Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin
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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.
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.
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.
While these results await confirmation in larger cohorts, the nature of the inverse Lp(a)–T2D association remains to be elucidated.
KeywordsInsulin Lipoprotein(a) Mendelian randomization Type 2 diabetes
We thank Dr. Tian Liu for her help with processing and managing the BASE-II GWAS data.
The BASE-II study was supported by the German Federal Ministry of Education and Research (BMBF Grant Numbers 16SV5536K, 16SV5538, 16SV5837 and 16SV5537). This work is supported by LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative.
Statement of data availability
Due to concerns for participant privacy, data are available only upon request. External scientists may apply to the Steering Committee of BASE-II for data access. Please contact Katrin Schaar, scientific coordinator, at firstname.lastname@example.org.
N.B. researched data and wrote the manuscript. M.S. researched data, designed/performed MR analyses and wrote the manuscript. C.L., R.B., K.N. and L.B. reviewed/edited the manuscript. R.E., M.L. and J.T. critically reviewed the manuscript. E.S.T. contributed to discussion and critically reviewed the manuscript. I.D. conceived the project, contributed to the analyses and wrote the manuscript. I.D. and M.S. are the guarantors of this work and, as such, had full access to all BASE-II data (I.D.) and LIFE-Adult/LIFE-Heart data (M.S.) in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Compliance with ethical standards
Conflict of interest
Dr. Steinhagen-Thiessen reports grants and personal fees from Sanofi, personal fees from MSD, Fresenius, personal fees from Amgen and Chiesi, outside the submitted work. Dr. Demuth reports grants from Sanofi, personal fees from uniQure biopharma B.V., outside the submitted work. Dr. Scholz received funding from Merck Serono in the framework of a pharmacokinetic modelling project not related to the present work. All other authors had nothing to disclose.
Human and animal rights
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the 1975 Declaration of Helsinki, as revised in 2008 (5).
Informed consent was obtained from all patients for being included in the study.
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