22
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Association and clinical utility of NAT2 in the prediction of isoniazid-induced liver injury in Singaporean patients

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background and aims

          Isoniazid (INH) is part of the first-line-therapy for tuberculosis (TB) but can cause drug-induced liver injury (DILI). Several candidate single nucleotide polymorphisms (SNPs) have been previously identified but the clinical utility of these SNPs in the prediction of INH-DILI remains uncertain. The aim of this study was to assess the association between selected candidate SNPs and the risk of INH-DILI and to assess the clinical validity of associated variants in a Singaporean population.

          Methods

          This was a case-control study where 24 INH-DILI cases and 79 controls were recruited from the TB control unit in a tertiary hospital. Logistic regression was used to test for the association between candidate SNPs and INH-DILI. NAT2 acetylator status was inferred from genotypes and tested for association with INH-DILI. Finally, clinical validity measures were estimated for significant variants.

          Results

          Two SNPs in NAT2 (rs1041983 and rs1495741) and NAT2 slow acetylators (SA) were significantly associated with INH-DILI (OR (95% CI) = 13.86 (4.30–44.70), 0.10 (0.03–0.33) and 9.98 (3.32–33.80), respectively). Based on an INH-DILI prevalence of 10%, the sensitivity, specificity, positive and negative predictive values of NAT2 SA were 75%, 78%, 28% and 97%, respectively. The population attributable fraction (PAF) and number needed to test (NNT) for NAT2 SA were estimated to be 0.67 and 4.08, respectively. A model with clinical and NAT2 acetylator status provided significantly better prediction for INH-DILI than a clinical model alone (area under receiver operating characteristic curve = 0.863 vs. 0.766, respectively, p = 0.027).

          Conclusions

          We show the association between NAT2 SA and INH-DILI in a Singaporean population and demonstrated its clinical utility in the prediction of INH-DILI.

          Related collections

          Most cited references52

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Second-generation PLINK: rising to the challenge of larger and richer datasets

          PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information. The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            Index for rating diagnostic tests.

              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Diagnostic tests 2: Predictive values.

                Bookmark

                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 October 2017
                2017
                : 12
                : 10
                : e0186200
                Affiliations
                [1 ] Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore and the National University of Singapore, Singapore
                [2 ] Department of Respiratory Medicine, Tan Tock Seng Hospital, Singapore
                [3 ] School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
                [4 ] Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada
                Rutgers Biomedical and Health Sciences, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-4204-1452
                http://orcid.org/0000-0001-8916-9758
                http://orcid.org/0000-0002-3686-3807
                Article
                PONE-D-17-22100
                10.1371/journal.pone.0186200
                5642896
                29036176
                93646694-3663-4a9a-8f78-efc8fa45c8a8
                © 2017 Chan et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 June 2017
                : 27 September 2017
                Page count
                Figures: 3, Tables: 2, Pages: 16
                Funding
                Funded by: Biomedical Research Council, Agency for Science Technology and Research
                Award ID: SPF2014/001
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000245, Michael Smith Foundation for Health Research;
                Award Recipient :
                This study was supported by the Biomedical Research Council of the Agency for Science, Technology and Research of Singapore (Strategic Positioning Funds - SPF2014/001) to LRB and by the National University of Singapore. LRB is supported by a Canadian Institutes of Health Research New Investigator award and a Michael Smith Foundation for Health Research Scholar Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Infectious Diseases
                Bacterial Diseases
                Tuberculosis
                Medicine and Health Sciences
                Tropical Diseases
                Tuberculosis
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Genotyping
                Research and Analysis Methods
                Molecular Biology Techniques
                Genotyping
                Biology and Life Sciences
                Biotechnology
                Pharmacogenomics
                Biology and Life Sciences
                Genetics
                Genomics
                Genomic Medicine
                Pharmacogenomics
                Medicine and Health Sciences
                Pharmacology
                Pharmacogenomics
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Mapping
                Variant Genotypes
                Biology and Life Sciences
                Genetics
                Molecular Genetics
                Biology and Life Sciences
                Molecular Biology
                Molecular Genetics
                Biology and Life Sciences
                Genetics
                Genetic Loci
                Alleles
                People and Places
                Population Groupings
                Ethnicities
                Chinese People
                People and Places
                Population Groupings
                Ethnicities
                Malay People
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized
                Uncategorized

                Comments

                Comment on this article