Lipoprotein-associated phospholipase A2 is related to risk of subclinical atherosclerosis but is not supported by Mendelian randomization analysis in a general Japanese population

Abstract Objective Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is an enzyme predominantly bound to low-density lipoprotein (LDL). Lp-PLA 2 is recognized as playing a key role in inflammatory processes and the development of atherosclerosis. This study aimed to investigate whether Lp-PLA 2 is related to subclinical atherosclerosis, independently from traditional risk factors, in a general Japanese population by analyses of both the observational study and Mendelian randomization using V279F polymorphism. Methods and results We cross-sectionally examined community-based sample of 929 Japanese men aged 40–79 years, without statin treatment, who were randomly selected from the resident registration. Multiple regression analyses of Lp-PLA 2 activity and concentration were undertaken separately for men aged 40–49 years and 50–79 years, to clarify interactions of age and Lp-PLA 2 . Lp-PLA 2 activity for men aged 50–79 years was significantly and positively related to intima-media thickness (IMT) ( P  = 0.013) and plaque index ( P  = 0.008) independent of traditional risk factors including small LDL particles, but not to coronary artery calcification (CAC) score. Associations with Lp-PLA 2 concentration were qualitatively similar to those of activity. Corresponding relationships were not observed in men aged 40–49 years. Mendelian randomization analyses based on V279F genotype did not show any significant associations with subclinical atherosclerosis, although the homozygote and heterozygote of V279F showed low Lp-PLA 2 activity and concentration. Conclusions Lp-PLA 2 activity in Japanese men aged 50–79 years was associated significantly and positively with IMT and plaque in the carotid artery but Mendelian randomization did not support that Lp-PLA 2 is a causative factor for subclinical atherosclerosis.