Innate-like Cytotoxic Function of Bystander-Activated CD8+ T Cells Is Associated with Liver Injury in Acute Hepatitis A.

Acute hepatitis A (AHA) involves severe CD8+ T cell-mediated liver injury. Here we showed during AHA, CD8+ T cells specific to unrelated viruses became activated. Hepatitis A virus (HAV)-infected cells produced IL-15 that induced T cell receptor (TCR)-independent activation of memory CD8+ T cells. TCR-independent activation of non-HAV-specific CD8+ T cells were detected in patients, as indicated by NKG2D upregulation, a marker of TCR-independent T cell activation by IL-15. CD8+ T cells derived from AHA patients exerted innate-like cytotoxicity triggered by activating receptors NKG2D and NKp30 without TCR engagement. We demonstrated that the severity of liver injury in AHA patients correlated with the activation of HAV-unrelated virus-specific CD8+ T cells and the innate-like cytolytic activity of CD8+ T cells, but not the activation of HAV-specific T cells. Thus, host injury in AHA is associated with innate-like cytotoxicity of bystander-activated CD8+ T cells, a result with implications for acute viral diseases.

Incidence of Clostridioides difficile Infections in Republic of Korea: A Prospective Study With Active Surveillance vs. National Data From Health Insurance Review & Assessment Service.

BACKGROUND: Since the emergence of hypervirulent strains of Clostridioides difficile, the incidence of C. difficile infections (CDI) has increased significantly. METHODS: To assess the incidence of CDI in Korea, we conducted a prospective multicentre observational study from October 2020 to October 2021. Additionally, we calculated the incidence of CDI from mass data obtained from the Health Insurance Review and Assessment Service (HIRA) from 2008 to 2020. RESULTS: In the prospective study with active surveillance, 30,212 patients had diarrhoea and 907 patients were diagnosed with CDI over 1,288,571 patient-days and 193,264 admissions in 18 participating hospitals during 3 months of study period; the CDI per 10,000 patient-days was 7.04 and the CDI per 1,000 admission was 4.69. The incidence of CDI was higher in general hospitals than in tertiary hospitals: 6.38 per 10,000 patient-days (range: 3.25-12.05) and 4.18 per 1,000 admissions (range: 1.92-8.59) in 11 tertiary hospitals, vs. 9.45 per 10,000 patient-days (range: 5.68-13.90) and 6.73 per 1,000 admissions (range: 3.18-15.85) in seven general hospitals. With regard to HIRA data, the incidence of CDI in all hospitals has been increasing over the 13-year-period: from 0.3 to 1.8 per 10,000 patient-days, 0.3 to 1.6 per 1,000 admissions, and 6.9 to 56.9 per 100,000 population, respectively. CONCLUSION: The incidence of CDI in Korea has been gradually increasing, and its recent value is as high as that in the United State and Europe. CDI is underestimated, particularly in general hospitals in Korea.

Bayesian network analysis incorporating genetic anchors complements conventional Mendelian randomization approaches for exploratory analysis of causal relationships in complex data.

Mendelian randomization (MR) implemented through instrumental variables analysis is an increasingly popular causal inference tool used in genetic epidemiology. But it can have limitations for evaluating simultaneous causal relationships in complex data sets that include, for example, multiple genetic predictors and multiple potential risk factors associated with the same genetic variant. Here we use real and simulated data to investigate Bayesian network analysis (BN) with the incorporation of directed arcs, representing genetic anchors, as an alternative approach. A Bayesian network describes the conditional dependencies/independencies of variables using a graphical model (a directed acyclic graph) with an accompanying joint probability. In real data, we found BN could be used to infer simultaneous causal relationships that confirmed the individual causal relationships suggested by bi-directional MR, while allowing for the existence of potential horizontal pleiotropy (that would violate MR assumptions). In simulated data, BN with two directional anchors (mimicking genetic instruments) had greater power for a fixed type 1 error than bi-directional MR, while BN with a single directional anchor performed better than or as well as bi-directional MR. Both BN and MR could be adversely affected by violations of their underlying assumptions (such as genetic confounding due to unmeasured horizontal pleiotropy). BN with no directional anchor generated inference that was no better than by chance, emphasizing the importance of directional anchors in BN (as in MR). Under highly pleiotropic simulated scenarios, BN outperformed both MR (and its recent extensions) and two recently-proposed alternative approaches: a multi-SNP mediation intersection-union test (SMUT) and a latent causal variable (LCV) test. We conclude that BN incorporating genetic anchors is a useful complementary method to conventional MR for exploring causal relationships in complex data sets such as those generated from modern "omics" technologies.

