An LDLR missense variant poses high risk of familial hypercholesterolemia in 30% of Greenlanders and offers potential of early cardiovascular disease intervention

Emil Jørsboe, Mette K. Andersen, Line Skotte, Frederik F. Stæger, Nils J. Færgeman, Kristian Hanghøj, Cindy G. Santander, Ninna K. Senftleber, Lars J. Diaz, Maria Overvad, Ryan K. Waples, Frank Geller, Peter Bjerregaard, Mads Melbye, Christina V.L. Larsen, Bjarke Feenstra, Koch Anders Koch, Marit E. Jørgensen*, Niels Grarup, Ida MoltkeAnders Albrechtsen, Torben Hansen

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

41 Downloads (Pure)

Abstract

The common Arctic-specific LDLR p.G137S variant was recently shown to be associated with elevated lipid levels. Motivated by this, we aimed to investigate the effect of p.G137S on metabolic health and cardiovascular disease risk among Greenlanders to quantify its impact on the population. In a population-based Greenlandic cohort (n = 5,063), we tested for associations between the p.G137S variant and metabolic health traits as well as cardiovascular disease risk based on registry data. In addition, we explored the variant's impact on plasma NMR measured lipoprotein concentration and composition in another Greenlandic cohort (n = 1,629); 29.5% of the individuals in the cohort carried at least one copy of the p.G137S risk allele. Furthermore, 25.4% of the heterozygous and 54.7% of the homozygous carriers had high levels (>4.9 mmol/L) of serum LDL cholesterol, which is above the diagnostic level for familial hypercholesterolemia (FH). Moreover, p.G137S was associated with an overall atherosclerotic lipid profile, and increased risk of ischemic heart disease (HR [95% CI], 1.51 [1.18–1.92], p = 0.00096), peripheral artery disease (1.69 [1.01–2.82], p = 0.046), and coronary operations (1.78 [1.21–2.62], p = 0.0035). Due to its high frequency and large effect sizes, p.G137S has a marked population-level impact, increasing the risk of FH and cardiovascular disease for up to 30% of the Greenlandic population. Thus, p.G137S is a potential marker for early intervention in Arctic populations.

Original languageEnglish
Article number100118
JournalHuman Genetics and Genomics Advances
Volume3
Issue number4
ISSN2666-2477
DOIs
Publication statusPublished - 13. Oct 2022

Keywords

  • cardiovascular disease
  • genetics
  • ischemic heart disease
  • LDL cholesterol
  • population medicine
  • precision medicine

Fingerprint

Dive into the research topics of 'An LDLR missense variant poses high risk of familial hypercholesterolemia in 30% of Greenlanders and offers potential of early cardiovascular disease intervention'. Together they form a unique fingerprint.

Cite this