Abstract 19939: Familial Hypercholesterolemia: Classification of Mutation Severity According To Percentile Low-Density Lipoprotein Cholesterol Useful for Predicting Coronary Artery Disease Risk
Introduction: The clinical variability in patients diagnosed with familial hypercholesterolemia (FH) is largely related to severity of the underlying mutation. International guidelines advise to group these mutations according to class 1 and non-class 1 mutations, but this classification does not incorporate available data on observed severity in terms of LDL-cholesterol (LDL-c) levels and coronary artery disease (CAD) risk.
Aims: We set out to establish CAD risk in patients with confirmed pathogenic LDLR mutations, with stratification according to percentile LDL-c (PLDL).
Methods: Individuals were eligible if they underwent family screening for FH in the Netherlands between 1994 and 2010. We calculated the mean pre-treatment age and gender corrected PLDL of each FH mutation and stratified these in 6 strata using the 75th , 88th, 92nd, 96,5th and 98th percentile as boundaries. We used Cox proportional hazard model to estimate the risk of major CAD (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft) for different FH mutation carriers versus unaffected relatives before 1990 (pre-statin). The reference population consisted of non-mutation carriers from the same families.
Results: A total of 34197 persons were tested for 456 different pathogenic LDLR mutations, identified in the index patient of their family. Of these, 12245 (36%) were found carriers. CAD risk inclined gradually from 2.2 for those with mutations associated with PLDL below the 75th percentile to 13 for those with mutations with a mean PLDL higher than then the 98th percentile.
Conclusions: Mutation severity classified based on PLDL allows more adequate risk stratification in FH than classification according to the dichotomy of class 1 versus non-class 1 mutations. The current proposed approach will likely be of clinical use in counseling patients on the expected risk based on their FH mutation as well as in identifying high risk patients for expensive treatments.
Author Disclosures: M.L. Hartgers: None. G.K. Hovingh: None. J.J. Kastelein: Consultant/Advisory Board; Modest; Sanofi, Amgen, Pfizer, Eli Lilly, The Medicines Company, Regeneron. R. Huijgen: None.
- © 2016 by American Heart Association, Inc.