Potential role of club cell secretory protein (CC16) in development of obese asthma: findings from a birth cohort and animal studies

• Project/Area Number: 20K10425
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 58020:Hygiene and public health-related: including laboratory approach
• Research Institution: Hokkaido University
• Principal Investigator: Goudarzi Houman 北海道大学, 医学研究院, 准教授 (40713607)
• Co-Investigator(Kenkyū-buntansha): 池田 敦子 (荒木 敦子) 北海道大学, 環境健康科学研究教育センター, 特任教授 (00619885) ; 今野 哲 北海道大学, 医学研究院, 教授 (20399835)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: adult/childhood asthma / CC16 / prospective birth cohort / adult asthma cohort / experimental studies / T2 phebotypes / Airway inflammation / Oxidative biomarkers / Asthma / Obesity / birth cohort / adult asthma patients / T helper 2 biomarkers / Experimental studies / Adults and children / Club cell protein (CC16) / In vivo study / Asthma and allergy / Obese asthma / Animal studies

Outline of Research at the Start

As clinical implications, CC16 levels could be applied for risk stratification for prevention of progressive airway inflammation, and optimization of asthma treatment in children especially obese individuals. With combination of epidemiological and animal studies, we may provide novel evidence that serial low CC16 concentration, as a risk factor, could be implemented in clinical setting for prevention of obese asthma (and other allergic diseases). Finally, CC16 may attract clinicians’ interest as a target of therapy in obese asthma phenotype in future studies.

Outline of Annual Research Achievements

1) Adult asthma cohort: BMI was significantly and monotonically associated with lower circulating CC16 levels in adult asthma patients. Also, CC16 was inversely associated with sputum eosinophils and blood periostin. Patients in the lowest tertile of serum CC16 levels at baseline had a -14.3 mL decline in FEV1 over five years of follow-up compared to those in the highest tertile (Goudarzi et al. Respiratory Medicine, 2023). 2) Experimental study: The percentage of CC16 cells was reduced in the small airways of obese mice and humans. Serum CC16 levels, but not SP-A and D, were significantly lower in obese mice than in non-obese control mice. 3) Hokkaido birth cohort: We measured circulating CC16 in 10-year-old children from the general population. BMI at ages 7 and 10 was associated with reduced CC16 at age 10. Children with wheeze had significantly lower plasma CC16 (median 5.2, IQR 3.8-6.1) compared to children without wheeze (median 5.6, IQR 4.3-7.1). Plasma CC16 was inversely associated with wheeze and asthma prevalence, with a 1 ng/mL increase in CC16 decreasing the risk of wheeze by 20% (adjusted odds ratio: 0.80, 95% CI: 0.66-0.99). CC16 was inversely associated with T2 phenotypes, including blood eosinophils and FeNO. Finally, we examined the association of urinary oxidative and lipid peroxidation with CC16 and the obese asthma phenotype. CC16 was inversely associated with urinary HNE and HEL, which are biomarkers of oxidative stress. We also completed genotyping of CC16 and found a significant influence of genotypes on circulating CC16.

