Lipoprotein-associated phospholipase A2 (Lp-PLA2) produces the proinﬂammatory mediators lysophosphatidylcholine and oxidized free fatty acids. Increased Lp-PLA2 activity has been associated with higher risks of occlusive vascular diseases, recent phase III trials of the Lp-PLA2 inhibitor darapladib, which reduces Lp-PLA2 activity by w60%, failed to establish a protective role of darapladib for prevention of major vascular events in patients with stable coronary heart disease (CHD) or acute coronary syndrome.
CKB researchers investigated a V279F loss-of-function variant in the PLA2G7 gene encoding Lp-PLA2, which results in 50% lower activity for each copy of the variant and is common in East Asians. Importantly it allows for an unbiased assessment of the causal effects of lifelong lower Lp-PLA2 activity, analogous to randomized trials of Lp-PLA2 inhibition. The research concluded that genetically determined lower Lp- PLA2 activity appeared to have no substantial causal effects on major vascular diseases, consistent with ﬁndings from randomized trials of Lp-PLA2–lowering therapy. These ﬁndings demonstrate that it may be valuable to use functional genetic variants in large-scale prospective studies with follow-up of a range of health outcomes to help predict any beneﬁcial and adverse effects of novel therapeutic strategies (as well as to identify any potential alternative indications) prior to undertaking costly clinical trials.