be 7.23%. eQTL analysis for rs12803256 for the genes related to vitamin D metabolism, including glutamine-dependent NAD(+) synthetase (NADSYN1) and 7-dehydrocholesterol reductase (DHCR7), showed significantly different expression according to alleles. @*Conclusion@#The genetic factors underlying vitamin D deficiency in Korea included polymorphisms in the GC, PDE3B, NADSYN1, and ACTE1P genes. The biological mechanism of a non-coding SNP (rs12803256) for DHCR7/NADSYN1 on vitamin D concentrations is unclear, warranting further investigations.
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Purpose@#The management of patients with colorectal cancer (CRC) who have liver cirrhosis (LC) requires a thorough understanding of both diseases; however, the prognoses and postoperative outcomes of such patients remain understudied. We investigated the effect of LC on surgical and oncologic outcomes in patients with CRC, and identified prognostic factors. @*Methods@#We analyzed 453 patients with CRC and LC (CRC-LC group), 906 with CRC only (CRC group), 906 with LC only (LC group), and 1,812 healthy subjects using health insurance claim data (2008–2013). @*Results@#The CRC-LC group had a higher frequency of intensive care unit admission than the CRC group; there were no differences between the 2 groups in terms of early and late postoperative small bowel obstruction and incisional hernia. However, the 30-day, 60-day, and 90-day mortality rates were all significantly higher in the CRC-LC group. The higher Charlson comorbidity index (hazard ratio [HR], 1.127) and the lower socioeconomic status (HR, 0.985) were significant worse predictors of 5-year survival. Patients with underlying LC had a significantly higher HR in both the advanced CRC (HR, 1.858) and nonadvanced CRC (HR, 1.799) subgroups. However, the nonadvanced CRC subgroup showed a lower HR than the LC group (HR, 0.730). @*Conclusion@#Patients with CRC who had underlying LC had a lower survival rate than did those without LC, although the incidence rates of postoperative complications were not significantly different. The presence of LC was associated with a significantly lower survival rate regardless of CRC presence.
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Purpose@#The management of patients with colorectal cancer (CRC) who have liver cirrhosis (LC) requires a thorough understanding of both diseases; however, the prognoses and postoperative outcomes of such patients remain understudied. We investigated the effect of LC on surgical and oncologic outcomes in patients with CRC, and identified prognostic factors. @*Methods@#We analyzed 453 patients with CRC and LC (CRC-LC group), 906 with CRC only (CRC group), 906 with LC only (LC group), and 1,812 healthy subjects using health insurance claim data (2008–2013). @*Results@#The CRC-LC group had a higher frequency of intensive care unit admission than the CRC group; there were no differences between the 2 groups in terms of early and late postoperative small bowel obstruction and incisional hernia. However, the 30-day, 60-day, and 90-day mortality rates were all significantly higher in the CRC-LC group. The higher Charlson comorbidity index (hazard ratio [HR], 1.127) and the lower socioeconomic status (HR, 0.985) were significant worse predictors of 5-year survival. Patients with underlying LC had a significantly higher HR in both the advanced CRC (HR, 1.858) and nonadvanced CRC (HR, 1.799) subgroups. However, the nonadvanced CRC subgroup showed a lower HR than the LC group (HR, 0.730). @*Conclusion@#Patients with CRC who had underlying LC had a lower survival rate than did those without LC, although the incidence rates of postoperative complications were not significantly different. The presence of LC was associated with a significantly lower survival rate regardless of CRC presence.
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Background/Aims@#The survival rate of gastric cancer (GC) is known to be higher in patients with a family history (FH) of GC. There is an association between a polymorphism in the transforming growth factor-β1 (
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BACKGROUND: This study aimed to estimate the nationwide prevalence of live births with Down syndrome (DS) and its trends and compare the observed and model-based predicted prevalence rates. Further, we compared the direct medical expenditures among DS and non-DS patients. METHODS: Using the health administrative data of Health Insurance Review and Assessment in Korea, we selected 2,301 children with DS who were born between 2007 and 2016 to estimate the prevalence of live births with DS, and 12,265 non-DS children who were born between 2010 and 2014 to compare the direct medical expenditures among patients. RESULTS: The prevalence of live births with DS was 5.03 per 10,000 births in 9 years, and 13% of children with DS were medical aid recipients during the study period. The medical expenditure of children with DS was about 10-fold higher than that of non-DS children and their out-of-pocket expenditure was about twice as high. CONCLUSION: The prevalence of live birth with DS is high in the low socioeconomic group and the healthcare costs for the children with DS are significantly higher than those for non-DS children. Therefore, health authorities should help mothers at lower socioeconomic levels to receive adequate antenatal care and consider the cost of medical care for children with DS.
