Introduction: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular diseases and mortality. Recent observational admixture mapping analysis and gene enrichment analysis linked genes and pathways associated with heme metabolism to OSA traits, but the causal contribution is unclear. Iron and heme metabolism is associated with OSA comorbidities and carotid body ventilatory control mechanisms. In this study, we use gene expression data to examine whether iron and heme related pathways have a causal effect on OSA.
Methods: We performed Mendelian randomization (MR) analyses considering the expression level of 15 candidate Gene Ontology pathways as exposures and four OSA traits as outcomes, including the apnea hypopnea index (AHI), and three nocturnal oxygen saturation measurements. In discovery analysis, we performed two-sample MR using local expression trait loci (cis-eQTLs) from the Genotype-Tissue Expression (GTEx) portal and published genome-wide association summary statistics for OSA traits (N>19,000). Significant pathways were then followed-up by one-sample MR using high coverage DNA and RNA sequencing data from the Multi-Ethnic Study of Atherosclerosis generated by the NHLBI Trans-Omics for Precision Medicine (TOPMed) project.
Results: Discovery analysis identified putative causal associations between up-regulated heme biosynthetic process pathway on increased AHI and overnight hypoxemia (minimum P-value=0.018 across OSA traits). These associations were supported in European and Hispanic/Latino Americans but not in African Americans in replication analysis, consistent with prior ancestry-specific associations between a heme-related gene and OSA traits.

Conclusion: This study suggested a causal association between heme biosynthetic processes and OSA severity, suggesting novel biomarkers and possibly treatment targets. Future work is needed to identify the mechanisms for this association and to exclude reverse causality.

Support: This study was supported by Sleep Research Society Foundation Career
Development Award 018-JP-18 to H.W. and NHLBI R35HL135818 to S.R. Molecular data for the TOPMed MESA (phs001416) was supported by NHLBI.