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

Autor:	Jørsboe E; Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Andersen MK; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Skotte L; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark., Stæger FF; Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Færgeman NJ; Villum Center for Bioanalytical Sciences, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark., Hanghøj K; Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Santander CG; Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Senftleber NK; Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Diaz LJ; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Overvad M; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Waples RK; Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Geller F; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark., Bjerregaard P; National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark., Melbye M; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; K.G.Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology (NTNU), Norway.; Center for Fertility and Health, Norwegian Institute of Public Health, Norway., Larsen CVL; National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.; Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland., Feenstra B; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark., Anders Koch; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.; Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland., Jørgensen ME; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.; Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland., Grarup N; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Moltke I; Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Albrechtsen A; Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Hansen T; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Jazyk:	angličtina
Zdroj:	HGG advances [HGG Adv] 2022 Jun 09; Vol. 3 (4), pp. 100118. Date of Electronic Publication: 2022 Jun 09 (Print Publication: 2022).
DOI:	10.1016/j.xhgg.2022.100118
Abstrakt:	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. Competing Interests: The authors declare no competing interests. (© 2022.)
Databáze:	MEDLINE
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