title: Identification of ITPA on chromosome 20 as a susceptibility gene for young-onset tuberculosis.
abstract: Tuberculosis (TB) is a complex disease, and both genetic and environmental factors contribute to disease progression. A previous genome-wide linkage study in Thailand determined that chromosome 20p13-12.3 may contain risk factors for young-onset disease. The present study aimed to identify novel susceptibility genes for young-onset TB within a 1-Mbp target region adjacent to the top-ranking risk marker in Chr.20p13-12.3. We performed next-generation sequencing (NGS) of the region in 13 young patients from multi-case families in Thailand. We then selected the functionally interesting single-nucleotide polymorphisms as candidates for subsequent analyses. The detected candidates rs13830 and rs1127354 in ITPA showed an association with young (<45 years old) TB patients. However, there was no association in old (⩾45 years old) patients. These findings confirm that stratifying patients based on age of TB onset can be important for identifying genetic risk factors for TB susceptibility. In addition, in silico expression quantitative trait loci analyses indicated that ITPA expression was associated with rs13830 genotype. This is the first study to use NGS resequencing to gain insight into host genetic factors associated with TB and to report a significant association for ITPA with host susceptibility in young-onset TB. The study also demonstrated the effectiveness of NGS in identifying susceptibility genes in common diseases.
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Nakauchi
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan.
authors.forename: Jing Hao
authors.initials: JH
authors.lastname: Wong
authors.affiliation: Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health , Nonthaburi, Thailand.
authors.forename: Surakameth
authors.initials: S
authors.lastname: Mahasirimongkol
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Fukujuji Hospital, Japan Anti-Tuberculosis Association (JATA), Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yanai
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Genomic Medicine Research Group, YARSI Research Institute, YARSI University, Jakarta, Indonesia.
authors.forename: Rika
authors.initials: R
authors.lastname: Yuliwulandari
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Mabuchi
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Xiaoxi
authors.identifier: 0000-0002-1933-8613
authors.initials: X
authors.lastname: Liu
authors.affiliation: Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences , Kanagawa, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.affiliation: Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health , Nonthaburi, Thailand.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Wattanapokayakit
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Miyagawa
authors.affiliation: Department of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association (JATA) , Tokyo, Japan.
authors.forename: Naoto
authors.identifier: 0000-0001-8232-9448
authors.initials: N
authors.lastname: Keicho
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga