Figure 2. Human genetics to facilitate drug development – Lipoprotein.

(a). Human genetics data serves as the foundation for ongoing efforts to develop therapies to reduce lipoprotein(a) levels, a causal risk factor for coronary artery disease. a | The selection of lipoprotein(a) as a therapeutic target was supported by a 2009 genome-wide association study comparing 1,145 CAD cases to 3,352 controls, noting a robust association between variants near the LPA gene, levels of circulating lipoprotein(a), and risk of coronary artery disease.⁷⁰ b | A dose-response relationship was noted, such that a given variant’s impact on circulating lipoprotein(a) levels was predictive of the association with CAD (Reproduced with permission from REF 91) c | In order to anticipate the full spectrum of phenotypic consequences of lipoprotein(a) reduction, a phenome-wide association study was performed among participants of the UK Biobank. A genetically-mediated one standard deviation decrease in levels of lipoprotein(a) was associated with a reduced risk of six distinct diseases (Reproduced with permission from REF 91). d | An antisense oligonucleotide targeting hepatic production of lipoprotein(a) was associated with a >80% decrease in circulating levels, providing proof-of-principle that targeting this causal pathway in a highly specific fashion (Reproduced with permission from REF 83).