Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes

Guðbjartsson, Daníel F.; Þorgeirsson, Guðmundur; Sulem, Patrick; Helgadóttir, Anna; Gylfason, Arnaldur; Saemundsdottir, Jona; Björnsson, Eyþór; Norddahl, Gudmundur L.; Jónasdóttir, Áslaug; Jónasdóttir, Aðalbjörg; Eggertsson, Hannes P.; Grétarsdóttir, Sólveig; Þorleifsson, Guðmar; Indridason, Ólafur S.; Pálsson, Runólfur; Jónasson, Friðbert; Jónsdóttir, Ingileif; Eyjolfsson, Gudmundur I.; Sigurðardóttir, Ólöf; Ólafsson, Ísleifur; Daníelsen, Ragnar; Matthíasson, Stefán E.; Kristmundsdóttir, Snædís; Halldórsson, Bjarni V.; Hreiðarsson, Ástráður B.; Valdimarsson, Einar Már; Guðnason, Þórarinn; Benediktsson, Rafn; Steinthórsdóttir, Valgerður; Þorsteinsdóttir, Unnur; Hólm, Hilma; Stefánsson, Kāri

doi:10.1016/j.jacc.2019.10.019

Cited by 157 publications

(145 citation statements)

References 43 publications

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“…Similar to the Lp(a) observation, the lipid marker low density lipoprotein (LDL) cholesterol also shows an inverse association with incident T2D and a positive association with incident CHD in observational [43,44], clinical [9], and Mendelian Randomization studies [45]. The effects and side-effects of therapies aimed at lowering Lp(a) and LDL levels to reduce the risk of CHD are consequently a field of active research [39,40,46,47]. According to the current state of knowledge, in individuals with elevated LDL levels being at increased risk of CVD, the CVD-preventive benefits of widespread LDL-lowering therapies clearly outweigh the increased T2D risk [39].…”

Section: Importance Of Single Pathways For T2d and Chd Development Inmentioning

confidence: 89%

“…The Lp(a) concentration is strongly genetically determined by the copy number variant kringle IV type 2 (KIV-2) and several single nucleotide polymorphisms in the LPA gene region [39]. Mendelian Randomization studies reported that genetic variants which lead to elevated Lp(a) levels were associated with higher CHD risk [39,40] and lower T2D risk [39][40][41][42]. The results of these Mendelian Randomization studies strongly point at causality.…”

Section: Importance Of Single Pathways For T2d and Chd Development Inmentioning

confidence: 99%

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Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Huth

Bauer

Zierer

et al. 2020

Cardiovasc Diabetol

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Background: Biomarkers may contribute to our understanding of the pathophysiology of various diseases. Type 2 diabetes (T2D) and coronary heart disease (CHD) share many clinical and lifestyle risk factors and several biomarkers are associated with both diseases. The current analysis aims to assess the relevance of biomarkers combined to pathway groups for the development of T2D and CHD in the same cohort. Methods: Forty-seven serum biomarkers were measured in the MONICA/KORA case-cohort study using clinical chemistry assays and ultrasensitive molecular counting technology. The T2D (CHD) analyses included 689 (568) incident cases and 1850 (2004) non-cases from three population-based surveys. At baseline, the study participants were 35-74 years old. The median follow-up was 14 years. We computed Cox regression models for each biomarker, adjusted for age, sex, and survey. Additionally, we assigned the biomarkers to 19 etiological pathways based on information from literature. One age-, sex-, and survey-controlled average variable was built for each pathway. We used the R 2 PM coefficient of determination to assess the explained disease risk. Results: The associations of many biomarkers, such as several cytokines or the iron marker soluble transferrin receptor (sTfR), were similar in strength for T2D and CHD, but we also observed important differences. Lipoprotein (a) (Lp(a)) and N-terminal pro B-type natriuretic peptide (NT-proBNP) even demonstrated opposite effect directions. All pathway variables together explained 49% of the T2D risk and 21% of the CHD risk. The insulin-like growth factor binding protein 2 (IGFBP-2, IGF/IGFBP system pathway) best explained the T2D risk (about 9% explained risk, independent of all other pathway variables). For CHD, the myocardial-injury-and lipid-related-pathways were most important and both explained about 4% of the CHD risk. Conclusions: The biomarker-derived pathway variables explained a higher proportion of the T2D risk compared to CHD. The ranking of the pathways differed between the two diseases, with the IGF/IGFBP-system-pathway being most strongly associated with T2D and the myocardial-injury-and lipid-related-pathways with CHD. Our results help to better understand the pathophysiology of the two diseases, with the ultimate goal of pointing out targets for lifestyle intervention and drug development to ideally prevent both T2D and CHD development.

