Exome variants influencing LDL cholesterol in early-onset myocardial infarction

Background: Low-density lipoprotein cholesterol (LDL-C) causes atherosclerotic cardiovascular diseases, including myocardial infarction (MI). The aim of the Italian Genetic Study on Early-onset MI was to evaluate the effect of the rare exome variants influencing LDL-C on the risk of recurrent ischemic events after a MI occurring before the age of 45 years. Methods: The study population consisted of 2,000 patients hospitalised because of a first early-onset MI, who were followed up for a median of 19.9 years for the occurrence of the primary endpoints of cardiovascular death, non-fatal MI or non-fatal stroke. Whole-exome sequencing led to the annotation of deleterious variants of 17 genes known to have a significant impact on LDL-C. Results: One hundred patients had exome variants influencing hypercholesterolemia (HYPER); 60 had variants influencing hypocholesterolemia (HYPO); and 1,840 had no variants (NV). At the time of the index event, the median plasma LDL-C level was 190 mg/dL (interquartile range [IQR] 136-251) in the HYPER group, 114 mg/dL (IQR 86-131) in the HYPO group, and 140 mg/dL (IQR 112-168) in the NV group (p for trend <0.001). During the long-term follow-up the progression of coronary atherosclerosis and the cumulative incidence of primary endpoints was significantly different among the groups, and trend analysis showed that the incremental risk was HYPO<NV<HYPER (p for trend <0.01 and <0.004, respectively). Conclusion: Exome variants influencing LDL-C have a measurable impact on coronary atherosclerosis progression and the probability of recurrent ischemic events after early-onset MI.