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

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.

Figure 1

Effect of p.G137S variant on circulating lipid levels (A) Mean levels of LDL cholesterol stratified per genotype, as well as estimated effect sizes from GEMMA according to a full model (hatched area) with 95% confidence intervals. The number of participants in each group is written inside the bars. (B) For each genotype group, the proportion of different LDL cholesterol level categories is shown. The LDL cholesterol level categories are according to US guidelines²⁸) with <2.6 mmol/L being Optimal, 2.6–3.3 mmol/L being Desirable, 3.4–4.0 mmol/L being Borderline high, 4.1–4.8 mmol/L being High, and ≥4.9 mmol/L being Very high.

Figure 2

Effect sizes and explained variance of common variants associated with LDL cholesterol and ischemic heart disease in Europeans and the LDLR p.G137S variant in Greenlanders (A) Comparison of LDL cholesterol variance explained by the p.G137S variant, BMI, sex, smoking, age, and waist-hip ratio, respectively, in a model including all terms (All terms) as well as a model including the terms one at a time (Single term) with 95% confidence intervals. (B) Estimated LDL cholesterol variance (using quantile transformed effect sizes) explained by LDLR p.G137S in Greenlanders, and the genetic variants identified to be associated with LDL cholesterol levels in Europeans. (C) LDL cholesterol effect sizes (SD, standard deviation) for LDLR p.G137S in Greenlanders, and the genetic variants identified to be associated with LDL cholesterol levels in Europeans. (D) The odds ratio for ischemic heart disease for LDLR p.G137S variant in Greenlanders, and genetic variants identified to be associated with increased risk of ischemic heart disease in Europeans. Genetic variants with a minor allele frequency <0.01, have been omitted from the plot.

Figure 3

Effect of the p.G137S variant on concentration of lipoprotein particles and cholesterol species Lipoprotein particle concentration and metabolic measures in Greenlanders with NMR phenotypes. Estimates of the effect size of the p.G137S variant are shown with their 95% confidence interval, furthermore the confidence intervals are colored red if their p-value is below the Bonferroni correction of 3.3⋅10⁻⁴, and gray otherwise. Phenotype values were quantile transformed to a standard normal distribution. XXL, extremely large; XL, very large; L, large; M, medium; S, small; XS, very small; VLDL, very low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; Apo, apolipoprotein.

Figure 4

Estimated hazard ratios for the p.G137S variant on CVD Hazard ratios are shown with their 95% confidence interval and p-values (P) estimated with Cox regression testing for an association between the p.G137S variant and risk of different types of CVD events. The red color denotes those where the p-value is below the Bonferroni correction of 0.00833.