BACKGROUND/OBJECTIVE: Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in LDLR, APOB, or PCSK9 in approximately 80% of the cases. It has been shown that mutation negative FH patient may be carrier of the polygenic form of familiar hypercholesterolemia (pFH). pFH can be detected based on LDL cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs).
METHODS: To address whether polygenic forms may explain hypercholesterolemia in FH mutation negative patients, we gathered data from 125 mutation-negative (FH-) and 295 mutation-positive FH patients (FH+), as well as from 933 controls and genotyped the patients for 6 GLGC SNPs and compared the 6-SNP genetic score among patient groups and controls.
RESULTS: Mutation-negative FH patients had significantly higher 6-SNP (0.69 ± 0.20) score than controls or mutation-positive FH patients (0.62 ± 0.21 and 0.58 ± 0.24, p<0.001 respectively). We observed lower scores in mutation-positive FH patients compared with controls and mutation negative subjects (p=0.037 and p<0.001, respectively). Plasma levels of LDL-C showed to be associated with patients’ genotyping as FH+ subjects had higher levels of LDL-C compared with FH- and controls (262.2 ± 84.9, 200.8 ± 48.3 and 116.1 ± 37.7, respectively) and the comparison between groups was statistically significant (p<0.001)
CONCLUSION: The present study demonstrates the utility of SNP score analysis for identifying polygenic FH in a cohort of clinically diagnosed FH patients by showing that small-effect common SNPs may cumulatively elevate LDL-C levels. In addition, the genetic risk score can be used also as a marker of the severity of hypercholesterolemia in FH patients.