What is polygenic hypercholesterolemia?

Updated: Apr 09, 2021
  • Author: Nainesh K Gandhi, MD, MSE; Chief Editor: Keith K Vaux, MD  more...
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Some studies have introduced the classification of polygenic hypercholesterolemia, in which a person has the FH phenotype but none of the classic mutations that lead to heterozygous or homozygous familial hypercholesterolemia. One study, which examined a population in the United Kingdom, showed that in 40% of those with the FH phenotype, no mutations in LDLR, ApoB, or PCSK9 were found. [33, 34, 35, 36, 37, 38, 39]

Given these findings, some have proposed the concept that less potent but more common LDLc-raising variants at specific loci across multiple genes may be playing a key role. [31] Based on GWA (genome-wide association) studies that utilize high-throughput genotyping techniques, many SNPs have been found to have significant associations with elevated LDLc. It is thought that an individual may carry multiple variants that work together to produce an FH-like phenotype. Some investigators have proposed utilizing a polygenic or genotype score, which tallies SNPs from multiple LDLc-raising alleles, to use in risk assessment. Interestingly, some studies have shown that higher genotype scores have correlated with higher CVD event rates. [34, 40, 41, 5, 36, 37, 42, 43, 44, 45, 46, 47]

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