AS)% )%( ycneuqerf epytoneG( foycneuqerFBBAA10080604020070Thai TB patientswith liver injuryP = 1.53××10-8Odds ratio: 8.8071.1%22.6%Tolerantcontrols(n=85)(n=53)Japanese AMR AFR EAS EUR SASRapidacetylator (RA)Intermediateacetylator (IA)Slowacetylator(SA)Research Network (SEAPharm) with five Asian countries (Korea, Indonesia, Malaysia, Taiwan, and Thailand) in 2012, and its membership has been steadily increasing to include Singapore, Vietnam, Nepal, Laos, the Philippines, Brunei, and Myanmar. SEAPharm aims to promote safer and more appropriate drug therapy by using pharmacogenomics (PGx) biomarkers associ-ated with drug responses, including drug efficacy and adverse drug reactions.One of the outcomes of SEAPharm is the identification of genes associated with anti-tuberculosis (TB) drug-induced liver injury in the Thai population. It has been shown that some pa-tients have genetically reduced enzymatic activity of NAT2, the cate with each other and function together in an immune re-sponse. Each cell expresses various recognition molecules such as antigen receptors and cytokine receptors on the cell surface and, upon receiving external stimuli, they participate in the overall response by expressing molecules on the cell surface or secreting molecules to exert effects on other cells through intracellular sig-nal transduction. Although each subset of immune cells originally has the same genome, it is believed that epigenomic changes are triggered by differentiation, external stimuli, and environmen-tal influences, and that these influences establish a mechanism for subset-specific gene expression. It is also clear that human populations are diverse and that immune functions differ among individuals. Factors that have been pointed out as influencing the diversity of human immune function include genetic variation, environmental factors (especially gut microbiota), gender, and age. With regard to genetic variation and gene expression, it is becoming clear that many of the genetic variants (estimated to be about 80% or more) associated with disease are expression Quan-titative Trait Locus (eQTL) loci for gene expression.major metabolizing enzyme of isoniazid, one of the first-line anti-TB drugs, and that NAT2 slow-acetylators (SA) have a signifi-cantly higher risk of liver injury induced by isoniazid (Figure A). Conversely, NAT2 rapid acetylators (RA) are more likely to fail initial TB treatment due to low levels of isoniazid in the blood. Because of the higher frequency of SA in the Thai population, in-cluded in South Asians (SAS), than in the Japanese (Figure B) and the need to evaluate the significance of clinical implementation of NAT2 genetic testing in TB treatment, an international proj-ect based on PGx studies was initiated in 2023 with the support of the Japan International Cooperation Agency (JICA) and the Japan Agency for Medical Research and Development (AMED).Considering these backgrounds, 10 teams of IMS are currently working together on a multi-omics analysis of a subset of human immune cells, focusing on genetic diversity, gene expression, epigenome, proteome, lipidome, gut microbiota and metabo-lome. Furthermore, the data generated from these analyses can be analyzed using statistical genetics and artificial intelligence (AI) approaches. We believe that these studies will enable us to understand, predict, and find ways to repair the human immune system.Figure: Safety and efficacy of isoniazid treatment based on NAT2 genetic testing(A) NAT2 slow acetylator status is associated with anti-TB drug-induced liver injury in Thai patients. (B) Frequency of NAT2 genotypes in 990 Japanese individuals and 2,504 individuals from five populations. To compare the genetic diversity in the frequencies of NAT2 genotypes, we also estimated NAT2 genotypes in African (AFR, N = 661), Ad mixed American (AMR, N = 347), East Asian (EAS, N = 504), European (EUR, N = 503), and South Asian (SAS, N = 489) populations collected by the 1000 Genomes Project.Figure: Multi-omics of studies of the human immune systemSEAPharm for establishment of stratified medicine in AsiaRIKEN established the Southeast Asia Pharmacogenomics Multi-omics studies of the human immune systemImmune cells are divided into many subsets, which communi-
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