title: Conventional and Mendelian randomization analyses suggest no association between lipoprotein(a) and early atherosclerosis: the Young Finns Study.
abstract: BACKGROUND
  Lipoprotein(a) [Lp(a)] is an established risk factor for coronary disease and stroke, but mechanisms underlying this association are unknown. We examined the association of Lp(a) with early atherosclerosis by using conventional epidemiologic analysis and a Mendelian randomization analysis. The latter utilized genetic variants that are associated with Lp(a) to estimate causal effect.
  
  
  METHODS
  A prospective population-based cohort study of 939 men and 1141 women was conducted. Lp(a) was measured repeatedly at mean ages 17 and 38 years. Measurements of carotid intima-media thickness (IMT) and brachial flow-mediated dilation (FMD) at mean ages 32 and 38 years were used to determine the level and 6-year progression of subclinical atherosclerosis. Lp(a)-related genetic variant, rs783147, was identified by a genome wide association analysis (P = 3.1 × 10⁻⁵⁸), and a genetic score was constructed based on 10 Lp(a)-related variants. Mendelian randomization test was performed using a two-stage instrumental variables analysis.
  
  
  RESULTS
  rs783147 and the genetic score were strong instruments for nonconfounded Lp(a) levels (F-statistics 269.6 and 446.0 in the first-stage instrumental variable analysis). However, Lp(a) levels were not associated with the levels of or change in IMT or FMD in any of the conventional and instrumental variables tests. The null finding was observed both with rs783147 and the genetic score as instruments and remained unchanged after adjustment for clinical characteristics, such as age, sex, HDL and LDL cholesterol, ApoB, systolic and diastolic blood pressure, diabetes and smoking.
  
  
  CONCLUSIONS
  Data from conventional and Mendelian randomization analyses provide no support for early atherogenic effects of increased Lp(a) levels.
authors.affiliation: Department of Epidemiology, University College London, London, UK. m.kivimaki@ucl.ac.uk
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimäki
authors.forename: Costan G
authors.initials: CG
authors.lastname: Magnussen
authors.forename: Markus
authors.initials: M
authors.lastname: Juonala
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Loo
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Jorma
authors.initials: J
authors.lastname: Viikari
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
mesh_terms: D000293:Adolescent; D000328:Adult; D050197:Atherosclerosis / Q000473:pathology*; D002339:Carotid Arteries / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005387:Finland; D055106:Genome-Wide Association Study; D056914:Genomic Structural Variation; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood* / Q000235:genetics*; D008297:Male; D057182:Mendelian Randomization Analysis; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D017270:Lipoprotein(a)