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

Abstract

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Iron and heme metabolism, implicated in ventilatory control and OSA comorbidities, was associated with OSA phenotypes in recent admixture mapping and gene enrichment analyses. However, its causal contribution was unclear. In this study, we performed pathway-level transcriptional Mendelian randomization (MR) analysis to investigate the causal relationships between iron and heme related pathways and OSA. In primary analysis, we examined the expression level of four iron/heme Reactome pathways as exposures and four OSA traits as outcomes using cross-tissue cis-eQTLs from the Genotype-Tissue Expression portal and published genome-wide summary statistics of OSA. We identify a significant putative causal association between up-regulated heme biosynthesis pathway with higher sleep time percentage of hypoxemia (p = 6.14 × 10-3). This association is supported by consistency of point estimates in one-sample MR in the Multi-Ethnic Study of Atherosclerosis using high coverage DNA and RNA sequencing data generated by the Trans-Omics for Precision Medicine project. Secondary analysis for 37 additional iron/heme Gene Ontology pathways did not reveal any significant causal associations. This study suggests a causal association between increased heme biosynthesis and OSA severity.

• Authors: Heming Wang, Nuzulul Kurniansyah, Brian E Cade, Matthew O Goodman, Han Chen, Daniel J Gottlieb, Sina A Gharib, Shaun M Purcell, Xihong Lin, Richa Saxena, Xiaofeng Zhu, Peter Durda, Russel Tracy, Yongmei Liu, Kent D Taylor, W Craig Johnson, Stacey Gabriel, Joshua D Smith, François Aguet, Kirstin Ardlie, Tom Blackwell, Alexander P Reiner, Jerome I Rotter, Stephen S Rich, TOPMed Sleep Traits Working Group, Susan Redline, Tamar Sofer
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 1472 (01 27 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35087136 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Heme
• Iron

Topics

• Aged
• Datasets as Topic
• Female
• Genetic Predisposition to Disease
• Heme (biosynthesis)
• Humans
• Iron (metabolism)
• Male
• Mendelian Randomization Analysis
• Metabolic Networks and Pathways (genetics)
• Middle Aged
• Polysomnography
• Quantitative Trait Loci
• Severity of Illness Index
• Sleep Apnea, Obstructive (blood, diagnosis, epidemiology, genetics)
• Up-Regulation