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Child , Humans , Down Syndrome , Health Care Costs , Health Expenditures , Insurance, Health , Korea , Live Birth , Mothers , Parturition , PrevalenceABSTRACT
OBJECTIVE: The mGluR1 (metabotropic glutamate receptor 1) gene, a G protein–coupled receptor, is known to mediate perceptions of umami tastes. Genetic variation in taste receptors may influence dietary intake, and in turn have an impact on nutritional status and risk of chronic disease. We investigated the association of mGluR1 rs2814863 polymorphism with lipid profiles and cardiovascular disease (CVD) risk, together with their modulation by macronutrient intake in Korean adults. METHODS: The subjects consisted of 8,380 Koreans aged 40-69 years participating in the Anseong and Ansan Cohort Study, which was a part of the Korean Genome Epidemiology Study (KoGES). Data was collected using self-administered questionnaires, anthropometric measurements, and blood chemical analysis. RESULTS: Carriers of C allele at mGluR1 rs2814863 was associated with decreased high density lipoprotein cholesterol (HDL-C) and increased triglyceride as compared to carriers of TT. Also, carriers of the C allele showed higher fat intake and lower carbohydrate intake than those with carriers of TT. After adjustment for multiple testing using false-discovery rate method, the significant difference of HDL-C, triglyceride, dietary fat, and carbohydrate across genotypes disappeared. Gene-diet interaction effects between rs2814863 and macronutrients intake were not significantly associated with HDL-C and triglyceride levels. However, carriers of C allele demonstrated significantly higher odds of CVD {odds ratio=1.13, 95% CI=1.02-1.25} compared with carriers of TT. CONCLUSIONS: Our findings support significant associations between the mGluR1 rs2814863 genotype and CVD-related variables in Korean adults. However, these associations are not modified by macronutrient intake.
Subject(s)
Adult , Humans , Alleles , Blood Chemical Analysis , Cardiovascular Diseases , Cholesterol, HDL , Chronic Disease , Cohort Studies , Dietary Fats , Epidemiology , Genes, vif , Genetic Variation , Genome , Genotype , Methods , Nutritional Status , Polymorphism, Single Nucleotide , Receptors, Glutamate , Receptors, Metabotropic Glutamate , TriglyceridesABSTRACT
BACKGROUND: External quality assessment (EQA) uses a standard deviation index (SDI), based on a peer group, to evaluate laboratory performance. However, evaluations using peer group SDIs often have limited applicability, because they are not statistically valid unless the number of institutions in the same peer group is large. The present study proposes a statistical model for simultaneously evaluating the performance of all participating institutions, as well as the performance of instruments on the market. METHODS: By assuming that proficiency test results were affected by the manufacturer, the instrument, and the institution, the effects of those factors were estimated using a linear mixed model. We used these effect estimates to calculate manufacturer, instrument, and institution SDIs. Using simulation, we evaluated the false positive rates and efficiencies of the proposed linear mixed model. RESULTS: Simulations showed that the linear mixed model empirical type I error rates preserved the nominal significance level. This model was also more statistically efficient than the peer group SDI. Rates of unacceptability were lower when using institution SDI than they were when using peer group SDI. Additional outliers that could not be evaluated using the current system were detected by the institution SDI statistic. The instrument SDI statistic detected outliers among different instrument groups. CONCLUSIONS: Institution and instrument SDIs are robust and efficient tools for EQA, and they can replace the currently used system of peer group SDI.