Association between CYP2D6 phenotype and recurrence of Plasmodium vivax infection in south Korean patients.

BACKGROUND: Primaquine is activated by CYP2D6 in the hepatocytes. In Korea, primaquine is the only hypnozoitocidal agent used for patients with vivax malaria. Thus, patients with poor CYP2D6 activity could have an increased risk of primaquine failure and subsequent relapse. The study sought to identify the association between CYP2D6 phenotype and recurrence of malaria in Korean patients. METHODS: A total of 102 patients with vivax malaria were prospectively enrolled from eight institutions in Korea. An additional 38 blood samples from patients with recurred vivax malaria were provided by the Korea Disease Control and Prevention Agency. Malaria recurrence was defined as more than one episode of vivax malaria in the same or consecutive years. CYP2D6 star alleles, phenotypes, and activity scores were examined. RESULTS: Genotyping for CYP2D6 was successful in 101 of the prospectively enrolled patients and 38 samples from the Korea Disease Control and Prevention Agency, of which 91 were included in the no-recurrence group and 48 were included in the recurrence group. Reduced CYP2D6 activity (intermediate metabolizer) phenotype was more common in the recurrence group than in the no-recurrence group (OR, 2.33 (95% CI, 1.14-4.77); p = 0.02). Patients with lower CYP2D6 activity had a higher probability of recurrence (p = 0.029). CONCLUSION: This study suggests that CYP2D6 polymorphism may affect primaquine efficacy and thus Plasmodium vivax recurrence in Korea.

Four Times of Relapse of Plasmodium vivax Malaria Despite Primaquine Treatment in a Patient with Impaired Cytochrome P450 2D6 Function.

Plasmodium vivax exhibits dormant liver-stage parasites, called hypnozoites, which can cause relapse of malaria. The only drug currently used for eliminating hypnozoites is primaquine. The antimalarial properties of primaquine are dependent on the production of oxidized metabolites by the cytochrome P450 isoenzyme 2D6 (CYP2D6). Reduced primaquine metabolism may be related to P. vivax relapses. We describe a case of 4 episodes of recurrence of vivax malaria in a patient with decreased CYP2D6 function. The patient was 52-year-old male with body weight of 52 kg. He received total gastrectomy and splenectomy 7 months before the first episode and was under chemotherapy for the gastric cancer. The first episode occurred in March 2019 and each episode had intervals of 34, 41, and 97 days, respectively. At the first and second episodes, primaquine was administered as 15 mg for 14 days. The primaquine dose was increased with 30 mg for 14 days at the third and fourth episodes. Seven gene sequences of P. vivax were analyzed and revealed totally identical for all the 4 samples. The CYP2D6 genotype was analyzed and intermediate metabolizer phenotype with decreased function was identified.

Retrosternal hematoma in sternal fracture for prediction of concomitant injury on chest CT.

BACKGROUND: Isolated sternal fracture, a benign injury, has been increasing in the pan-scan era, although one-third of patients with sternal fracture still has trouble with concomitant injury. The differentiation of these two entities is important to optimize patient management. PURPOSE: To evaluate correlation between retrosternal hematoma and concomitant injury in patients with sternal fracture and to identify predicting factors for concomitant injury in sternal fracture. MATERIAL AND METHODS: A total of 139 patients (84 men; mean age = 54.9 ± 15.3 years) with traumatic sternal fracture were enrolled in this study. We reviewed medical charts and multiplanar computed tomography (CT) images to evaluate cause, location, and degree of sternal fracture, retrosternal hematoma, and concomitant injury. Univariate and multivariate analysis were used to identify variables that were associated with concomitant injury. RESULTS: Concomitant injury on chest CT was observed in 85 patients with sternal fracture. Of the patients, 98 (70.5%) were accompanied by retrosternal hematoma. Multivariate analysis revealed that retrosternal hematoma (odds ratio [OR] = 5.350; P < 0.001), manubrium fracture (OR = 6.848; P = 0.015), and motor vehicle accident (OR = 0.342; P = 0.015) were significantly associated with sternal fracture with concomitant injury. CONCLUSION: Manubrium fracture and retrosternal hematoma portend a high risk of concomitant injury and indicate the need for further clinical and radiologic work-up.

