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Methionine homozygosity for PRNP polymorphism and susceptibility to human prion diseases

Koki Kosami1, Ryusuke Ae2, Tsuyoshi Hamaguchi3

  • 1Division of Public Health, Center for Community Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Journal of Neurology, Neurosurgery, and Psychiatry
|April 7, 2022
PubMed
Abstract

Insights

Methionine homozygosity at codon 129 increases sporadic Creutzfeldt-Jakob disease (CJD) risk but protects against genetic CJD and Gerstmann-Sträussler-Scheinker disease (GSS). The impact varies with specific prion protein abnormalities.

Area of Science:

  • Neuroscience
  • Genetics
  • Epidemiology

Background:

  • Prion diseases, including Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker disease (GSS), represent a significant neurological challenge.
  • The role of specific genetic polymorphisms, such as methionine homozygosity at codon 129, in prion disease susceptibility requires further elucidation.
  • Previous research has not comprehensively assessed the independent association of codon 129 polymorphisms with prion disease risk, considering other genetic factors and population-based data.

Purpose of the Study:

  • To investigate the independent association between methionine homozygosity at codon 129 and the risk of developing various prion diseases.
  • To control for the influence of codon 219 polymorphisms and other potential confounders in a large-scale, population-based study.
  • To analyze the differential impact of codon 129 polymorphism on specific subtypes of prion diseases, including sporadic CJD, genetic CJD, and GSS.

Main Methods:

  • A case-control study was conducted using a Japanese nationwide surveillance database for prion diseases.
  • The primary exposure variable was methionine homozygosity at codon 129, with the development of prion diseases as the outcome.
  • Multivariable logistic regression models were utilized to analyze the associations for sporadic CJD, genetic CJD, and GSS, adjusting for codon 219 polymorphisms.

Main Results:

  • The analysis included 2440 cases and 796 controls from a database of 5461 patients.
  • Methionine homozygosity at codon 129 was associated with an increased risk of sporadic CJD (adjusted OR: 2.21) but a decreased risk of genetic CJD (adjusted OR: 0.47) and GSS (adjusted OR: 0.3).
  • The effect of methionine homozygosity varied significantly among patients with specific prion protein abnormalities, with some genotypes showing increased or decreased risk.

Conclusions:

  • Methionine homozygosity at codon 129 predisposes individuals to sporadic CJD while conferring protection against genetic CJD and GSS, even after adjusting for codon 219 polymorphisms.
  • The study highlights the complex interplay between PRNP codon 129 genotype and prion disease development.
  • The findings underscore the necessity of considering specific prion protein abnormalities when evaluating the impact of codon 129 polymorphism on prion disease risk.
Keywords:
epidemiologyprion

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