Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin

Acta Diabetol. 2017 Nov;54(11):1031-1038. doi: 10.1007/s00592-017-1036-4. Epub 2017 Sep 2.


Aims: Inverse relationships have been described between the largely genetically determined levels of serum/plasma lipoprotein(a) [Lp(a)], type 2 diabetes (T2D) and fasting insulin. Here, we aimed to evaluate the nature of these relationships with respect to causality.

Methods: We tested whether we could replicate the recent negative findings on causality between Lp(a) and T2D by employing the Mendelian randomization (MR) approach using cross-sectional data from three independent cohorts, Berlin Aging Study II (BASE-II; n = 2012), LIFE-Adult (n = 3281) and LIFE-Heart (n = 2816). Next, we explored another frequently discussed hypothesis in this context: Increasing insulin levels during the course of T2D disease development inhibits hepatic Lp(a) synthesis and thereby might explain the inverse Lp(a)-T2D association. We used two fasting insulin-associated variants, rs780094 and rs10195252, as instrumental variables in MR analysis of n = 4937 individuals from BASE-II and LIFE-Adult. We further investigated causality of the association between fasting insulin and Lp(a) by combined MR analysis of 12 additional SNPs in LIFE-Adult.

Results: While an Lp(a)-T2D association was observed in the combined analysis (meta-effect of OR [95% CI] = 0.91 [0.87-0.96] per quintile, p = 1.3x10-4), we found no evidence of causality in the Lp(a)-T2D association (p = 0.29, fixed effect model) when using the variant rs10455872 as the instrumental variable in the MR analyses. Likewise, no evidence of a causal effect of insulin on Lp(a) levels was found.

Conclusions: While these results await confirmation in larger cohorts, the nature of the inverse Lp(a)-T2D association remains to be elucidated.

Keywords: Insulin; Lipoprotein(a); Mendelian randomization; Type 2 diabetes.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Apolipoproteins A / genetics
  • Case-Control Studies
  • Cohort Studies
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / genetics
  • Fasting / blood
  • Female
  • Humans
  • Insulin / blood*
  • Lipoprotein(a) / blood*
  • Male
  • Mendelian Randomization Analysis
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Young Adult


  • Apolipoproteins A
  • Insulin
  • Lipoprotein(a)