Environmental and Biological Markers of Survival in Septuagenarians and Octogenarians Carrying FH-Causing LDLR Gene Mutations*

Abstracts xanthomas and premature cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) loss of function (LOF) mutations, as well as novels PCSK9 inhibitors, are both associated with lower LDL-C concentrations in FH and non-FH subjects. Recently, it has been shown that the PCSK9 R46L LOF mutations, affecting approximately 1/50 individuals, was also associated with a significant lower risk of cardiovascular disease in FH subjetcs. Objective/Purpose: The objective of this crosssectional cohort study is to assess if 2 LOF variants of PCSK9 (R46L and InsLeu) are associated with a reduced risk of recurrent cardiovascular events (RCE) in patients with FH. Furthermore we aimed at identifying the strongest determinants of RCE in FH subjects. Methods: The data for this study come from the Nutrition, Metabolism and Atherosclerosis Clinic of Institut de recherches cliniques de Montreal (IRCM) database. We selected 724 FH subjects with a known mutation in the LDL receptor (LDLR) gene and we screened for both the R46L and InsLeu PCSK9 LOF mutations. The medical file of 308 of these subjects was available and reviewed to identify recurrent cardiovascular events (angina, myocardial infarction, angioplasty, coronary bypass, stroke and claudication). Results: Among the 69 InsLeu carriers, 80% never had RCE (0 or 1 cardiovascular event) whereas 20% of them experienced RCE (.1 events). This proportion was similar in the non-carriers (81% and 19%, respectively) (p50.86). Among the 18 R46L-carriers, none of them experienced RCE, whereas 21% of non-carriers had at least 1 episode of recurrence. There was a significant difference between the proportion of these two groups (p50.03). Logistical regression showed that sex, the type of LDLR mutation and HTN were other strong predictors of RCE. Patients with a class 1 LDLR mutation and HTN had a 3.7-fold increase for men and an 11.4-fold increase for women in the frequency of RCE compared to controls. Conclusions: PCSK9 R46L LOF mutation, but not InsLeu mutation, is associated with a reduced risk of RCE in patients with FH. Furthermore, it is likely that patients with a class 1 LDLR mutation and HTN would benefit greatly from further LDL and CVD risk reduction using novel therapies.

125 Environmental and Biological Markers of Survival in Septuagenarians and Octogenarians Carrying FH-Causing LDLR Gene Mutations* Etienne Khoury, PhD, Diane Brisson, PhD, Nathalie Roy, MD, Karine Tremblay, PhD, Gerald Tremblay, MD, Daniel Gaudet, MD, PhD, (Chicoutimi, QC)

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Lead Author’s Financial Disclosures: None Study Funding: None Background/Synopsis: Familial hypercholesterolemia (FH) is an autosomal dominant trait associated with increased risk of premature (, 50 years) coronary artery disease (CAD). It is acknowledged that statin therapy is a key pharmacological component of premature CAD prevention in FH. Because statins were prescribable only since 1987, it means that FH patients aged . 70 years have survived at least 40 years in the pre-statin era. Objective/Purpose: The objective of this study consists in identifying environmental and biological factors associated with unexpected survival in patients aged . 70 years carrying FH-causing LDL receptor (LDLR) gene mutations. Methods: The analysis of 2086 individuals carrying either the French-canadian Type 1 (15KB deletion), the French-canadian Type 2 (W66G), the C646Y, E207K and Y468X mutations, which are all FH-causing LDLR gene mutations, was performed. Results: We identified 197 FH subjects over 70 years of age (range between 70-84 years) and 263 patients with premature CAD aged # 50 years (range between 8-50 years) carrying the same mutations. Group comparisons including multivariate regression analyses revealed that the gender (female), smoking (no), waist circumference, highdensity lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) concentration, drug and diet response, and the type of mutation in the LDLR (non-null) were among the most significant contributory factors of survival in FH . 70 years (p-value less than 0.001). In these models, the contribution of HDL-C was independent from LDL-C. Genetic markers of survival were also identified and will be presented. Exome sequencing analyses are ongoing. Conclusions: These results suggest that beyond the FHcausing genotype, life habits and biological markers influence the risk trajectory of FH septuagenarians and octogenarians and possibly constitute major targets for cardiovascular disease risk management. 126 Association Between Frequent Gene-Smoking Interactions And Plama Apolipoprotein B Levels Among Low-Risk Individuals Nathalie Roy, MD, Daniel Gaudet, MD, PhD, Diane Brisson, PhD, (Chicoutimi, Quebec)

Lead Author’s Financial Disclosures: None Study Funding: None Background/Synopsis: Hyperapobetalipoproteinemia (hyperapoB) is a strong predictor of cardiovascular disease (CVD), even in patients who achieve recommended LDLCholesterol (LDL-C) goals, which shown its superiority over