title: No Evidence of a Causal Relationship between Plasma Homocysteine and Type 2 Diabetes: A Mendelian Randomization Study.
abstract: BACKGROUND
  Several observational studies have shown an association between increased circulating homocysteine and risk of type 2 diabetes (T2D). We aimed to assess whether this relation is causal using genetic data from large populations of individuals of European descent.
  
  
  METHODS
  We investigated the association between homocysteine concentrations and blood glucose, plasma insulin, T2D in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort (n = 1,016). A score of five previously published single nucleotide polymorphisms (SNPs) from genes involved in homocysteine metabolism were utilized as genetic instrument for homocysteine concentrations. The effect estimate of this genetic score with T2D was determined using results from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (including 34,840 cases and 114,981 controls). Further, the effects of the genetic score with fasting glucose and insulin were determined using results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (up to 38,238 non-diabetic participants).
  
  
  RESULTS
  The genetic score provided a strong instrument for homocysteine concentrations (P = 2.7 × 10(-143), F = 650). In the PIVUS cohort, we found an association of homocysteine with fasting insulin [β = 0.056 (95% CI 0.021, 0.090), P = 0.001], but not with incident diabetes. We did not find any evidence of a causal effect of homocysteine on fasting glucose, fasting insulin, or T2D (P > 0.05 for all analyses) when using data from DIAGRAM or MAGIC studies.
  
  
  CONCLUSIONS
  No evidence of a causal relationship of levels of plasma homocysteine with fasting glucose, fasting insulin, or T2D was observed.
authors.affiliation: Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University , Uppsala , Sweden.
authors.forename: Jitender
authors.initials: J
authors.lastname: Kumar
authors.affiliation: Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University , Uppsala , Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Cardiovascular Epidemiology, Department of Medical Sciences, Uppsala University , Uppsala , Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University , Uppsala , Sweden.
authors.forename: Tove
authors.initials: T
authors.lastname: Fall
keywords: MTHFR; Mendelian randomization; association; homocysteine; type 2 diabetes