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

Nikolaus Buchmann, Markus Scholz, Christina M. Lill, Ralph Burkhardt, Rahel Eckardt, Kristina Norman, Markus Loeffler, Lars Bertram, Joachim Thiery, Elisabeth Steinhagen-Thiessen, Ilja Demuth*

*Corresponding author for this work


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.

Original languageEnglish
JournalActa Diabetologica
Issue number11
Pages (from-to)1031-1038
Number of pages8
Publication statusPublished - 01.11.2017


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