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Section: Importance Of Single Pathways For T2d and Chd Development Inmentioning

confidence: 89%

Section: Importance Of Single Pathways For T2d and Chd Development Inmentioning

confidence: 99%

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Huth

Bauer

Zierer

et al. 2020

Cardiovasc Diabetol

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“…However, lipoprotein(a) levels (i.e. molar concentration), rather than apo(a) isoform size, appears to be most strongly associated with risk of CAD 20,41,42 .…”

Section: Effect Of Coronary Artery Disease Genomic Risk Score On Othementioning

confidence: 99%

Polygenic modulation of lipoprotein(a)-associated cardiovascular risk

Trinder¹,

Brunham

2020

Preprint

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Aims: Elevated levels of lipoprotein(a) are one of the strongest inherited risk factors for coronary artery disease (CAD). However, there is variability in cardiovascular risk among individuals with elevated lipoprotein(a). The sources of this variability are incompletely understood. We assessed the effects of a genomic risk score (GRS) for CAD on risk of myocardial infarction among individuals with elevated lipoprotein(a). Methods: We calculated CAD GRSs for 408,896 individuals of British white ancestry from the UK Biobank using 6.27 million common genetic variants. Lipoprotein(a) levels were measured in 310,020 individuals. The prevalence and risk of myocardial infarction versus CAD GRS percentiles were compared for individuals with and without elevated lipoprotein(a) defined as ≥120 or 168 nmol/L (≈50 or 70 mg/dL, respectively). Results: Individuals with elevated lipoprotein(a) displayed significantly greater CAD GRSs than individuals without elevated lipoprotein(a), which was largely dependent on the influence of genetic variants within or near the LPA gene. Continuous levels of CAD GRS percentile were significantly associated with risk of myocardial infarction for individuals with elevated lipoprotein(a). Notably, the risk of myocardial infarction for males with elevated lipoprotein(a) levels, but a CAD GRS percentile in the lower quintile (<20th percentile), was less than the overall risk of myocardial infarction for males with non-elevated lipoprotein(a) levels (hazard ratio [95% CI]: 0.79 [0.64-0.97], p=0.02). Similar results were observed for females. Conclusion: These data suggest that CAD genomic scores influence cardiovascular risk among individuals with elevated lipoprotein(a) and may aid in identifying candidates for preventive therapies.

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“…The mean percent change from baseline ranged from 11.6% to 20.4% in the pravastatin group and 18.7% to 24.2% in the atorvastatin group. Incubation of HepG2 hepatocytes with atorvastatin showed an increase in expression of LPA mRNA and apolipoprotein(a) protein Gudbjartsson et al (2019) [ 31 ] Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8734 with T2D Mendelian randomization; This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk Cardiovascular disease incidence and prevalence; incident and prevalent type 2 diabetes mellitus Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size.…”

Section: Introductionmentioning

confidence: 99%

Lipoprotein(a) and Cardiovascular Disease Prevention across Diverse Populations

Pearson

Rodríguez

2020

Cardiol Ther

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Lipoprotein(a) (Lp(a)) is a highly proatherogenic lipid fraction that is genetically determined and minimally responsive to lifestyle or behavior changes. Mendelian randomization studies have suggested a causal link between elevated Lp(a) and heart disease, stroke, and aortic stenosis. There is substantial inter-ethnic variation in Lp(a) levels, with persons of African descent having the highest median values. Monitoring of Lp(a) has historically been limited by lack of standardization of assays. With the advent of novel therapeutic modalities to lower Lp(a) levels including proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and targeted antisense oligonucleotides, it is increasingly important to screen patients who have family or personal history of atherosclerotic cardiovascular disease for elevations in Lp(a). Further study is needed to establish a causal relationship between elevated Lp(a) and cardiovascular disease across diverse ethnic populations.

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Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes

Cited by 157 publications

References 43 publications

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Polygenic modulation of lipoprotein(a)-associated cardiovascular risk

Lipoprotein(a) and Cardiovascular Disease Prevention across Diverse Populations

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