USING GENETICS TO INFORM LIPOPROTEIN (A) INTERVENTIONS

Lipoprotein(a) [Lp(a)] is a genetically determined and causal risk factor for atherosclerotic cardiovascular disease (ASCVD). With the recent development of novel therapies that can reduce Lp(a) by up to 99%, assessing both anticipated and unanticipated effects, including the potential safety of substantial Lp(a) lowering, has become imperative. However, the phenotypic consequences of very low Lp(a) remain incompletely understood. Especially, the relationship between Lp(a) and type 2 diabetes remains debated, with prior studies suggesting increased risk at very low Lp(a) levels. Beyond diabetes risk, it is equally important to evaluate the implications of low Lp(a) across clinically relevant disease domains, given prior studies suggesting potential associations with other high-priority phenotypes including bleeding, inflammation and cancer.The LPA null allele rs41272114 mimics the mechanism of emerging Lp(a)-lowering therapies and results in lifelong very low to undetectable Lp(a) levels serving as natural experiments that can help address current evidence gaps. Importantly, this variant occurs at higher frequency in Hispanic/Latino populations, enabling more robust evaluation in multi-ethnic analyses. Thus, we conducted large multi-ethnic studies of European, Hispanic/Latino, and South Asian populations to comprehensively characterize the effects of LPA null allele rs41272114 on type 2 diabetes and glycemic traits, as well as on high-priority outcomes across hemostatic, inflammatory, and neoplastic disease domains to inform the clinical implications of emerging Lp(a)-targeted therapies.Our studies demonstrated that genetically inferred very low Lp(a) was not associated with type 2 diabetes and glycemic biomarkers. In the broader phenotypic analysis, the effects of the null allele were largely confined to reduced myocardial infarction risk. We observed no meaningful associations with hemostatic outcomes including plasminogen activity and bleeding, cancer incidence or mortality, or most inflammatory markers. Collectively, these findings provide a comprehensive characterization of the phenotypic consequences of lifelong very low Lp(a) across glycemic, cardiovascular, hemostatic, inflammatory, and neoplastic domains. The overall pattern of our results suggests that substantial Lp(a) reduction is unlikely to meaningfully impact most non-atherosclerotic disease domains. Taken together, these findings help contextualize the broader implications of emerging Lp(a)-lowering therapies and highlight the importance of leveraging multi-ethnic populations to strengthen causal inference.