The Association Between Circulating Lipoprotein(a) and T2D
The Association Between Circulating Lipoprotein(a) and T2D
Epidemiological evidence supports a direct and causal association between lipoprotein(a) [Lp(a)] levels and coronary risk, but the nature of the association between Lp(a) levels and risk of type 2 diabetes (T2D) is unclear. In this study, we assessed the association of Lp(a) levels with risk of incident T2D and tested whether Lp(a) levels are causally linked to T2D. We analyzed data on 18,490 participants from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort that included adults aged 40–79 years at baseline 1993–1997. During an average 10 years of follow-up, 593 participants developed incident T2D. Cox regression models were used to estimate the association between Lp(a) levels and T2D. In Mendelian randomization analyses, based on EPIC-Norfolk combined with DIAbetes Genetics Replication And Meta-analysis data involving a total of 10,088 diabetes case participants and 68,346 control participants, we used a genetic variant (rs10455872) as an instrument to test whether the association between Lp(a) levels and T2D is causal. In adjusted analyses, there was an inverse association between Lp(a) levels and T2D: hazard ratio was 0.63 (95% CI 0.49–0.81; P trend = 0.003) comparing the top versus bottom quintile of Lp(a). In EPIC-Norfolk, a 1-SD increase in logLp(a) was associated with a lower risk of T2D (odds ratio [OR] 0.88 [95% CI: 0.80–0.95]). However, in Mendelian randomization analyses, a 1-SD increase in logLp(a) due to rs10455872, which explained 26.8% of the variability in Lp(a) levels, was not associated with risk of T2D (OR 1.03 [0.96–1.10]; P = 0.41). These prospective findings demonstrate a strong inverse association of Lp(a) levels with risk of T2D. However, a genetic variant that elevated Lp(a) levels was not associated with risk of T2D, suggesting that elevated Lp(a) levels are not causally associated with a lower risk of T2D.
Lipoprotein(a) [Lp(a)] is an LDL-like particle synthesized by the liver that contains an apolipoprotein B100 molecule covalently bound to a plasminogen-like glycoprotein, apolipoprotein(a) [apo(a)]. Several meta-analyses of prospective epidemiological studies have demonstrated that elevated baseline concentrations of Lp(a) increase the risk of incident cardiovascular disease (CVD), particularly for coronary heart disease (CHD). Recently, we reported a significant positive association of Lp(a) levels with coronary artery disease and peripheral arterial disease, but not with ischemic stroke in the European Prospective Investigation of Cancer (EPIC)-Norfolk study. Based on the common soil hypothesis of the etiology of diabetes and CVD, it might be anticipated that Lp(a) levels would also be associated in a similar, direct manner with risk of type 2 diabetes (T2D).
The only prospective study assessing the association of Lp(a) levels and T2D to date, the Women's Health Study (WHS), suggested that Lp(a) levels were inversely associated with risk of T2D in women. In adjusted analyses, the hazard ratio (HR) was 0.78 (95% CI: 0.67–0.91) in a comparison of women in the top quintile versus those in the bottom quintile of the Lp(a) distribution. The findings were confirmed in a Danish population, in whom a similarly inverse association with prevalent diabetes was found in a cross-sectional analysis. In a meta-analysis of 34 prospective studies, it was reported that Lp(a) levels were 11% lower in people with a self-reported history of diabetes compared with those without. Other investigators have reported inconsistent results on the association of Lp(a) levels with T2D in small case-control or cross-sectional studies, with some but not all showing lower Lp(a) levels in patients with diabetes than among control participants. There remains considerable uncertainty about the association between Lp(a) levels and risk of T2D.
Moreover, it is currently unknown whether any observed association between Lp(a) levels and risk of T2D is likely to be causal or due to residual confounding or reverse causality, as this has not yet been investigated. A likely causal nature of association between Lp(a) and CHD has been inferred by reports of associations of Lp(a)-related genetic variants with CHD risk, and a similar approach using a Mendelian randomization experiment, could be applied to investigate a causal association between Lp(a) levels and T2D risk.
Our primary objective was to investigate the prospective association between baseline Lp(a) levels and incident T2D and to test for a causal association using the Mendelian randomization approach. A secondary objective was to investigate the association of Lp(a) with incident CHD within the same longitudinal study to enable a direct comparison of baseline Lp(a) concentration with both disease end points in a single study using the same methods, in order to gain a better understanding of the nature of the association.
