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.
Bibliografisk noteFunding Information:
We gratefully acknowledge the participants in the Greenlandic health surveys. Funding: This project was funded by the Danish Council for Independent Research ( DFF-4090-00244 , Sapere Aude grant DFF-11-120909 and DFF-4181- 00383 ), the Steno Diabetes Center Copenhagen ( www.steno.dk ), the Lundbeck Foundation ( R215-2015-4174 ), and the Novo Nordisk Foundation ( NNF0064142 , NNF16OC0019986 , NNF17SH0027192 , NNF17OC0028136 , NNF18CC0034900 and NNFCC0018486 ). The Greenlandic health surveys (IHIT and B99) were supported by Karen Elise Jensen’s Foundation , the Department of Health in Greenland , NunaFonden , Medical Research Council of Denmark , Medical Research Council of Greenland, and the Commission for Scientific Research in Greenland . The population-based study referred to as “the cohort with NMR data” was supported by grants from the Danish Council for Independent Research , The Greenlandic Ministry of Education, Church, Culture and Gender Equality , the Maersk Foundation (Fonden til Lægevidenskabens Fremme), and the Aase and Ejnar Danielsens Foundation . Samples were handled and stored in the Danish National Biobank, which is supported by the Novo Nordisk Foundation . In addition, Ida Moltke was supported by a Danish National Research Foundation Award ( DNRF 143 ). Bjarke Feenstra was supported by the Oak Foundation . Line Skotte was supported by the Carlsberg Foundation . Mette K. Andersen was supported by a research grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation . Anders Albrechtsen and Kristian Hanghøj were supported by the Novo Nordisk Foundation ( NNF20OC0061343 ) and the Danish Research Foundation 0135-00211B .