Coronary artery calcium severity grading on non-ECG-gated low-dose chest computed tomography: a multiple-observer study in a nationwide lung cancer screening registry.

OBJECTIVES: To identify the optimal method for evaluation of coronary artery calcium (CAC) severity on non-electrocardiogram-gated low-dose chest computed tomography (LDCT) in a nationwide lung cancer screening registry. METHODS: A total of 256 subjects were retrospectively enrolled from participants of the Korean Lung Cancer Screening (K-LUCAS) project (an LDCT lung cancer screening registry for high-risk individuals). Four board-certified cardiothoracic radiologists independently assessed CAC severity using four different scoring methods (visual assessment, artery-based grading, segment-involvement grading, and segment-based grading) and classified severity for each case using all four methods as none, mild, moderate, or severe. Agreements between the four observers for CAC category classification and between the four different scoring methods for the same observer were assessed by Fleiss kappa statistics. Evaluation time for CAC grading was compared between observers and between grading methods. RESULTS: Interobserver agreement was moderate for visual assessment (Fleiss kappa 0.451) and substantial for the other three methods (Fleiss kappa 0.673-0.704). Agreement between the four grading methods for the same observer was substantial for three observers (Fleiss kappa 0.610-0.705) and moderate for one (Fleiss kappa 0.578). Mean evaluation time differed significantly between methods (visual assessment, 14.3 ± 11.8 s; artery-based grading, 17.6 ± 22.3 s, segment-involvement grading, 19.2 ± 6.8 s; segment-based grading, 34.2 ± 37.4 s; p < 0.01). CONCLUSION: Artery-based grading could be appropriate with substantial interobserver agreement and an acceptable mean evaluation time. KEY POINTS: • CAC severity grading methods on LDCT show moderate to substantial agreements between grading methods and observers. • Artery-based grading could be appropriate with substantial interobserver agreement and a mean evaluation time of 17.6 s. • Visual assessment is disadvantaged by high interobserver variability despite having the shortest evaluation time.

GenoType NTM-DR Performance Evaluation for Identification of Mycobacterium avium Complex and Mycobacterium abscessus and Determination of Clarithromycin and Amikacin Resistance.

We evaluated the GenoType NTM-DR (NTM-DR) line probe assay for identifying Mycobacterium avium complex (MAC) species and Mycobacterium abscessus subspecies and for determining clarithromycin and amikacin resistance. Thirty-eight reference strains and 145 clinical isolates (58 MAC and 87 M. abscessus isolates), including 54 clarithromycin- and/or amikacin-resistant strains, were involved. The performance of the NTM-DR assay in rapid identification was evaluated by comparison with results of multigene sequence-based typing, whereas performance in rapid detection of clarithromycin and amikacin resistance was evaluated by comparison with sequencing of the erm(41), rrl, and rrs genes and drug susceptibility testing (DST). The accuracies of MAC and M. abscessus (sub)species identification were 92.1% (35/38) and 100% (145/145) for the 38 reference strains and 145 clinical isolates, respectively. Three MAC strains other than M. intracellulare were found to cross-react with the M. intracellulare probe in the assay. Regarding clarithromycin resistance, NTM-DR detected rrl mutations in 52 isolates and yielded 99.3% (144/145) and 98.6% (143/145) concordant results with sequencing and DST, respectively. NTM-DR sensitivity and specificity in the detection of clarithromycin resistance were 96.3% (52/54) and 100% (91/91), respectively. The NTM-DR yielded accurate erm(41) genotype results for all 87 M. abscessus isolates. Regarding amikacin resistance, NTM-DR detected rrs mutations in five isolates and yielded 99.3% (144/145) and 97.9% (142/145) concordant results with sequencing and DST, respectively. Our results indicate that the NTM-DR assay is a straightforward and accurate approach for discriminating MAC and M. abscessus (sub)species and for detecting clarithromycin and amikacin resistance mutations and that it is a useful tool in the clinical setting.

Application of next-generation sequencing to detect variants of drug-resistant Mycobacterium tuberculosis: genotype-phenotype correlation.

