Genetic variants associated with Fabry disease progression despite enzyme replacement therapy

Area of Science:

• Genetics
• Pharmacogenomics
• Rare Diseases

Background:

• Fabry disease is a rare X-linked disorder treated with enzyme replacement therapy (ERT).
• Patient response to ERT varies, with some experiencing disease progression despite treatment, particularly renal, cardiovascular, and cerebrovascular complications.
• The underlying reasons for this variability, especially concerning drug metabolism and transport, remain incompletely understood.

Purpose of the Study:

• To investigate the association between drug absorption, distribution, metabolism, and excretion (ADME) gene variants and treatment response variability in Fabry disease patients receiving ERT.
• To identify specific genetic markers that may predict the risk of ERT non-response and disease progression.

Main Methods:

• Genotyping of 37 Fabry disease patients undergoing ERT using the Affymetrix Drug Metabolizing Enzyme and Transporters (DMET) Plus microarray.
• Analysis of single nucleotide polymorphisms (SNPs) in genes related to drug metabolism and transport.
• Statistical analysis to correlate identified SNPs with clinical outcomes, specifically disease progression.

Main Results:

• Four specific single nucleotide polymorphisms (SNPs) were found to be significantly associated with disease progression in patients receiving ERT (p < 0.05).
• Three of these SNPs were located in the human alcohol dehydrogenase (ADH)4 gene (rs1126670, rs1126671, rs2032349).
• One SNP was identified in the ADH5 gene (rs2602836).

Conclusions:

• Genetic variants in ADH4 and ADH5 genes are associated with ERT response variability in Fabry disease.
• These findings suggest a potential role for pharmacogenomics in predicting ERT outcomes.
• The identified SNPs may serve as biomarkers for identifying patients at risk of ERT non-response, facilitating personalized treatment approaches for Fabry disease.