Associations between plasma metabolites and heavy metal exposure in residents of environmentally polluted areas.

Heavy metals are commonly released into the environment through industrial processes such as mining and refining. The rapid industrialization that occurred in South Korea during the 1960s and 1970s contributed significantly to the economy of the country; however, the associated mining and refining led to considerable environmental pollution, and although mining is now in decline in South Korea, the detrimental effects on residents inhabiting the surrounding areas remain. The bioaccumulation of toxic heavy metals leads to metabolic alterations in human homeostasis, with disruptions in this balance leading to various health issues. This study used metabolomics to explore metabolomic alterations in the plasma samples of residents living in mining and refining areas. The results showed significant increases in metabolites involved in glycolysis and the surrounding metabolic pathways, such as glucose-6-phosphate, phosphoenolpyruvate, lactate, and inosine monophosphate, in those inhabiting polluted areas. An investigation of the associations between metabolites and blood clinical parameters through meet-in-the-middle analysis indicated that female residents were more affected by heavy metal exposure, resulting in more metabolomic alterations. For women, inhabiting the abandoned mine area, metabolites in the glycolysis and pentose phosphate pathways, such as ribose-5-phosphate and 3-phosphoglycerate, have shown a negative correlation with albumin and calcium. Finally, Mendelian randomization(MR) was used to determine the causal effects of these heavy metal exposure-related metabolites on heavy metal exposure-related clinical parameters. Metabolite biomarkers could provide insights into altered metabolic pathways related to exposure to toxic heavy metals and improve our understanding of the molecular mechanisms underlying the health effects of toxic heavy metal exposure.

Genome-wide association study implicates the role of TBXAS1 in the pathogenesis of depressive symptoms among the Korean population.

Although depression is an emerging disorder affecting many people worldwide, most genetic studies have been performed in European descent populations. Herein, a genome-wide association study (GWAS) was conducted in Korean population to elucidate the genomic loci associated with depressive symptoms. Two independent cohorts were used as discovery datasets, which consisted of 6474 (1484 cases and 4990 controls) and 1654 (557 cases and 1097 controls) Korean participants, respectively. The participants were divided into case and control groups based on the Beck Depression Inventory (BDI). Meta-analysis using the two cohorts revealed that rs6945590 was significantly associated with the risk of depressive symptoms [P = 2.83 × 10-8; odds ratio (OR) = 1.23; 95% confidence interval (CI): 1.15-1.33]. This association was validated in other independent cohorts which were another Korean cohort (258 cases and 1757 controls) and the East Asian study of the Psychiatric Genomics Consortium (PGC) (12,455 cases and 85,548 controls). The predicted expression levels of thromboxane A synthase 1 gene (TBXAS1), which encodes the enzyme thromboxane A synthase 1 and participates in the arachidonic acid (AA) cascade, was significantly decreased in the whole blood tissues of the participants with depressive symptoms. Furthermore, Mendelian randomization (MR) analysis showed a causal association between TBXAS1 expression and the risk of depressive symptoms. In conclusion, as the number of risk alleles (A) of rs6945590 increased, TBXAS1 expression decreased, which subsequently caused an increase in the risk of depressive symptoms.

Heritability of cognitive abilities and regional brain structures in middle-aged to elderly East Asians.

This study examined the single-nucleotide polymorphism heritability and genetic correlations of cognitive abilities and brain structural measures (regional subcortical volume and cortical thickness) in middle-aged and elderly East Asians (Korean) from the Gwangju Alzheimer's and Related Dementias cohort study. Significant heritability was found in memory function, caudate volume, thickness of the entorhinal cortices, pars opercularis, superior frontal gyri, and transverse temporal gyri. There were 3 significant genetic correlations between (i) the caudate volume and the thickness of the entorhinal cortices, (ii) the thickness of the superior frontal gyri and pars opercularis, and (iii) the thickness of the superior frontal and transverse temporal gyri. This is the first study to describe the heritability and genetic correlations of cognitive and neuroanatomical traits in middle-aged to elderly East Asians. Our results support the previous findings showing that genetic factors play a substantial role in the cognitive and neuroanatomical traits in middle to advanced age. Moreover, by demonstrating shared genetic effects on different brain regions, it gives us a genetic insight into understanding cognitive and brain changes with age, such as aging-related cognitive decline, cortical atrophy, and neural compensation.

Identification of genetic variants associated with diabetic kidney disease in multiple Korean cohorts via a genome-wide association study mega-analysis.

