Hirotsugu Ueshima1, Takashi Kadowaki2, Takashi Hisamatsu3, Akira Fujiyoshi2, Katsuyuki Miura4, Takayoshi Ohkubo5, Akira Sekikawa6, Aya Kadota4, Sayaka Kadowaki2, Yasuyuki Nakamura7, Naoko Miyagawa2, Tomonori Okamura8, Yoshikuni Kita9, Naoyuki Takashima2, Atsunori Kashiwagi10, Hiroshi Maegawa11, Minoru Horie12, Takashi Yamamoto12, Takeshi Kimura13, Toru Kita14. 1. Department of Public Health, Shiga University of Medical Science, Otsu, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan. Electronic address: hueshima@belle.shiga-med.ac.jp. 2. Department of Public Health, Shiga University of Medical Science, Otsu, Japan. 3. Department of Public Health, Shiga University of Medical Science, Otsu, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan; Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan. 4. Department of Public Health, Shiga University of Medical Science, Otsu, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan. 5. Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan. 6. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 7. Department of Food Science and Human Nutrition, Faculty of Agriculture, Ryukoku University, Otsu, Japan. 8. Department of Preventive Medicine and Public Health, School of Medicine, Keio University, Tokyo, Japan. 9. Faculty of Nursing Science, Tsuruga Nursing University, Tsuruga, Japan. 10. Kusatsu General Hospital, Kusatsu, Japan. 11. Division of Diabetology, Endocrinology, Nephrology and Neurology, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan. 12. Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan. 13. Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. 14. Kobe Home Care Institute General Incorporated Foundation, Kobe, Japan.
Abstract
OBJECTIVE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme predominantly bound to low-density lipoprotein (LDL). Lp-PLA2 is recognized as playing a key role in inflammatory processes and the development of atherosclerosis. This study aimed to investigate whether Lp-PLA2 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-PLA2 activity and concentration were undertaken separately for men aged 40-49 years and 50-79 years, to clarify interactions of age and Lp-PLA2. Lp-PLA2 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-PLA2 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-PLA2 activity and concentration. CONCLUSIONS: Lp-PLA2 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-PLA2 is a causative factor for subclinical atherosclerosis.
OBJECTIVE:Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme predominantly bound to low-density lipoprotein (LDL). Lp-PLA2 is recognized as playing a key role in inflammatory processes and the development of atherosclerosis. This study aimed to investigate whether Lp-PLA2 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-PLA2 activity and concentration were undertaken separately for men aged 40-49 years and 50-79 years, to clarify interactions of age and Lp-PLA2. Lp-PLA2 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-PLA2 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-PLA2 activity and concentration. CONCLUSIONS:Lp-PLA2 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-PLA2 is a causative factor for subclinical atherosclerosis.