{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T16:49:07Z","timestamp":1788454147041,"version":"build-2803163510"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2009,12,1]],"date-time":"2009-12-01T00:00:00Z","timestamp":1259625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>IL-18 is a unique cytokine that enhances innate immunity and both Th1- and Th2-driven immune responses. Recent murine and human genetic studies have shown its role in the pathogenesis of asthma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We conducted an association study in a Japanese population to discover variants of IL-18 that might have an effect on asthma susceptibility and\/or progression and conducted functional analyses of the related variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The IL-18 gene locus was resequenced in 48 human chromosomes. Asthma severity was determined according to the 2002 Global Initiative for Asthma Guidelines. Association and haplotype analyses were performed using 1,172 subjects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Although no polymorphisms differed significantly in frequency between the control and adult asthma groups, rs5744247 C&amp;gt;G was significantly associated with the severity of adult asthma (steps 1, 2 vs. steps 3, 4; P = 0.0034). We also found a positive association with a haplotype (P = 0.0026). By in vitro functional analyses, the rs5744247 variant was found to increase enhancer-reporter activity of the IL-18 gene in bronchial epithelial cells. Expression levels of IL-18 in response to LPS stimulation in monocytes were significantly greater in subjects homozygous for the susceptibility G allele at rs5744247 C&amp;gt;G. Furthermore, we found a significant correlation between the serum IL-18 level and the genotype of rs5744247 (P = 0.031).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Although the association results need to be replicated by other studies, IL-18 variants are significantly associated with asthma severity, and the rs5744247 variant reflects higher transcriptional activity and higher expression of IL-18 in LPS-stimulated monocytes and a higher serum IL-18 level.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.200905-0652oc","type":"journal-article","created":{"date-parts":[[2009,9,10]],"date-time":"2009-09-10T22:02:02Z","timestamp":1252620122000},"page":"1048-1055","source":"Crossref","is-referenced-by-count":73,"title":["A Functional Polymorphism in\n                    <i>IL-18<\/i>\n                    Is Associated with Severity of Bronchial Asthma"],"prefix":"10.1093","volume":"180","author":[{"given":"Michishige","family":"Harada","sequence":"first","affiliation":[{"name":"Laboratory for Respiratory Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Kanagawa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Obara","sequence":"additional","affiliation":[{"name":"Hitachi Chemical Co., Ltd., Hitachi, Ibaraki"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomitsu","family":"Hirota","sequence":"additional","affiliation":[{"name":"Laboratory for Respiratory Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Kanagawa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Yoshimoto","sequence":"additional","affiliation":[{"name":"Department of Immunology and Medical Zoology, Hyogo College of Medicine, Hyogo"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Hitomi","sequence":"additional","affiliation":[{"name":"Laboratory for Respiratory Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Kanagawa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Sakashita","sequence":"additional","affiliation":[{"name":"Laboratory for Respiratory Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Kanagawa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Doi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Allergy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Miyatake","sequence":"additional","affiliation":[{"name":"Miyatake Asthma Clinic, Osaka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimie","family":"Fujita","sequence":"additional","affiliation":[{"name":"School of Human Nursing, The University of Shiga Prefecture, Shiga"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadao","family":"Enomoto","sequence":"additional","affiliation":[{"name":"NPO Japan Health Promotion Supporting Network, Wakayama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masami","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Kanagawa; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noritaka","family":"Higashi","sequence":"additional","affiliation":[{"name":"Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Kanagawa; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuma","family":"Fukutomi","sequence":"additional","affiliation":[{"name":"Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Kanagawa; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Immunology and Medical Zoology, Hyogo College of Medicine, Hyogo"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayumi","family":"Tamari","sequence":"additional","affiliation":[{"name":"Laboratory for Respiratory Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), 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