BACKGROUND: Drug resistance in Mycobacterium tuberculosis (MTB) is a major health issue worldwide. Recently, next-generation sequencing (NGS) technology has begun to be used to detect resistance genes of MTB. We aimed to assess the clinical usefulness of Ion S5 NGS TB research panel for detecting MTB resistance in Korean tuberculosis patients. METHODS: Mycobacterium tuberculosis with various drug resistance profiles including susceptible strains (N = 36) were isolated from clinical specimens. Nucleic acids were extracted from inactivated culture medium and underwent amplicon-based NGS to detect resistance variants in eight genes (gyrA, rpoB, pncA, katG, eis, rpsL, embB, and inhA). Data from previous studies using the same panel were merged to yield pooled sensitivity and specificity values for detecting drug resistance compared to phenotype-based methods. RESULTS: The sequencing reactions were successful for all samples. A total of 24 variants were considered to be related to resistance, and 6 of them were novel. Agreement between the phenotypic and genotypic results was excellent for isoniazid, rifampicin, and ethambutol, and was poor for streptomycin, amikacin, and kanamycin. The negative predictive values were greater than 97% for all drug classes, while the positive predictive values varied (44% to 100%). There was a possibility that common mutations could not be detected owing to the low coverage. CONCLUSIONS: We successfully applied NGS for genetic analysis of drug resistances in MTB, as well as for susceptible strains. We obtained lists of polymorphisms and possible polymorphisms, which could be used as a guide for future tests applying NGS in mycobacteriology laboratories. When analyzing the results of NGS, coverage analysis of each samples for each gene and benign polymorphisms not related to drug resistance should be considered.

Evaluation of a new matrix-assisted laser desorption/ionization time-of-flight mass spectrometry system for the identification of yeast isolation.

BACKGROUND: Currently, three commercial in vitro diagnostic matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) systems are widely used in clinical laboratories. The ASTA MicroIDSys system (ASTA Inc, South Korea) is a newly developed MALDI-TOF MS system used for the identification of pathogenic microorganisms. In the present study, we assessed the performance of the ASTA MALDI-TOF MS system for the identification of pathogenic yeast from clinical samples. METHODS: We tested 284 clinical yeast isolates from various clinical specimens using ASTA MALDI-TOF MS, and the results were compared with those using molecular sequencing of the ITS or D1-D2 regions of rDNA and biochemical assays. RESULTS: A total of 284 isolates were tested and found to be distributed across 14 species including Candida albicans (n = 100) and other yeast species (n = 184). ASTA MALDI-TOF MS correctly identified 95.1% (270/284) of the yeast species compared to molecular sequencing. Among them, 262 isolates showed acceptable MALDI-TOF MS scores (≥140), and 98.1% (257/262) isolates were identified correctly. In addition, among 22 isolates with a MALDI-TOF MS score <140, 59.1% (13/22) of the isolates showed concordance with molecular typing at the species level. Clustering analysis revealed the effectiveness of the new MALDI-TOF MS system for the identification of yeast species. CONCLUSIONS: ASTA MALDI-TOF MS showed high accuracy in the identification of yeast species; it involves facile sample preparation and extraction procedures. ASTA MALDI-TOF MS is expected to be useful for yeast identification in clinical microbiology laboratories due to its reliability and cost-effectiveness.

A comparison of methods for inferring causal relationships between genotype and phenotype using additional biological measurements.

Genome wide association studies (GWAS) have been very successful over the last decade at identifying genetic variants associated with disease phenotypes. However, interpretation of the results obtained can be challenging. Incorporation of further relevant biological measurements (e.g. 'omics' data) measured in the same individuals for whom we have genotype and phenotype data may help us to learn more about the mechanism and pathways through which causal genetic variants affect disease. We review various methods for causal inference that can be used for assessing the relationships between genetic variables, other biological measures, and phenotypic outcome, and present a simulation study assessing the performance of the methods under different conditions. In general, the methods we considered did well at inferring the causal structure for data simulated under simple scenarios. However, the presence of an unknown and unmeasured common environmental effect could lead to spurious inferences, with the methods we considered displaying varying degrees of robustness to this confounder. The use of causal inference techniques to integrate omics and GWAS data has the potential to improve biological understanding of the pathways leading to disease. Our study demonstrates the suitability of various methods for performing causal inference under several biologically plausible scenarios.

Serum gamma-glutamyl transferase and risk of type 2 diabetes in the general Korean population: a Mendelian randomization study.

