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.

• Authors: Mark Trinder, Martine Paquette, Lubomira Cermakova, Matthew R Ban, Robert A Hegele, Alexis Baass, Liam R Brunham
• Journal: Circulation. Genomic and precision medicine (Circ Genom Precis Med) Vol. 13 Issue 5 Pg. 515-523 (10 2020) ISSN: 2574-8300 [Electronic] United States
• PMID: 33079599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholesterol, LDL

Topics

• Adult
• Cholesterol, LDL (blood)
• Heart Disease Risk Factors
• Humans
• Hyperlipoproteinemia Type II (diagnosis, genetics)
• Male
• Middle Aged
• Multifactorial Inheritance (genetics)
• Polymorphism, Single Nucleotide
• Proportional Hazards Models