Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia

Abstract

Background: Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Even among individuals with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence of an LDL-C polygenic score on levels of LDL-C and risk of ASCVD for individuals with monogenic FH.

Methods: We constructed a weighted LDL-C polygenic score, composed of 28 single-nucleotide variants, for individuals with monogenic FH from the British Columbia FH (n=262); Nutrition, Metabolism and Atherosclerosis Clinic (n=552); and UK Biobank cohorts (n=306). We assessed the association between LDL-C polygenic score with LDL-C levels and ASCVD risk using linear regression and Cox-proportional hazard models, respectively. ASCVD was defined as myocardial infarction, coronary or carotid revascularization, transient ischemic attack, or stroke. The results from individual cohorts were combined in fixed-effect meta-analyses.

Results: Levels of LDL-C were significantly associated with LDL-C polygenic score in the Nutrition, Metabolism and Atherosclerosis Clinic cohort, UK Biobank cohort, and in the meta-analysis (β [95% CI]=0.13 [0.072-0.19] per a 20% increase in LDL-C polygenic score percentile, P<0.0001). Additionally, an elevated LDL-C polygenic score (≥80th percentile) was associated with a trend towards increased ASCVD risk in all 3 cohorts individually. This association was statistically significant in the meta-analysis (hazard ratio [95% CI]=1.48 [1.02-2.14], P=0.04).

Conclusions: Polygenic contributions to LDL-C explain some of the heterogeneity in clinical presentation and ASCVD risk for individuals with FH.

Keywords: coronary artery disease; hypercholesterolemia; lipids; lipoproteins; metabolism.

Figure 1.

Association between LDL-C (low-density lipoprotein cholesterol) levels and LDL-C polygenic score percentile among individuals with familial hypercholesterolemia. The association between LDL-C levels and LDL-C polygenic score percentile is displayed for the (A) British Columbia Familial Hypercholesterolemia (BCFH), (B) Nutrition, Metabolism and Atherosclerosis Clinic (CNMA), and (C) UK Biobank cohorts. The blue lines and associated gray shading represent the linear regression line of best fit and 95% CI, respectively. D, A fixed-effect meta-analysis of the β coefficients and standard errors obtained from the linear regression models of LDL-C levels (mmol/L) vs continuous LDL-C polygenic score (per 20% increase) are shown. Linear regression models were adjusted for age and sex.

Figure 2.

Association between LDL-C (low-density lipoprotein cholesterol) levels and LDL-C polygenic score percentile among individuals with the same familial hypercholesterolemia (FH)-associated variant. The association between LDL-C levels and LDL-C polygenic score percentile is displayed for the individuals from the Nutrition, Metabolism and Atherosclerosis Clinic (CNMA) that were carriers for (A) the LDLR 15 kb promoter and exon 1 deletion and (B) the LDLR exon 3 missense variant p.Trp87Arg. The blue lines and associated grey shading represent the linear regression line of best fit and 95% CI, respectively.

Figure 3.

Association between risk of events and LDL-C (low-density lipoprotein cholesterol) polygenic score percentile among individuals with familial hypercholesterolemia. Atherosclerotic cardiovascular events included myocardial infarction, cardiovascular or carotid revascularization, and stroke. A, A fixed-effect meta-analyses of the β coefficients (ln[hazard ratio (HR)]) and SE obtained from Cox-proportional hazard models for risk of atherosclerotic cardiovascular events is shown for an LDL-C polygenic score ≥80th percentile score relative to and LDL-C polygenic score <80th percentile score. These Cox-proportional hazard models were adjusted for sex and used age as the time-to-event time scale. The studies included in the meta-analysis were the British Columbia Familial Hypercholesterolemia (BCFH), Nutrition, Metabolism and Atherosclerosis Clinic (CNMA), and UK Biobank cohorts. B, The time-to-atherosclerotic cardiovascular event curves are shown for the combined cohorts stratified by LDL-C polygenic score percentile above and below the 80th percentile. C, Sex-adjusted Cox-proportional hazard models are shown for the combined cohorts stratified by quintiles of LDL-C polygenic score percentile. ASCVD indicates atherosclerotic cardiovascular disease.

Figure 4.

LDL-C (Low-density lipoprotein cholesterol) polygenic score associates with the penetrance of familial hypercholesterolemia (FH). A, Individuals with monogenic FH and an LDL-C ≥5 mmol/L had significantly higher LDL-C polygenic score percentiles than those with monogenic FH and an LDL-C <5 mmol/L. Individuals with monogenic FH and an LDL-C polygenic score ≥50th percentile had a greater prevalence of (B) LDL-C levels ≥5 mmol/L and (C) parental history of heart disease relative to those with monogenic FH and an LDL-C polygenic score <50th percentile.