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Neurodegeneration
Original research
Methionine homozygosity for PRNP polymorphism and susceptibility to human prion diseases
  1. Koki Kosami1,
  2. Ryusuke Ae1,
  3. Tsuyoshi Hamaguchi2,
  4. Nobuo Sanjo3,
  5. Tadashi Tsukamoto4,
  6. Tetsuyuki Kitamoto5,
  7. Masahito Yamada6,
  8. Hidehiro Mizusawa4,
  9. Yosikazu Nakamura1
  1. 1 Division of Public Health, Center for Community Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
  2. 2 Neurology & Neurobiology of Aging, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
  3. 3 Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  4. 4 Department of Neurology, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
  5. 5 Department of Neurological Science, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
  6. 6 Division of Neurology, Department of Internal Medicine, Kudanzaka Hospital, Chiyoda-ku, Tokyo, Japan
  1. Correspondence to Dr Ryusuke Ae, Division of Public Health, Center for Community Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan; shirouae{at}jichi.ac.jp

Abstract

Background No studies have assessed the independent association of methionine homozygosity at codon 129 with the susceptibility to prion diseases, controlling for the effects of the codon 219 polymorphisms and other potential confounders, using a large-scale population-based dataset.

Methods We conducted a case-control study using a Japanese nationwide surveillance database for prion diseases. The main exposure was methionine homozygosity at codon 129, and the outcome was development of prion diseases. Multivariable logistic regression models were employed for specific disease subtypes (sporadic Creutzfeldt-Jakob disease (CJD), genetic CJD and Gerstmann-Sträussler-Scheinker disease (GSS)).

Results Of 5461 patients registered in the database, 2440 cases and 796 controls remained for the analysis. The cases comprised 1676 patients with sporadic CJD (69%), 649 with genetic CJD (27%) and 115 with GSS (5%). For patients with methionine homozygosity, potential risk for occurring prion diseases: adjusted OR (95% CI) was 2.21 (1.46 to 3.34) in sporadic CJD, 0.47 (0.32 to 0.68) in genetic CJD and 0.3 (0.17 to 0.55) in GSS. Among patients with specific prion protein abnormalities, the potential risk was 0.27 (0.17 to 0.41) in genetic CJD with 180 Val/Ile, 1.66 (0.65 to 5.58) in genetic CJD with 200 Glu/Lys, 3.97 (1.2 to 24.62) in genetic CJD with 232 Met/Arg and 0.71 (0.34 to 1.67) in GSS with 102 Pro/Leu.

Conclusions Methionine homozygosity at codon 129 was predisposing to sporadic CJD, but protective against genetic CJD and GSS, after adjustment for codon 219 polymorphism effect. However, the impacts differed completely among patients with specific prion protein abnormalities.

  • prion
  • epidemiology

Data availability statement

Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author on reasonable request.

https://doi.org/10.1136/jnnp-2021-328720

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    Data availability statement

    Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author on reasonable request.

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    Footnotes

    • Contributors Study concept and design: KK, RA, TK and YN. Data acquisition: TH, NS, TT, TK, HM and MY. Database management: KK, RA and YN. Analysis and interpretation: KK, RA, TH, NS and TK. Drafting of the manuscript: KK, RA and YN. Critical review of the manuscript for important intellectual content: TH, NS, TT, TK, HM and MY. Funding acquisition: HM and MY. Project management: HM and MY. RA acts as guarantor.

    • Funding This study was supported by the Research Committee of Surveillance and Infection Control of Prion Disease, the Ministry of Health, Labour and Welfare of the Japanese government (Grant number: not applicable).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.