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Blood Lipid Levels Linked to Rare Long, Noncoding RNA Variants in TOPMed Cohort

NEW YORK – Dozens of rare genetic variants falling in long noncoding RNAs appear to coincide with levels of various blood lipids, according to new research by a team led by investigators at the Boston University School of Medicine.

"Rare genetic variants in long noncoding RNAs (lncRNAs) have not been previously assessed for blood lipid levels," senior and corresponding author Gina Peloso, a biostatistics researcher at Boston University School of Public Health, said in an email. The paper appeared in the American Journal of Human Genetics on Thursday.

Using high-coverage whole-genome sequence data, the researchers searched for rare lncRNAs variants with ties to total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels in blood samples from more than 66,300 participants in the US National Heart, Lung, and Blood Institute's Trans-omics for Precision Medicine (TOPMed) program.

"Whole-genome sequencing allows us to test genetic variation that is not captured by genotyping or exome sequencing with complex traits such as blood lipid levels," Peloso added.

By analyzing rare variant patterns across nearly 165,400 lncRNA genes, the team turned to conditional analyses to narrow in on 83 rare variants in lncRNA genes that were significantly linked to blood lipid levels.

Nearly three-quarters of the associations were independent of lipid-related common regulatory variants or rare protein-coding variants occurring at the same sites in the genome in the conditional analyses, the investigators explained. They confirmed 34 of the 61 independent rare variant lncRNA associations using whole-genome sequence data from UK Biobank participants.

All of the newly detected associations involved rare variants falling in or around loci previously associated with blood lipid traits via genome-wide association studies (GWAS) in the past, the authors noted, adding that their results "expand the genetic architecture of blood lipids to rare variants in lncRNAs."

"[O]ur manuscript reports associations between rare variants in lncRNAs near previously identified lipid genes that are distinct from GWAS variants or the nearby protein coding genes," Peloso explained. "This indicates another functional element in the genome that contributes to genetic variability in blood lipid levels."

Given their findings so far, the researchers suggested that it may ultimately be possible to target certain blood lipid-related lncRNAs in the clinic as a strategy for tweaking the blood levels of lipids linked to conditions such as coronary heart disease.

"Our results highlight the therapeutic potential of lncRNAs that overlap with nearby protein-coding genes in both the anti-sense and sense direction," the authors wrote in their paper, adding that it may ultimately be possible to target lipid-linked lncRNAs with gene editing or small interfering RNA strategies.