Abstract 12962: A Rare Deletion in the 3‘ Untranslated Region of LDLR Causes Very Low Levels of LDL Cholesterol

The low-density lipoprotein (LDL) receptor plays a central role in uptake and clearance of LDL cholesterol. Using whole-genome sequence data from 43,202 Icelanders, we searched for deletions in the LDL receptor gene (LDLR) using a recently developed paired-read based algorithm. We identified a 2.7 kilobase deletion involving the 3’ untranslated region (3’-UTR) of LDLR that was present in four closely related individuals. Three carriers with available lipid measurements have very low mean levels of LDL cholesterol0.55, 1.01 and 1.19 mmol/L, respectively. This translates to 72% lower mean LDL cholesterol than in non-carriers (0.92 vs. 3.3 mmol/L [35.5 vs. 127.4 mg/dL], respectively; P = 3.1 х 10; total sample of 87,788 individuals, SD = 0.90 mmol/L). Mean levels of HDL cholesterol and triglycerides are within normal range. Three of the carriers are alive at ages 33 to 60 and apparently healthy, the fourth died at the age of 84. No carrier has a known history of diabetes or dementia. Functional analyses using whole blood available from one carrier indicate that the deletion induces polyadenylation at a proximal, alternative polyadenylation site. This results in production of LDLR mRNA with a short 3‘-UTR that does not contain many known negative regulatory elements present on the native, long 3‘-UTR. The net effect is higher expression of LDLR, leading to enhanced hepatic uptake and clearance of LDL cholesterol. Additional functional experiments in this carrier and other family members are ongoing. To our knowledge, this is the first report of a sequence variant in LDLR that causes extremely low levels of LDL cholesterol. The magnitude of LDL cholesterol reduction accompanying the deletion is comparable to the reported ~60% reduction through pharmacologic lowering with PCSK9-inhibitors. These findings provide insights into the safety of lifelong very low levels of LDL cholesterol and may reveal new, potential therapeutic targets for hypercholesterolemia.