Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

摘要

Recently, a compelling new therapeutic target for lowering low-density lipoprotein cholesterol (LDL-C) emerged from human genetics: the proprotein convertase subtilisin/ kexin type 9 gene (PCSK9 [MIM 607786]). PCSK9 protein-coding sequence variants that are low in frequency (defined here as allele frequencies from 0.1% to 5%) have been associated with lower plasma LDL-C and reduced risk for coronary heart disease (CHD). With the identification of low-frequency variants that protected against CHD, many pharmaceutical companies have established drug development programs targeting PCSK9. These observations have raised the question of whether the PCSK9 example is a paradigm for complex diseases like CHD or an exception.