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Monogenic Hypercholesterolemia Increases Cardiovascular Disease Risk More Than Polygenic Form

NEW YORK – Researchers at the University of British Columbia have determined that monogenic hypercholesterolemia appears to be associated with a greater risk of atherosclerotic cardiovascular disease (CVD) than polygenic hypercholesterolemia among individuals with comparable levels of low-density lipoprotein cholesterol (LDL-C).

Monogenic familial hypercholesterolemia (FH) is associated with lifelong elevation in levels of LDL-C and increased risk of atherosclerotic CVD. However, many individuals' hypercholesterolemia has a polygenic rather than a monogenic cause, and it is unclear if polygenic variants also alter the risk of CVD, the authors wrote in a study published on Wednesday in JAMA Cardiology.

The researchers assessed whether any genetic variant for hypercholesterolemia altered the risk of atherosclerotic CVD, and evaluated how this risk compared with that of nongenetic hypercholesterolemia. They conducted a genetic-association case-control cohort study on 48,741 individuals who were recruited by the UK Biobank, using genotyping array and exome sequencing data to identify individuals with monogenic or polygenic hypercholesterolemia.

A monogenic cause for hypercholesterolemia was found in 277 participants and a polygenic cause in 2,379 participants. Overall, monogenic FH-associated variants were found in the LDLR gene for 257 individuals, in PCSK9 for 13 individuals, and in APOB for seven individuals. The researchers identified a total of 121 unique monogenic FH-associated variants, most of which were in LDLR.

Both polygenic and monogenic causes of hypercholesterolemia appeared to be associated with an increased risk of CVD compared with hypercholesterolemia with an undetermined cause, the researchers wrote. However, monogenic hypercholesterolemia was associated with the greatest risk of CVD.

Participants with monogenic FH were significantly more likely than those without to experience an atherosclerotic CVD event at 55 years or younger — 17 of the 277 (6.1 percent) individuals with monogenic hypercholesterolemia experienced such an event compared to 988 (2 percent) of the remaining 48,464 individuals.

"The findings of this study suggest that among individuals with hypercholesterolemia, genetic determinants of LDL-C levels may impose additional risk of CVD," the authors wrote. "Thus, understanding the possible genetic cause of hypercholesterolemia may provide important prognostic information to treat patients."

They also noted that 60 percent of individuals with monogenic hypercholesterolemia compared with 24.6 percent of individuals with polygenic hypercholesterolemia reported a history of high cholesterol at the time of enrollment in the UK Biobank study, which may be consistent with earlier manifestation of the condition in those with a monogenic cause. Polygenic hypercholesterolemia may also respond better than monogenic FH to cholesterol-lowering medication.

These findings support the possible need for routine genetic testing of patients with clinically suspected FH to reduce the incidence of premature CVD, the researchers said. The autosomal codominant inheritance of monogenic FH-associated variants could enable clinicians to efficiently screen relatives of probands in cascade screening in order to initiate lifestyle modification and cholesterol-lowering medication when necessary.

"Individuals with monogenic FH have the highest risk of CVD and are likely to derive the most benefit from statin and ezetimibe therapy, and, if needed, more costly cholesterol-lowering medications such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors," the authors noted.

In a related editorial published in JAMA Cardiology, Christopher O'Donnell, the journal's associate editor and a researcher at Brigham and Women’s Hospital noted that a fundamental question this study didn't answer is whether risk levels from polygenic risk scores, monogenic risk, or the combination of the two could offer any incremental value above LDL-C levels and burden of cardiovascular disease risk.

However, he added, this paper is one of the first prospective studies of cardiovascular disease comparing polygenic risk to monogenic risk in a population with available genome sequences.

"The findings point to questions to be addressed in future genome sequencing studies in large biobanks," O'Donnell wrote, including which polygenic risk score (PRS) algorithms should be used in risk assessment and treatment decisions, what appropriate PRS thresholds for elevated risk are, how PRS modifies monogenic risk, and what the appropriate PRS risk algorithms are for multiethnic populations, including African Americans and Hispanic Americans.

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