Research Products

• [Int'l Joint Research] Icahn School of Medicine at Mount Sinai/The Murray M. Rosenberg/Department of Pulmonary Medicine(米国)
• [Int'l Joint Research] Taipei Medical University/School of Medical/Laboratory Science and Biotechnology(中国)
• [Int'l Joint Research] Icahn School of Medicine at Mount Sinai/New York/Prof. Monica Kraft(米国)
• [Int'l Joint Research] Johns Hopkins University/Baltimore/Prof. Shau-ku Huang(米国)
• [Int'l Joint Research] University of Arizona/Tucson/Prof. Monica Kraft(米国)
• [Int'l Joint Research] Johns Hopkins University/Baltimore, MD, USA/Prof. Shau-ku Huang(米国)
• [Int'l Joint Research] University of Arizona/Tucson/Prof. Monica Kraft(米国)
• [Int'l Joint Research] Johns Hopkins University/Baltimore, MD, USA/Prof. Shau-ku Huang(米国)
• [Journal Article] Global fertility in 204 countries and territories, 1950ー2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021 (2024)
  • Author(s): GBD 2021 Fertility and Forecasting Collaborator
  • Journal Title: Lancet Volume: - Issue: 10440 Pages: 00550-6
  • DOI: 10.1016/s0140-6736(24)00550-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021 (2024)
  • Author(s): Mohsen Naghavi, Kanyin Liane Ong, Amirali Aali, Hazim S Ababneh, ..., Goudarzi Houman, ..., Murray Christopher J L
  • Journal Title: The Lancet Volume: 403 Issue: 10440 Pages: 2100-2132
  • DOI: 10.1016/s0140-6736(24)00367-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of the Covid-19 pandemic and ensuing online teaching on pre-clinical medical education (2024)
  • Author(s): Goudarzi Houman、Onozawa Masahiro、Takahashi Makoto
  • Journal Title: BMC Medical Education Volume: 24 Issue: 1
  • DOI: 10.1186/s12909-023-04967-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Applicable predictive factors extracted from peak flow trajectory for the prediction of asthma exacerbation (2024)
  • Author(s): Yang Yichi、Kimura Hirokazu、Goudarzi Houman、Ishikuro Akihiko、Ohtsuka Yoshihiro、Watanabe Kazuhiko
  • Journal Title: Annals of Allergy, Asthma & Immunology Volume: 132 Issue: 4 Pages: 469-476
  • DOI: 10.1016/j.anai.2023.11.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Association of serum CC16 levels with eosinophilic inflammation and respiratory dysfunction in severe asthma (2023)
  • Author(s): Goudarzi Houman、Kimura Hirokazu、Kimura Hiroki、Makita Hironi、Takimoto-Sato Michiko、Abe Yuki、Oguma Akira、Matsumoto Munehiro、Takei Nozomu、Matsumoto-Sasaki Machiko、Shimizu Kaoruko、Suzuki Masaru、Shijubo Noriharu、Huang Shau-ku、Hizawa Nobuyuki、Nishimura Masaharu、Konno Satoshi
  • Journal Title: Respiratory Medicine Volume: 206 Pages: 107089-107089
  • DOI: 10.1016/j.rmed.2022.107089
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Exposure to organophosphate flame retardants and plasticizers is positively associated with wheeze and FeNO and eosinophil levels among school-aged children: The Hokkaido study (2023)
  • Author(s): Zeng Yi、Goudarzi Houman、Ait Bamai Yu、Ketema Rahel Mesfin、Roggeman Maarten、den Ouden Fatima、Gys Celine、Miyashita Chihiro、Ito Sachiko、Konno Satoshi、Covaci Adrian、Kishi Reiko、Ikeda-Araki Atsuko
  • Journal Title: Environment International Volume: 181 Pages: 108278-108278
  • DOI: 10.1016/j.envint.2023.108278
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Potential determinants of T helper 2 markers and their distribution in school-aged children (2023)
  • Author(s): Goudarzi Houman、Ikeda-Araki Atsuko、Bamai Yu Ait、Ito Sachiko、Inao Tasuku、Yokota Isao、Miyashita Chihiro、Kishi Reiko、Konno Satoshi
  • Journal Title: Allergology International Volume: 72 Issue: 1 Pages: 100-106
  • DOI: 10.1016/j.alit.2022.07.009
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of obesity on CC16 and their potential role in overweight/obese asthma (2023)
  • Author(s): Goudarzi Houman、Kimura Hirokazu、Kimura Hiroki、Nakamura Akinobu、Hizawa Nobuyuki、Atsumi Tatsuya、Huang Shau-ku、Ito Yoichi M.、Nishimura Masaharu、Konno Satoshi
  • Journal Title: Respiratory Research Volume: 23 Issue: 1 Pages: 174-174
  • DOI: 10.1186/s12931-022-02038-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation (2023)
