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Upregulated heme biosynthesis increases obstructive sleep apnea severity: a pathway-based Mendelian randomization

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Area of Science:

  • Genetics and Sleep Medicine
  • Metabolic Pathway Analysis
  • Cardiovascular Epidemiology

Background:

  • Obstructive sleep apnea (OSA) is a prevalent condition linked to significant cardiovascular risks.
  • Iron and heme metabolism pathways are implicated in OSA pathophysiology and comorbidities.
  • Previous genetic studies suggested associations, but causal links remained unclear.

Purpose of the Study:

  • To investigate the causal relationship between iron and heme metabolism pathways and obstructive sleep apnea.
  • To utilize pathway-level Mendelian randomization to assess genetic evidence for these links.

Main Methods:

  • Pathway-level transcriptional Mendelian randomization (MR) analysis was employed.
  • Cross-tissue cis-eQTL data from the Genotype-Tissue Expression (GTEx) portal was used.
  • Published genome-wide summary statistics for OSA traits and the Multi-Ethnic Study of Atherosclerosis (MESA) dataset were utilized.

Main Results:

  • A significant putative causal association was found between an up-regulated heme biosynthesis pathway and a higher percentage of sleep time with hypoxemia (p = 6.14 × 10-3).
  • This finding was corroborated by one-sample MR analysis using Trans-Omics for Precision Medicine (TOPMed) data.
  • Secondary analyses of other iron/heme pathways did not yield significant results.

Conclusions:

  • Increased heme biosynthesis is suggested to have a causal association with obstructive sleep apnea severity.
  • This research highlights a potential metabolic link contributing to OSA pathophysiology.