title: 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 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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Ueshima
authors.affiliation: Department of Public Health, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.affiliation: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hisamatsu
authors.affiliation: Department of Public Health, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fujiyoshi
authors.affiliation: Department of Public Health, Shiga University of Medical Science, Otsu, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Miura
authors.affiliation: Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Ohkubo
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Sekikawa
authors.affiliation: Department of Public Health, Shiga University of Medical Science, Otsu, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kadota
authors.affiliation: Department of Public Health, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kadowaki
authors.affiliation: Department of Food Science and Human Nutrition, Faculty of Agriculture, Ryukoku University, Otsu, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Public Health, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Miyagawa
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Okamura
authors.affiliation: Faculty of Nursing Science, Tsuruga Nursing University, Tsuruga, Japan.
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Kita
authors.affiliation: Department of Public Health, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Takashima
authors.affiliation: Kusatsu General Hospital, Kusatsu, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.affiliation: Division of Diabetology, Endocrinology, Nephrology and Neurology, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.affiliation: Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.affiliation: Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Kobe Home Care Institute General Incorporated Foundation, Kobe, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000097:blood* / Q000235:genetics; D000328:Adult; D000368:Aged; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000097:blood; D002340:Carotid Artery Diseases / Q000097:blood* / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics; D059168:Carotid Intima-Media Thickness; D000072226:Computed Tomography Angiography; D017023:Coronary Angiography / Q000379:methods; D003324:Coronary Artery Disease / Q000097:blood* / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics; D003430:Cross-Sectional Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D061330:Multidetector Computed Tomography; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D061205:Vascular Calcification / Q000097:blood* / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics
chemical_list: D015415:Biomarkers; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human
keywords: Carotid intima-media thickness; Carotid plaque; Coronary artery calcification; Lp-PLA(2); Mendelian randomization