Abstract and Introduction
Abstract
Epidemiological evidence supports a direct and causal association between lipoprotein(a) [Lp(a)] levels and coronary risk, but the nature of the association between Lp(a) levels and risk of type 2 diabetes (T2D) is unclear. In this study, we assessed the association of Lp(a) levels with risk of incident T2D and tested whether Lp(a) levels are causally linked to T2D. We analyzed data on 18,490 participants from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort that included adults aged 40–79 years at baseline 1993–1997. During an average 10 years of follow-up, 593 participants developed incident T2D. Cox regression models were used to estimate the association between Lp(a) levels and T2D. In Mendelian randomization analyses, based on EPIC-Norfolk combined with DIAbetes Genetics Replication And Meta-analysis data involving a total of 10,088 diabetes case participants and 68,346 control participants, we used a genetic variant (rs10455872) as an instrument to test whether the association between Lp(a) levels and T2D is causal. In adjusted analyses, there was an inverse association between Lp(a) levels and T2D: hazard ratio was 0.63 (95% CI 0.49–0.81; P trend = 0.003) comparing the top versus bottom quintile of Lp(a). In EPIC-Norfolk, a 1-SD increase in logLp(a) was associated with a lower risk of T2D (odds ratio [OR] 0.88 [95% CI: 0.80–0.95]). However, in Mendelian randomization analyses, a 1-SD increase in logLp(a) due to rs10455872, which explained 26.8% of the variability in Lp(a) levels, was not associated with risk of T2D (OR 1.03 [0.96–1.10]; P = 0.41). These prospective findings demonstrate a strong inverse association of Lp(a) levels with risk of T2D. However, a genetic variant that elevated Lp(a) levels was not associated with risk of T2D, suggesting that elevated Lp(a) levels are not causally associated with a lower risk of T2D.
Introduction
Lipoprotein(a) [Lp(a)] is an LDL-like particle synthesized by the liver that contains an apolipoprotein B100 molecule covalently bound to a plasminogen-like glycoprotein, apolipoprotein(a) [apo(a)]. Several meta-analyses of prospective epidemiological studies have demonstrated that elevated baseline concentrations of Lp(a) increase the risk of incident cardiovascular disease (CVD), particularly for coronary heart disease (CHD). Recently, we reported a significant positive association of Lp(a) levels with coronary artery disease and peripheral arterial disease, but not with ischemic stroke in the European Prospective Investigation of Cancer (EPIC)-Norfolk study. Based on the common soil hypothesis of the etiology of diabetes and CVD, it might be anticipated that Lp(a) levels would also be associated in a similar, direct manner with risk of type 2 diabetes (T2D).
The only prospective study assessing the association of Lp(a) levels and T2D to date, the Women's Health Study (WHS), suggested that Lp(a) levels were inversely associated with risk of T2D in women. In adjusted analyses, the hazard ratio (HR) was 0.78 (95% CI: 0.67–0.91) in a comparison of women in the top quintile versus those in the bottom quintile of the Lp(a) distribution. The findings were confirmed in a Danish population, in whom a similarly inverse association with prevalent diabetes was found in a cross-sectional analysis. In a meta-analysis of 34 prospective studies, it was reported that Lp(a) levels were 11% lower in people with a self-reported history of diabetes compared with those without. Other investigators have reported inconsistent results on the association of Lp(a) levels with T2D in small case-control or cross-sectional studies, with some but not all showing lower Lp(a) levels in patients with diabetes than among control participants. There remains considerable uncertainty about the association between Lp(a) levels and risk of T2D.
Moreover, it is currently unknown whether any observed association between Lp(a) levels and risk of T2D is likely to be causal or due to residual confounding or reverse causality, as this has not yet been investigated. A likely causal nature of association between Lp(a) and CHD has been inferred by reports of associations of Lp(a)-related genetic variants with CHD risk, and a similar approach using a Mendelian randomization experiment, could be applied to investigate a causal association between Lp(a) levels and T2D risk.
Our primary objective was to investigate the prospective association between baseline Lp(a) levels and incident T2D and to test for a causal association using the Mendelian randomization approach. A secondary objective was to investigate the association of Lp(a) with incident CHD within the same longitudinal study to enable a direct comparison of baseline Lp(a) concentration with both disease end points in a single study using the same methods, in order to gain a better understanding of the nature of the association.
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