  • Author(s): Oguma Akira、Shimizu Kaoruko、Kimura Hirokazu、Tanabe Naoya、Sato Susumu、Yokota Isao、Takimoto-Sato Michiko、Matsumoto-Sasaki Machiko、Abe Yuki、Takei Nozomu、Goudarzi Houman、Suzuki Masaru、Makita Hironi、Hirai Toyohiro、Nishimura Masaharu、Konno Satoshi
  • Journal Title: Allergology International Volume: 72 Issue: 2 Pages: 262-270
  • DOI: 10.1016/j.alit.2022.10.007
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Blood eosinophil count variability in chronic obstructive pulmonary disease and severe asthma (2023)
  • Author(s): Abe Yuki、Suzuki Masaru、Kimura Hirokazu、Shimizu Kaoruko、Takei Nozomu、Oguma Akira、Matsumoto-Sasaki Machiko、Goudarzi Houman、Makita Hironi、Nishimura Masaharu、Konno Satoshi
  • Journal Title: Allergology International Volume: 72 Issue: 3 Pages: 402-410
  • DOI: 10.1016/j.alit.2022.11.012
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Further evidence for association of YKL-40 with severe asthma airway remodeling (2022)
  • Author(s): Kimura H, Shimizu K, Tanabe N, Makita H, Taniguchi N, Kimura H, Suzuki M, Abe Y, Matsumoto-Sasaki M, Oguma A, Takimoto-Sato M, Takei N, Matsumoto M, Goudarzi H, Sato S, Ono J, Izuhara K, Hirai T, Nishimura M, Konno S
  • Journal Title: Annals of Allergy, Asthma & Immunology Volume: - Issue: 6 Pages: 682-688
  • DOI: 10.1016/j.anai.2022.03.016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Future career plans of medical students and the COVID‐19 pandemic: Time to recover? (2022)
  • Author(s): Goudarzi Houman、Onozawa Masahiro、Takahashi Makoto
  • Journal Title: Journal of General and Family Medicine Volume: 24 Issue: 2 Pages: 139-140
  • DOI: 10.1002/jgf2.591
  • Peer Reviewed
• [Journal Article] Association of abdominal visceral adiposity with sputum IL-5 levels in asthma (2022)
  • Author(s): Goudarzi Houman、Kimura Hirokazu、Makita Hironi、Abe Yuki、Oguma Akira、Sato Michiko、Matsumoto Munehiro、Takei Nozomu、Kimura Hiroki、Shimizu Kaoruko、Suzuki Masaru、Ito Yoichi M.、Nishimura Masaharu、Konno Satoshi
  • Journal Title: Allergology International Volume: 71 Issue: 1 Pages: 137-139
  • DOI: 10.1016/j.alit.2021.08.003
  • NAID: 130008145220
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Determination of the cutoff values of Th2 markers for the prediction of future exacerbation in severe asthma: An analysis from the Hokkaido Severe Asthma Cohort Study (2021)
  • Author(s): Kimura Hirokazu、Makita Hironi、Taniguchi Natsuko、Takei Nozomu、Matsumoto Munehiro、Kimura Hiroki、Goudarzi Houman、Shimizu Kaoruko、Suzuki Masaru、Nishimura Masaharu、Konno Satoshi
  • Journal Title: Allergology International Volume: 70 Issue: 1 Pages: 68-73
  • DOI: 10.1016/j.alit.2020.09.001
  • NAID: 130007966772
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hokkaido birth cohort study on environment and children’s health: cohort profile 2021 (2021)
  • Author(s): Kishi Reiko、Ikeda-Araki Atsuko、Miyashita Chihiro、Itoh Sachiko、Kobayashi Sumitaka、Ait Bamai Yu、Yamazaki Keiko、Tamura Naomi、et al.
  • Journal Title: Environmental Health and Preventive Medicine Volume: 26 Issue: 1 Pages: 1-20
  • DOI: 10.1186/s12199-021-00980-y
  • NAID: 210000159057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Mediation effect of CC16 on the associations between urinary phosphate flame retardants and fractional exhaled nitric oxide among children: The Hokkaido Study. (2024)
  • Author(s): 曾 怡, Houman Goudarzi，アイツバマイ ゆふ, 山口 健史, Rahel Mesfin Ketema, Maarten Roggeman, Fatima Den Ouden, Celine Gys, Megasari Marsela, 安田 彩夏、宮下 ちひろ, 今野 哲, Adrian Covaci, 岸 玲子, 池田 敦子
  • Organizer: 94th Annual Meeting of Japanese Society for Hygiene, Kagoshima, Japan
  • Int'l Joint Research
• [Presentation] Exploring individual and joint effects of phthalates on allergies among school children: The Hokkaido Study. (2024)
  • Author(s): Ketema Rahel Mesfin, Ait Bamai Yu, Miyashita Chihiro, Yamaguchi Takeshi, Zeng Yi, Yasuda Ayaka, Marsela Megasari, Goudarzi Houman, Konno Satoshi, Kishi Reiko, Ikeda Atsuko
  • Organizer: 94th Annual Meeting of Japanese Society for Hygiene, Kagoshima, Japan
  • Int'l Joint Research
• [Presentation] Association of circulatory CC16 with type 2 inflammation and pulmonary dysfunction: Potential role of CC16 in obese asthma. (2023)
