We sought to determine if a common polymorphism can increase vulnerability to a modifiable risk factor for cardiovascular disease (CVD), and thereby influence the expected clinical benefit from therapies used to treat that risk factor.In two meta-analyses and a meta-regression analysis involving approximately 150,000 participants, we show that a common KIF6 polymorphism increases vulnerability to LDL cholesterol (LDL-C), and thereby influences the expected benefit from therapies that reduce serum LDL-C.