Elevated gamma-glutamyl transferase (GGT) levels are associated with higher risk of type 2 diabetes in observational studies, but the underlying causal relationship is still unclear. Here, we tested a hypothesis that GGT levels have a causal effect on type 2 diabetes risk using Mendelian randomization. Data were collected from 7640 participants in a South Korean population. In a single instrumental variable (IV) analysis using two stage least squares regression with the rs4820599 in the GGT1 gene region as an instrument, one unit of GGT levels (IU/L) was associated with 11% higher risk of type 2 diabetes (odds ratio (OR) = 1.11, 95% confidence interval (CI): 1.04 to 1.19). In a multiple IV analysis using seven genetic variants that have previously been demonstrated to be associated with GGT at a genome-wide level of significance, the corresponding estimate suggested a 2.6% increase in risk (OR = 1.026, 95% CI: 1.001 to 1.052). In a two-sample Mendelian randomization analysis using genetic associations with type 2 diabetes taken from a trans-ethnic GWAS study of 110 452 independent samples, the single IV analysis confirmed an association between the rs4820599 and type 2 diabetes risk (P-value = 0.04); however, the estimate from the multiple IV analysis was compatible with the null (OR = 1.007, 95% CI: 0.993 to 1.022) with considerable heterogeneity between the causal effects estimated using different genetic variants. Overall, there is weak genetic evidence that GGT levels may have a causal role in the development of type 2 diabetes.

Seventy-five genetic loci influencing the human red blood cell.

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Differences in drug susceptibility pattern between Mycobacterium avium and Mycobacterium intracellulare isolated in respiratory specimens.

Mycobacterium avium complex (MAC) is the most common etiologic organisms of nontuberculous mycobacteria (NTM) lung disease. In this study, we aimed to retrospectively investigate the differences in drug susceptibility patterns of two major MAC species; Mycobacterium avium and Mycobacterium intracellulare. A total of 1883 major two MAC isolates (1060 M. avium and 823 M. intracellulare) from respiratory specimens were included in this study during the period 2011─2016. The minimum inhibitory concentrations (MICs) were determined by broth microdilution method and MIC50/MIC90 values were derived from MIC distribution. M. intracellulare had generally low susceptible rates than M. avium for almost all tested antimicrobials except ethambutol and amikacin. The susceptible rate to clarithromycin was >94% of the MAC without significant differences between the two species. The MIC50 values of ciprofloxacin, clarithromycin, linezolid, moxifloxacin, and rifampicin were higher in M. intracellulare than in M. avium, contrary to the results of ethambutol with a higher MIC50 in M. avium. In general, M. intracellulare showed a higher resistance rate and higher MIC50 values than M. avium. Differences between this study and previous reports suggest regional differences in drug susceptibility profile of MAC species.

Comparison and Combination of Strain and Shear Wave Elastography of Breast Masses for Differentiation of Benign and Malignant Lesions by Quantitative Assessment: Preliminary Study.

OBJECTIVES: To compare the diagnostic performance of strain and shear wave elastography of breast masses for quantitative assessment in differentiating benign and malignant lesions and to evaluate the diagnostic accuracy of combined strain and shear wave elastography. METHODS: Between January and February 2016, 37 women with 45 breast masses underwent both strain and shear wave ultrasound (US) elastographic examinations. The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) final assessment on B-mode US imaging was assessed. We calculated strain ratios for strain elastography and the mean elasticity value and elasticity ratio of the lesion to fat for shear wave elastography. Diagnostic performances were compared by using the area under the receiver operating characteristic curve (AUC). RESULTS: The 37 women had a mean age of 47.4 years (range, 20-79 years). Of the 45 lesions, 20 were malignant, and 25 were benign. The AUCs for elasticity values on strain and shear wave elastography showed no significant differences (strain ratio, 0.929; mean elasticity, 0.898; and elasticity ratio, 0.868; P > .05). After selectively downgrading BI-RADS category 4a lesions based on strain and shear wave elastographic cutoffs, the AUCs for the combined sets of B-mode US and elastography were improved (B-mode + strain, 0.940; B-mode + shear wave; 0.964; and B-mode, 0.724; P < .001). Combined strain and shear wave elastography showed significantly higher diagnostic accuracy than each individual elastographic modality (P = .031). CONCLUSIONS: These preliminary results showed that strain and shear wave elastography had similar diagnostic performance. The addition of strain and shear wave elastography to B-mode US improved diagnostic performance. The combination of strain and shear wave elastography results in a higher diagnostic yield than each individual elastographic modality.

Improvement in Ventilation-Perfusion Mismatch after Bronchoscopic Lung Volume Reduction: Quantitative Image Analysis.

