Monogenic FH, polygenic hypercholesterolemia increase CVD risk
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Genetic determinants of LDL levels may increase the risk for CVD among patients with hypercholesterolemia, according to a study published in JAMA Cardiology.
“The findings establish that among patient with very high cholesterol, the genetic cause of the high cholesterol has a significant impact on risk, with monogenic high cholesterol conferring a greater risk than polygenic high cholesterol,” Liam R. Brunham, MD, PhD, assistant professor in the department of medicine and associate director of the MD/PhD program at University of British Columbia in Vancouver, Canada, told Healio. “They suggest that understanding the genetic cause of a patient’s high cholesterol can provide important prognostic information.”
UK Biobank data
Mark Trinder, MSc, MD/PhD student in the division of experimental medicine at University of British Columbia, and colleagues analyzed genotyping array and exome sequencing data from 48,741 patients (mean age, 57 years; 55% women) from the UK Biobank. Patients were considered to have monogenic familial hypercholesterolemia (FH)-associated variants if LDLR, PCSK9 and APOB were noted as pathogenic or likely pathogenic. Polygenic hypercholesterolemia was defined as an LDL polygenic store higher than the 95th percentile based on 223 single nucleotide variants.
An outcome of interest was CVD events, defined as MI, coronary and carotid revascularization, all-cause mortality and ischemic stroke.
Of the patients in the study, 2,379 had polygenic hypercholesterolemia, 277 had monogenic FH and 2,232 had nongenetic hypercholesterolemia. The prevalence of a monogenic FH variant for hypercholesterolemia was 0.57%, or 1 in 176 patients.
Compared with patients without monogenic familial hypercholesterolemia, those with the disease were more likely to experience an atherosclerotic CVD event at age 55 years or younger (6.1% vs. 2%; HR = 3.17; 95% CI, 1.96-5.12). Patients with monogenic and polygenic hypercholesterolemia had an increased risk for CVD events compared with the general population.
Monogenic (HR = 1.93; 95% CI, 1.34-2.77) and polygenic hypercholesterolemia (adjusted HR = 1.26; 95% CI, 1.03-1.55) in patients with comparable LDL levels were significantly linked to an increased risk for CVD events vs. the risk in patients without an identified genetic cause of hypercholesterolemia.
“It will be important to extend these findings to other non-European ethnic groups,” Brunham said in an interview. “Also, while we have shown that risk of CVD differs, it remains unknown how response to treatment may or may not differ between monogenic and polygenic forms of high cholesterol.”
Potential of polygenic risk scores
In an Editor’s Note, Christopher J. O’Donnell, MD, MPH, chief of cardiology at VA Boston Healthcare System, associate professor of medicine at Harvard Medical School and associate editor of JAMA Cardiology, wrote: “Emerging evidence suggests that a polygenic risk score incorporating millions of gene variants may modify the risk conferred by monogenic variants. A fundamental question unanswered by the current study is whether risk levels from polygenic risk scores, monogenic risk or both together offer incremental value over and above LDL-C levels and burden of cardiovascular disease risk. Nevertheless, this study represents among the first prospective studies of cardiovascular disease comparing polygenic risk scores vs. monogenic risk in a population with genome sequences. The modest statistical significance in this study reflects the small sample sizes examined.” – by Darlene Dobkowski
For more information:
Liam R. Brunham, MD, PhD, can be reached at liam.brunham@ubc.ca; Twitter: @liambrunham.
Disclosures: The study authors report no relevant financial disclosures. O’Donnell reports he received funding from the Veterans Administration and the NIH.
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