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

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

Author information

1
Lipid Clinic at the Interdisciplinary Metabolism Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.
2
Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.
3
LIFE Leipzig Research Center of Civilization Diseases, University of Leipzig, Leipzig, Germany.
4
Genetic and Molecular Epidemiology Group, Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
5
Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
6
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig, Germany.
7
Research Group on Geriatrics, Charité - Universitätsmedizin Berlin, Reinickendorfer Str. 61, 13347, Berlin, Germany.
8
School of Public Health, Faculty of Medicine, Imperial College, London, UK.
9
Lipid Clinic at the Interdisciplinary Metabolism Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany. ilja.demuth@charite.de.
10
Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 , Berlin, Germany. ilja.demuth@charite.de.

Abstract

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

PMID:
28866807
DOI:
10.1007/s00592-017-1036-4
[Indexed for MEDLINE]

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