Purpose To evaluate whether bronchoscopic lung volume reduction (BLVR) increases ventilation and therefore improves ventilation-perfusion (V/Q) mismatch. Materials and Methods All patients provided written informed consent to be included in this study, which was approved by the Institutional Review Board (2013-0368) of Asan Medical Center. The physiologic changes that occurred after BLVR were measured by using xenon-enhanced ventilation and iodine-enhanced perfusion dual-energy computed tomography (CT). Patients with severe emphysema plus hyperinflation who did not respond to usual treatments were eligible. Pulmonary function tests, the 6-minute walking distance (6MWD) test, quality of life assessment, and dual-energy CT were performed at baseline and 3 months after BLVR. The effect of BLVR was assessed with repeated-measures analysis of variance. Results Twenty-one patients were enrolled in this study (median age, 68 years; mean forced expiratory volume in 1 second [FEV1], 0.75 L ± 0.29). After BLVR, FEV1 (P < .001) and 6MWD (P = .002) improved significantly. Despite the reduction in lung volume (-0.39 L ± 0.44), both ventilation per voxel (P < .001) and total ventilation (P = .01) improved after BLVR. However, neither perfusion per voxel (P = .16) nor total perfusion changed significantly (P = .49). Patients with lung volume reduction of 50% or greater had significantly better improvement in FEV1 (P = .02) and ventilation per voxel (P = .03) than patients with lung volume reduction of less than 50%. V/Q mismatch also improved after BLVR (P = .005), mainly owing to the improvement in ventilation. Conclusion The dual-energy CT analyses showed that BLVR improved ventilation and V/Q mismatch. This increased lung efficiency may be the primary mechanism of improvement after BLVR, despite the reduction in lung volume. © RSNA, 2017 Online supplemental material is available for this article.

Human metabolic individuality in biomedical and pharmaceutical research.

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.

New gene functions in megakaryopoiesis and platelet formation.

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

Epidemiology and Clinical Characteristics of Zika Virus Infections Imported into Korea from March to October 2016.

Zika is a re-emerging, mosquito-borne viral infection, which has been recently shown to cause microcephaly and Guillain-Barré syndrome. Since 2015 the number of infected patients has increased significantly in South America. The purpose of this study was to identify the epidemiologic and clinical characteristics of patients with Zika virus (ZIKV) infections in Korea. Patients who had visited areas of risk and tested positive in the ZIKV reverse transcriptase polymerase chain reaction (RT-PCR) in blood, urine, or saliva specimens were included. The first Korean case of ZIKV infection was reported in March 2016, and 14 cases had been reported by October 2016. The median age of the patients was 34 years (19-64 years). Ten patients had been exposed in Southeast Asia and 4 in Latin America. Rash was the most common symptom (92.9%; 13/14), followed by myalgia (50.0%; 7/14), and arthralgia (28.6%, 4/14). There were no neurologic abnormalities and none of the patients was pregnant. Results of biochemical tests were normal. Positivity rates of RT-PCR for ZIKV in serum, urine, and saliva were 53.8%, 100.0%, and 83.3%, respectively in the first week of symptoms. In conclusion, 14 patients with ZIKV infections were reported in Korea by October 2016 and all of them had mild clinical symptoms.

Novel genetic associations with serum level metabolites identified by phenotype set enrichment analyses.

Availability of standardized metabolite panels and genome-wide single-nucleotide polymorphism data endorse the comprehensive analysis of gene-metabolite association. Currently, many studies use genome-wide association analysis to investigate the genetic effects on single metabolites (mGWAS) separately. Such studies have identified several loci that are associated not only with one but with multiple metabolites, facilitated by the fact that metabolite panels often include metabolites of the same or related pathways. Strategies that analyse several phenotypes in a combined way were shown to be able to detect additional genetic loci. One of those methods is the phenotype set enrichment analysis (PSEA) that tests sets of metabolites for enrichment at genes. Here we applied PSEA on two different panels of serum metabolites together with genome-wide data. All analyses were performed as a two-step identification-validation approach, using data from the population-based KORA cohort and the TwinsUK study. In addition to confirming genes that were already known from mGWAS, we were able to identify and validate 12 new genes. Knowledge about gene function was supported by the enriched metabolite sets. For loci with unknown gene functions, the results suggest a function that is interrelated with the metabolites, and hint at the underlying pathways.