  • Author(s): Satoshi Konno, Houman Goudarzi, Hirokazu Kimura, Masaru Suzuki, Kaoruko Shimizu, Hiroki Kimura, Noriharu Shijubo, Shau-ku Huang, Masaharu Nishimura.
  • Organizer: 65th Annual Meeting of Thomas L. Petty Aspen Lung Conference, Aspen, Colorado, USA
  • Int'l Joint Research / Invited
• [Presentation] Organophosphate Flame Retardants Mixture Exposure associate with Increased Levels of Urinary Oxidative Stress Biomarkers among School Children: The Hokkaido Study. (2023)
  • Author(s): Yi Zeng, Atsuko Ikeda-Araki, Houman Goudarzi, Yu Ait Bamai, Rahel Mesfin Ketema, Maarten Roggeman, Fatima Den Ouden, Celine Gys, Chihiro Miyashita, Sachiko Ito, Satoshi Konno, Adrian Covaci, Reiko Kishi.
  • Organizer: 35th Annual ISEE Conference in Kaohsiung, Taiwan,
  • Int'l Joint Research
• [Presentation] Blood eosinophil count variability in chronic obstructive pulmonary disease and severe asthma. (2023)
  • Author(s): Yuki Abe, Masaru Suzuki, Hirokazu Kimura, Kaoruko Shimizu, Nozomu Takei, Akira Oguma, Machiko Matsumoto-Sasaki,Houman Goudarzi, Hironi Makita, Masaharu Nishimura, Satoshi Konno.
  • Organizer: American Thoracic Society (ATS) International Conference 2023, Washington, DC, USA
  • Int'l Joint Research
• [Presentation] Association of serum CC16 levels with eosinophilic inflammation and respiratory dysfunction in severe asthma. (2023)
  • Author(s): Houman Goudarzi, Hirokazu Kimura, Hiroki Kimura, Hironi Makita, Michiko Takimoto-Sato, Yuki Abe, Akira Oguma, Munehiro Matsumoto, Nozomu Takei, Machiko Matsumoto-Sasaki, Kaoruko Shimizu, Masaru Suzuki, Noriharu Shijubo, Shau-Ku Huang, Nobuyuki Hizawa, Masaharu Nishimura, Satoshi Konno
  • Organizer: Japanese Society of Allergology (JSA) 72st Annual Meeting, Tokyo, Japan.
  • Int'l Joint Research
• [Presentation] Predictors of academic performance among medical students using a cluster-analytic approach. (2023)
  • Author(s): Houman Goudarzi, Masahiro Onozawa, Yoichi M. Ito, Makoto Takahashi.
  • Organizer: The 55th Annual Meeting of the Japan Society for Medical Education (JSME), Nagasaki, Japan.
  • Int'l Joint Research
• [Presentation] Effects of COVID-19 pandemic on career plans and academic performance of medical students. (2023)
  • Author(s): Houman Goudarzi, Masahiro Onozawa, Makoto Takahashi.
  • Organizer: The 26th Academic Meeting of the JASMEE, Tokyo, Japan.
  • Int'l Joint Research
• [Presentation] Effects of obesity on CC16 and their potential role in obese asthma (2022)
  • Author(s): Houman Goudarzi, Hirokazu Kimura, Hironi Makita, Mune Matsumoto, Nozomu Takei, Kaoruko Shimizu, Taku Watanabe, Masaharu Nishimura, Satoshi Konno
  • Organizer: Japan Society for Allergology 71st Annual Meeting, 2022 October 7-9, Tokyo Japan I received the best presentation award)
  • Int'l Joint Research
• [Presentation] Career plans and academic performance of medical students before, during, and beyond COVID-19 pandemic: Time to recover? (2022)
  • Author(s): Houman Goudarzi, Masahiro Onozawa, Makoto Takahashi
  • Organizer: The 54th Annual meeting of the Japan Society for Medical Education, 2022 August 5-6, Gunma, Japan
  • Int'l Joint Research
• [Presentation] Mixture exposure to plastic-related short half-life chemicals and associations with childhood asthma and allergies: The Hokkaido Study (2022)
  • Author(s): Yu Ait Bamai, Celine Guys, Michiel Bastiaensen, Atsuko Ikeda-Araki, Rahel Mesfin Ketema, Houman Goudarzi, Chihito Miyashita, Satoshi Konno, Reiko Kishi
  • Organizer: The 34th Annual ISEE conference, 2022 September 18-21, Athens, Greece
  • Int'l Joint Research
• [Presentation] Prevalence and time trends of allergic disease among Japanese children: Interpretation of T helper 2 biomarker levels for clinical applications. (2020)
  • Author(s): Houman Goudarzi, Atsuko Araki, Chihiro Miyashita, Yu Ait Bamai, Sachiko Ito, Reiko Kishi, Masaharu Nishimura, Satoshi Konno.
  • Organizer: JSA/WAO Joint Congress 2020, 2020, Kyoto, Japan
  • Int'l Joint Research
• [Remarks] https://researchmap.jp/houman
• [Remarks] https://www.cehs.hokudai.ac.jp/
• [Remarks] https://www.cehs.hokudai.ac.jp/en
• [Remarks] Website of Hokkaido Study
  • URL: https://www.cehs.hokudai.ac.jp/hokkaidostudy/