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; Anders Koch; Marit E Jørgensen; Niels Grarup; Ida Moltke; Anders Albrechtsen; Torben Hansen

doi:10.1016/j.xhgg.2022.100118

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

HGG Adv. 2022 Jun 9;3(4):100118. doi: 10.1016/j.xhgg.2022.100118. eCollection 2022 Oct 13.

Authors

Emil Jørsboe^{1

2}, Mette K Andersen², Line Skotte³, Frederik F Stæger¹, Nils J Færgeman⁴, Kristian Hanghøj¹, Cindy G Santander¹, Ninna K Senftleber^{1

5}, Lars J Diaz⁵, Maria Overvad⁵, Ryan K Waples¹, Frank Geller³, Peter Bjerregaard⁶, Mads Melbye^{7

8

9

10}, Christina V L Larsen^{6

11}, Bjarke Feenstra³, Anders Koch^{3

11}, Marit E Jørgensen^{5

6

11}, Niels Grarup², Ida Moltke¹, Anders Albrechtsen¹, Torben Hansen^{2

12}

Affiliations

¹ Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
² Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
⁴ Villum Center for Bioanalytical Sciences, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark.
⁵ Steno Diabetes Center Copenhagen, Gentofte, Denmark.
⁶ National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
⁷ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹ K.G.Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology (NTNU), Norway.
¹⁰ Center for Fertility and Health, Norwegian Institute of Public Health, Norway.
¹¹ Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland.
¹² Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

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.

Keywords: LDL cholesterol; cardiovascular disease; genetics; ischemic heart disease; population medicine; precision medicine.