TY - JOUR
T1 - Association between lipoprotein(a) level and type 2 diabetes: No evidence for a causal role of lipoprotein(a) and insulin
AU - Buchmann, Nikolaus
AU - Scholz, Markus
AU - Lill, Christina M.
AU - Burkhardt, Ralph
AU - Eckardt, Rahel
AU - Norman, Kristina
AU - Loeffler, Markus
AU - Bertram, Lars
AU - Thiery, Joachim
AU - Steinhagen-Thiessen, Elisabeth
AU - Demuth, Ilja
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85028756162&partnerID=8YFLogxK
U2 - 10.1007/s00592-017-1036-4
DO - 10.1007/s00592-017-1036-4
M3 - Journal articles
C2 - 28866807
AN - SCOPUS:85028756162
SN - 0940-5429
VL - 54
SP - 1031
EP - 1038
JO - Acta Diabetologica
JF - Acta Diabetologica
IS - 11
ER -