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Laboratory Proficiency Testing , Models, Statistical , Peer GroupABSTRACT
Over the past decade, the detection of gene-gene interactions has become more and more popular in the field of genome-wide association studies (GWASs). The goal of the GWAS is to identify genetic susceptibility to complex diseases by assaying and analyzing hundreds of thousands of single-nucleotide polymorphisms. However, such tests are computationally demanding and methodologically challenging. Recently, a simple but powerful method, named “BOolean Operation-based Screening and Testing” (BOOST), was proposed for genome-wide gene-gene interaction analyses. BOOST was designed with a Boolean representation of genotype data and is approximately equivalent to the log-linear model. It is extremely fast, and genome-wide gene-gene interaction analyses can be completed within a few hours. However, BOOST can not adjust for covariate effects, and its type-1 error control is not correct. Thus, we considered two-step approaches for gene-gene interaction analyses. First, we selected gene-gene interactions with BOOST and applied logistic regression with covariate adjustments to select gene-gene interactions. We applied the two-step approach to type 2 diabetes (T2D) in the Korea Association Resource (KARE) cohort and identified some promising pairs of single-nucleotide polymorphisms associated with T2D.
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Cohort Studies , Diabetes Mellitus, Type 2 , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Korea , Linear Models , Logistic Models , Mass Screening , MethodsABSTRACT
PURPOSE: Lynch syndrome, the commonest hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair (MMR) genes. Three recently developed prediction models for MMR gene mutations based on family history and clinical features (MMRPredict, PREMM1,2,6, and MMRPro) have been validated only in Western countries. In this study, we propose validating these prediction models in the Korean population. MATERIALS AND METHODS: We collected MMR gene analysis data from 188 individuals in the Korean Hereditary Tumor Registry. The probability of gene mutation was calculated using three prediction models, and the overall diagnostic value of each model compared using receiver operator characteristic (ROC) curves and area under the ROC curve (AUC). Quantitative test characteristics were calculated at sensitivities of 90%, 95%, and 98%. RESULTS: Of the individuals analyzed, 101 satisfied Amsterdam criteria II, and 87 were suspected hereditary nonpolyposis colorectal cancer. MMR mutations were identified in 62 of the 188 subjects (33.0%). All three prediction models showed a poor predictive value of AUC (MMRPredict, 0.683; PREMM1,2,6, 0.709; MMRPro, 0.590). Within the range of acceptable sensitivity (> 90%), PREMM1,2,6 demonstrated higher specificity than the other models. CONCLUSION: In the Korean population, overall predictive values of the three models (MMRPredict, PREMM1,2,6, MMRPro) for MMR gene mutations are poor, compared with their performance in Western populations. A new prediction model is therefore required for the Korean population to detect MMR mutation carriers, reflecting ethnic differences in genotype-phenotype associations.
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Humans , Area Under Curve , Colorectal Neoplasms , Colorectal Neoplasms, Hereditary Nonpolyposis , DNA Mismatch Repair , Genetic Association Studies , Genetic Testing , Germ-Line Mutation , ROC Curve , Sensitivity and SpecificityABSTRACT
PURPOSE: Multiple genetic factors are associated with chronic obstructive pulmonary disease (COPD). The association of gene encoding vitamin D binding protein (VDBP, GC) with COPD has been controversial. We sought to investigate the types of GC variants in the Korean population and determine the association of GC variants with COPD and lung function in the Korean population. MATERIALS AND METHODS: The study cohort consisted of 203 COPD patients and 157 control subjects. GC variants were genotyped by the restriction fragment-length polymorphism method. Repeated measures of lung function data were analyzed using a linear mixed model including sex, age, height, and pack-years of smoking to investigate the association of GC genetic factors and lung function. RESULTS: GC1F variant was most frequently observed in COPD (46.1%) and controls (42.0%). GC1S variant (29.0% vs. 21.4%; p=0.020) and genotype 1S-1S (8.3% vs. 3.4%; p=0.047) were more commonly detected in control than COPD. According to linear mixed model analysis including controls and COPD, subjects with genotype 1S-1S had 0.427 L higher forced expiratory volume in 1 second (FEV1) than those with other genotypes (p=0.029). However, interaction between the genotype and smoking pack-year was found to be particularly significant among subjects with genotype 1S-1S; FEV1 decreased by 0.014 L per smoking pack-year (p=0.001). CONCLUSION: This study suggested that GC polymorphism might be associated with lung function and risk of COPD in Korean population. GC1S variant and genotype 1S-1S were more frequently observed in control than in COPD. Moreover, GC1S variant was more common in non-decliners than in rapid decliners among COPD.