BACKGROUND: The pathogenesis of diabetic kidney disease (DKD) is complex, involving metabolic and hemodynamic factors. Although DKD has been established as a heritable disorder and several genetic studies have been conducted, the identification of unique genetic variants for DKD is limited by its multiplex classification based on the phenotypes of diabetes mellitus (DM) and chronic kidney disease (CKD). Thus, we aimed to identify the genetic variants related to DKD that differentiate it from type 2 DM and CKD. METHODS: We conducted a large-scale genome-wide association study mega-analysis, combining Korean multi-cohorts using multinomial logistic regression. A total of 33,879 patients were classified into four groups-normal, DM without CKD, CKD without DM, and DKD-and were further analyzed to identify novel single-nucleotide polymorphisms (SNPs) associated with DKD. Additionally, fine-mapping analysis was conducted to investigate whether the variants of interest contribute to a trait. Conditional analyses adjusting for the effect of type 1 DM (T1D)-associated HLA variants were also performed to remove confounding factors of genetic association with T1D. Moreover, analysis of expression quantitative trait loci (eQTL) was performed using the Genotype-Tissue Expression project. Differentially expressed genes (DEGs) were analyzed using the Gene Expression Omnibus database (GSE30529). The significant eQTL DEGs were used to explore the predicted interaction networks using search tools for the retrieval of interacting genes and proteins. RESULTS: We identified three novel SNPs [rs3128852 (P = 8.21×10-25), rs117744700 (P = 8.28×10-10), and rs28366355 (P = 2.04×10-8)] associated with DKD. Moreover, the fine-mapping study validated the causal relationship between rs3128852 and DKD. rs3128852 is an eQTL for TRIM27 in whole blood tissues and HLA-A in adipose-subcutaneous tissues. rs28366355 is an eQTL for HLA-group genes present in most tissues. CONCLUSIONS: We successfully identified SNPs (rs3128852, rs117744700, and rs28366355) associated with DKD and verified the causal association between rs3128852 and DKD. According to the in silico analysis, TRIM27 and HLA-A can define DKD pathophysiology and are associated with immune response and autophagy. However, further research is necessary to understand the mechanism of immunity and autophagy in the pathophysiology of DKD and to prevent and treat DKD.

A genome-wide association study implicates the pleiotropic effect of NMUR2 on asthma and COPD.

Asthma and chronic obstructive pulmonary disease (COPD) are two distinct diseases that are associated with chronic inflammation. They share common features in terms of their advanced stages and genetic factors. This study aimed to identify novel genes underlying both asthma and COPD using genome-wide association study (GWAS) to differentiate between the two diseases. We performed a GWAS of asthma and COPD in 7828 Koreans from three hospitals. In addition, we investigated genetic correlations. The UK Biobank dataset was used for the replication studies. We found that rs2961757, located near neuromedin U receptor 2 (NMUR2) on chromosome 5, was genome-wide significant ([Formula: see text] = 0.44, P-valueAsthma-COPD = 3.41 × 10-8), and significant results were replicated with the UK Biobank data ([Formula: see text] = 0.04, P-valueAsthma-COPD = 0.0431). A positive genetic correlation was observed between asthma and COPD (39.8% in the Korean dataset and 49.8% in the UK Biobank dataset). In this study, 40-45% of the genetic effects were common to asthma and COPD. Moreover, NMUR2 increases the risk of asthma development and suppresses COPD development. This indicates that NMUR2 allows for better differentiation of both diseases, which can facilitate tailored medical therapy.

Genome-Wide Association Study of Airway Wall Thickening in a Korean Chronic Obstructive Pulmonary Disease Cohort.

Airway wall thickening (AWT) plays an important pathophysiological role in airway diseases such as chronic obstructive pulmonary disease (COPD). There are only a few studies on the genetic components contributing to AWT in the Korean population. This study aimed to identify AWT-related single-nucleotide polymorphisms (SNPs) using a genome-wide association study (GWAS). We performed GWAS for AWT using the CODA and KUCOPD cohorts. Thereafter, a meta-analysis was performed. Airway wall thickness was measured using automatic segmentation software. The AWT at an internal perimeter of 10 mm (AWT-Pi10) was calculated by the square root of the theoretical airway wall area using the full-width-half-maximum method. We identified a significant SNP (rs11648772, p = 1.41 × 10-8) located in LINC02127, near SALL1. This gene is involved in the inhibition of epithelial-mesenchymal transition in glial cells, and it affects bronchial wall depression in COPD patients. Additionally, we identified other SNPs (rs11970854, p = 1.92 × 10-6; rs16920168, p = 5.29 × 10-6) involved in airway inflammation and proliferation and found that AWT is influenced by these genetic variants. Our study helps identify the genetic cause of COPD in an Asian population and provides a potential basis for treatment.

Unveiling genetic variants for age-related sarcopenia by conducting a genome-wide association study on Korean cohorts.

