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Why do patients with #FamilialHypercholesterolemia have elevated #lipoprotein(a)?
Excited to share new work by @UBC MD/PhD student @marketrinder. His new study published in @JACCJournals.
https://www.onlinejacc.org/content/75/21/2682
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Excited to share new work by @UBC MD/PhD student @marketrinder. His new study published in @JACCJournals.
https://www.onlinejacc.org/content/75/21/2682
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Background:
FH is a common genetic condition affecting 1 in 250 individuals, caused (usually) by mutations in the LDLR gene. Whereas ~20% of the general population have elevated Lp(a), ~40% of patients with FH have elevated Lp(a). Why would this be?
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FH is a common genetic condition affecting 1 in 250 individuals, caused (usually) by mutations in the LDLR gene. Whereas ~20% of the general population have elevated Lp(a), ~40% of patients with FH have elevated Lp(a). Why would this be?
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Two hypotheses:
1)FH causes high Lp(a) because of impaired clearance of Lp(a). If so, one would expect higher Lp(a) in patients with LDLR mutations.
2)Lp(a) causes FH ( https://pubmed.ncbi.nlm.nih.gov/27185354 ). If so, one would expect higher Lp(a) levels in those without LDLR mutations.
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1)FH causes high Lp(a) because of impaired clearance of Lp(a). If so, one would expect higher Lp(a) in patients with LDLR mutations.
2)Lp(a) causes FH ( https://pubmed.ncbi.nlm.nih.gov/27185354 ). If so, one would expect higher Lp(a) levels in those without LDLR mutations.
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Our findings suggest: 3) none of the above.
Similar to previous studies, we found that Lp(a) levels were high in those with clinical FH.
Interestingly, among those with clinical FH, there was no difference in Lp(a) levels between those with or without an FH-causing variant.
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Similar to previous studies, we found that Lp(a) levels were high in those with clinical FH.
Interestingly, among those with clinical FH, there was no difference in Lp(a) levels between those with or without an FH-causing variant.
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So high Lp(a) in FH is not due to LDLR mutations. In contrast, we found that Lp(a) levels in patients with clinical FH are correlated with LPA KIV-2 repeat length. And the frequency of LPA genotypes that increase Lp(a) are significantly higher in patients with clinical FH.
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In a PheWAS, LPA genotypes were associated with many phenotypes relevant to FH, including hypercholesterolemia, atherosclerotic heart disease, and family history of ischemic heart disease.
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This suggests LPA genotypes increase Lp(a) levels, leading to phenotypes that increase the likelihood that a patient will be identified as having FH. In other words, ascertainment for clinical FH enriches for individuals who carry LPA genotypes that increase Lp(a).
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As a consequence, one would predict that in patients ascertained for FH genetically from the general population, without reference to the clinical phenotype, there should be no difference in Lp(a) levels. This is what we observed in @uk_biobank.
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Bottom line, patients ascertained clinically for FH are enriched for high Lp(a), thus it is critical to measure Lp(a) in all patients with clinical FH.
Thank you to patients in BCFH registry who participated, to @uk_biobank, @InnovationCA and @ComputeCanada.
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Thank you to patients in BCFH registry who participated, to @uk_biobank, @InnovationCA and @ComputeCanada.
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