Lipoprotein-associated phospholipase A₂ and risk of incident peripheral arterial disease: Findings from The Atherosclerosis Risk in Communities study (ARIC)

Background and aims Results from prospective studies evaluating the relationship between elevated lipoprotein-associated phospholipase A₂ (Lp-PLA₂) activity and incident peripheral arterial disease (PAD) have been mixed. We investigated whether higher Lp-PLA₂ levels are associated with increased risk of incident PAD and whether PLA2G7 gene variants, which result in lower Lp-PLA₂ levels, are associated with reduced risk of incident PAD. Methods Our analysis included 9922 participants (56% female; 21% African-American; mean age 63 years) without baseline PAD at ARIC Visit 4 (1996–1998), who had Lp-PLA₂ activity measured and were subsequently followed for the development of PAD, defined by occurrence of a PAD-related hospitalization, through 2012. Cox proportional hazard models were performed to determine the association of Lp-PLA₂ levels and PLA2G7 gene variants with incident PAD. Results During a median follow-up of 14.9 years, we identified 756 incident cases of PAD. In analyses adjusting for age, race, and sex, each standard deviation increment in Lp-PLA₂ activity (62 nmol/ml/min) was associated with a higher risk of developing PAD (hazard ratio (HR) 1.17; 95% confidence interval (CI) 1.09, 1.26). This association remained significant after additional adjustment for risk factors, other cardiovascular disease, and medication use, but was strongly attenuated (HR: 1.09; 95% CI 1.00, 1.20). PLA2G7 variants were not associated with a lower risk of PAD in both white carriers (HR: 1.21; 95% CI: 0.17–8.56) and African-American carriers (HR: 0.83; 95% CI: 0.41–1.67), although statistical power was quite limited for this analysis, particularly in whites. Conclusions While higher Lp-PLA₂ activity was associated with an increased risk for incident PAD, it is likely a risk marker largely represented by traditional risk factors.