Sarcopenia is an age-related disorder characterised by a progressive decrease in skeletal muscle mass. As the genetic biomarkers for sarcopenia are not yet well characterised, this study aimed to investigate the genetic variations related to sarcopenia in a relatively aged cohort, using genome-wide association study (GWAS) meta-analyses of lean body mass (LBM) in 6961 subjects. Two Korean cohorts were analysed, and subgroup GWAS was conducted for appendicular skeletal muscle mass (ASM) and skeletal muscle index. The effects of significant single nucleotide polymorphisms (SNPs) on gene expression were also investigated using multiple expression quantitative trait loci datasets, differentially expressed gene analysis, and gene ontology analyses. Novel genetic biomarkers were identified for LBM (rs1187118; rs3768582) and ASM (rs6772958). Their related genes, including RPS10, NUDT3, NCF2, SMG7, and ARPC5, were differently expressed in skeletal muscle tissue, while GPD1L was not. Furthermore, the 'mRNA destabilisation' biological process was enriched for sarcopenia. Our study identified RPS10, NUDT3, and GPD1L as significant genetic biomarkers for sarcopenia. These genetic loci were related to lipid and energy metabolism, suggesting that genes involved in metabolic dysregulation may lead to the pathogenesis of age-related sarcopenia.

Unveiling Genetic Variants Underlying Vitamin D Deficiency in Multiple Korean Cohorts by a Genome-Wide Association Study.

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.

A missense variant in SHARPIN mediates Alzheimer's disease-specific brain damages.

Established genetic risk factors for Alzheimer's disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10-9) and hippocampal volume (p = 5.1 × 10-12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-ß accumulation (p = 0.03) and measures of memory (p = 1.0 × 10-4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer's Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10-6) and AddNeuroMed (rs138412600, p = 5.9 × 10-5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.

Genome-Wide Association Study of Korean Asthmatics: A Comparison With UK Asthmatics.

PURPOSE: Although genome-wide association studies (GWASs) represent the most powerful approach for identifying genes that influence asthma, to date, no studies have established genetic susceptibility to asthma in the Korean population. This study aimed to identify genetic variants associated with adult Korean asthmatics and compare them with the significant single nucleotide polymorphisms (SNPs) of UK asthmatics from the UK Biobank. METHODS: Patients were defined as having asthma if they were diagnosed by a doctor or taking medications for asthma. Controls were defined as individuals without asthma or chronic obstructive pulmonary disease. We performed quality control, genotype imputation, GWAS, and PrediXcan analyses. In the GWAS, a P value of < 5 × 10-8 was considered significant. We compared significant SNPs between Korean and UK patients with asthma. RESULTS: A total of 1,386 asthmatic patients and 5,205 controls were analyzed. The SNP rs1770, located near the human leukocyte antigen (HLA)-DQB1, was the most significant SNP (P = 4.5 × 10-10). In comparison with 24 SNPs in a GWAS of UK asthmatics, six SNPs were significant with the same odds ratio (OR) direction, including signals related to type 2 inflammation (e.g., IL1RL1, TSLP, and GATA3) and mucus plugging (e.g., MUC5AC). HLA-DQA1 showed an opposite OR direction. The HLA-DQB1 gene demonstrated significantly imputed mRNA expression in the lung tissue and whole blood. CONCLUSIONS: The SNP rs1770 of HLA-DQB1 was the most significant in Korean asthmatics. Similarities and discrepancies were found in the genetic variants between Korean and UK asthmatics. GWAS of Korean asthmatics should be replicated and compared with those of GWAS of other ethnicities.

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. FUNDING: US National Institutes of Health, Wellcome Trust.

Antiobesity Effects of Short-Chain Chitosan in Diet-Induced Obese Mice.

Dietary chitosan is known for its antiobesity effects by combining with bile acid and lipid droplets. When the chitosan structure is broken into short chains, the fat-binding capacity increases. The aim of this study was to compare long-chain chitosan (LC) with short-chain chitosan (SC) for their antiobesity effects in high-fat diet (HFD)-induced obese C57BL/6J mice for 12 weeks. The body weights of mice in both chitosan groups were decreased, especially in the SC group compared with the LC group. Total white adipose tissue and visceral fat weights were also decreased in mice of the SC group more than those of the HFD group. Moreover, SC supplementation lowered plasma triglyceride (TG) and cholesterol levels, whereas LC only lowered plasma free fatty acid level. Fecal lipids were increased in mice of both LC and SC groups, and hepatic TG and cholesterol levels were decreased in both groups. SC lowered phosphatidate phosphohydrolase activity and elevated ß-oxidation in the liver. Furthermore, SC decreased the expression of the hepatic lipid-regulating genes, including fatty acid synthase, peroxisome proliferator-activated receptor (PPAR)γ1, and PPARγ2; and increased the expression of carnitine palmitoyl transferase 1α and peroxisome proliferator-activated receptor γ coactivator (PGC)1α genes. In conclusion, we demonstrated that long-term supplementation of SC can ameliorate body weight and lipid levels by increasing lipid excretion and regulating lipid metabolism, including some enzyme activities and gene expression levels, in HFD-induced obese mice.