Genetics of severe hypercholesterolemia in the general population: Insights from the STANISLAS cohort

Background: Severe hypercholesterolemia (SH) is a common condition characterized by increased levels of total and low-density lipoprotein cholesterol (LDLc). Methods: The aim of this study is to screen for prevalence of hypercholesterolemia, perform heritability estimation of circulating lipoproteins and study the association between SH cases and surrogate cardiovascular disease markers among participants of STANISLAS cohort. Gene candidate analyses were utilized to investigate the association between lipid levels, SH and polymorphisms from the three commonly reported genes (APOB, LDLR and PCSK9). Results: Participants with SH (n=102; 6.9%) were older (58 vs. 51yr), had higher total cholesterol (290 vs. 209mg/dL), LDLc (206 vs. 136mg/dL) and triglycerides (114 vs. 88 mg/dL). Despite smoking less, they had carotid plaques more frequently (21.2 vs. 9.3%), higher cIMT (676 vs. 597µm), and had more frequent family history cardiovascular disease. The circulating lipid levels have an important heritability: LDLc 51.6%, HDLc 66.6%, total cholesterol 49.8%, and triglycerides 41.4%. The SNPs located in LDLR gene present the strongest association with LDLc levels: rs55997232, rs17242395, rs1010679, and rs11668477. Conclusion: In a healthy cohort, participants with SH had premature vascular damage. LDLc had an important component of heritability and SNPs linked to the LDLR gene presented a strong association with LDLc. These findings reinforce the need for an early identification and treatment of SH subjects, which is mostly polygenic.