| Title: | Polygenic Contribution to Low-density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia |
| Journal: | Circulation Genomic and Precision Medicine |
| Published: | 13 Aug 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33079599/ |
| DOI: | https://doi.org/10.1161/circgen.120.002919 |
| URL: | https://www.ahajournals.org/doi/pdf/10.1161/CIRCGEN.120.002919 |
Publication 5565
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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.</p>
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.</p>
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).</p>
CONCLUSIONS: Polygenic contributions to LDL-C explain some of the heterogeneity in clinical presentation and ASCVD risk for individuals with FH.</p>
10 Keywords
- Adult
- Cholesterol, LDL
- Heart Disease Risk Factors
- Humans
- Hyperlipoproteinemia Type II
- Male
- Middle Aged
- Multifactorial Inheritance
- Polymorphism, Single Nucleotide
- Proportional Hazards Models
7 Authors
- Mark Trinder
- Martine Paquette
- Lubomira Cermakova
- Matthew R. Ban
- Robert A. Hegele
- Alexis Baass
- Liam R. Brunham
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