Niemann-Pick C1-like 1 (NPC1L1) protein is expressed in the small intestine and liver and facilitates the transport of intraluminal dietary cholesterol into enterocytes. This transporter is the target of the drug ezetimibe and inhibition of the transporter is known to significantly reduce plasma levels of LDL cholesterol. In this genetic study, the authors first sequenced NPC1L1 to search for mutations that inactivated the transporter and then determined whether these mutations were correlated with a lower risk of coronary heart disease. First, NPC1L1 was sequenced in 7364 patients with known coronary heart disease and in 14,728 healthy controls. The authors identified 15 distinct NPC1L1 inactivating mutations with the most common mutation being p.Arg406X. In a larger cohort of 22,590 patients with coronary heart disease and 68,412 controls, the authors genotyped study participants for p.Arg406X and data on LDL levels and coronary event rates were compared between patients with and without this mutation. After correction for statin use, heterozygous carriers of p.Arg406X were found to have a mean LDL cholesterol level that was 0.31 mmol/l lower than non-carriers (P=0.04). In addition, carriers of the mutation had a lower rate of coronary events (OR, 0.47; 95% CI, 0.25 to 0.87; P=0.008).

Conclusions: Mutations that disrupt the function of the NPC1L1 cholesterol transporter gene are associated with both lower LDL cholesterol levels and a lower coronary event rate. These findings provide support for LDL cholesterol contributing to coronary disease risk and promote the concept of LDL control in reducing event rates.

Summarized by Hussain Contractor and Steven M. Bradley

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