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Numerous Variants in Single Gene Linked to Decreased Blood Oxygen During Sleep

NEW YORK – A new analysis has uncovered dozens of variants within a single gene that are associated with decreased blood oxygen levels during sleep.

People's blood oxygen levels typically fall as they sleep, and conditions like sleep apnea and lung diseases can lead those levels to fall even further, sometimes to a dangerous degree. Sleep apnea increases people's risk of other conditions like heart disease, dementia, and death. But people's blood oxygen levels are variable and are thought to have a genetic component.

"A person's average blood oxygen levels during sleep are hereditary, and relatively easy to measure," study author Susan Redline, senior physician in the Division of Sleep and Circadian Disorders at Brigham and Women's Hospital and professor at Harvard Medical School, said in a statement. "Studying the genetic basis of this trait can help explain why some people are more susceptible to sleep-disordered breathing and its related morbidities." 

In a study appearing this week in the American Journal of Human Genetics, Redline and her colleagues analyzed whole-genome sequencing data from the National Heart, Lung, and Blood Institutes Trans-Omics for Precision Medicine (TOPMED) project. By homing in on chromosomal region linked to blood oxygen levels in a previous linkage analysis, they uncovered 57 different variants in the DLC1 gene that affect blood oxygen levels during sleep.

That prior analysis of arterial oxyhemoglobin saturation during sleep — which can be measured using a pulse oximeter — in 617 individuals of European ancestry from 132 families from the Cleveland Family Study (CFS) uncovered a linkage peak on chromosome 8p23.

A further genotyping analysis of this cohort identified 18 families that potentially carry rare or low-frequency variants that affect these nighttime blood oxygen levels. Sequencing of 487 individuals from CFS uncovered 212,282 variants that had a minor allele frequency of less than 0.05 in this linkage region. After filtering for variants near protein-coding genes, gene burden tests, and more, the researchers zeroed in on five genes identified through functional coding variant analysis and eight identified through non-coding variant analysis for follow-up study. 

They examined these regions in nearly 2,500 individuals from the TOPMed cohorts through two meta-analyses, one of individuals of European ancestry and one of individuals of African ancestry. Through this, they uncovered a significant association between variants within the DLC1 gene and arterial oxyhemoglobin saturation during sleep, and suggestive associations at CSMD1 and MYOM2.

DLC1, the researchers noted, is highly expressed in lung tissue and regulates GTPases and activates PLCD1. They replicated this link between DLC1 and arterial oxyhemoglobin saturation during sleep using genotyping data from an additional 5,042 individuals.

In all, the researchers identified 57 variants — six coding and 51 noncoding variants — within DLC1 that are associated with blood oxygen levels during sleep. They further estimated that all these variants in DLC1 account for about 1 percent of the variance in arterial oxyhemoglobin saturation levels during sleep. 

Within a human lung fibroblast cell line, cells that produce scar tissue in the lungs, the researchers found that the 51 noncoding variants they found are enriched in regulatory features and influence variation in DLC1 expression. A further Mendelian randomization analysis indicated a causal relationship between DLC1 expression and blood oxygen levels during sleep.

According to James Kiley, director of the Division of Lung Diseases at NHLBI, this link between how these DLC1 variants affect fibroblasts and blood oxygen levels during sleep indicates there could be a shared molecular pathway that both influences whether someone might suffer low oxygen due to disordered breathing during sleep and other lung conditions like emphysema, as he noted in a statement.