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Circulating lipoprotein(a) levels and health outcomes: Phenome-wide Mendelian randomization and disease-trajectory analyses

  • Author Footnotes
    1 Shared first authorship.
    Susanna C. Larsson
    Footnotes
    1 Shared first authorship.
    Affiliations
    Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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  • Author Footnotes
    1 Shared first authorship.
    Lijuan Wang
    Footnotes
    1 Shared first authorship.
    Affiliations
    Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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  • Xue Li
    Correspondence
    Corresponding author.
    Affiliations
    Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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  • Fangyuan Jiang
    Affiliations
    Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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  • Xiangjun Chen
    Affiliations
    Eye Center of the Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
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  • Christos S. Mantzoros
    Affiliations
    Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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  • Author Footnotes
    1 Shared first authorship.
Published:November 14, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155347

      Highlights

      • Higher Lp(a) levels were associated with risk of many circulatory system diseases.
      • Higher Lp(a) levels were associated with an increased risk of anemia.
      • There was a suggestive association of higher Lp(a) levels with higher diabetes risk.
      • Three major sequential patterns of multiple morbidities related to high Lp(a) was found.

      Abstract

      Background

      Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerotic and valvular diseases, but its possible role in other diseases has not yet been established. We conducted phenome-wide Mendelian randomization and disease-trajectory analyses to assess any associations of circulating Lp(a) levels with a broad range of diseases.

      Methods

      A weighted polygenic risk score was constructed using independent genetic variants in the LPA gene and with an established effect on Lp(a) levels. The PheWAS analysis included 1081 phenotype outcomes ascertained among 385,917 White participants of the UK Biobank. Novel findings were investigated in MR analysis using data from the FinnGen consortium. Disease-trajectory and comorbidity analyses were further conducted to explore the sequential patterns of multiple morbidities related to high circulating Lp(a) levels.

      Results

      PheWAS revealed statistically significant associations of higher circulating Lp(a) levels with increased risk of a large number of circulatory system diseases (including various cardiac diseases, peripheral vascular disease, hypertension, and valvular and cerebrovascular diseases) as well as some endocrine/metabolic diseases (including hyperlipidemia, hypercholesterolemia, disorders of lipoid metabolism, and type 2 diabetes), genitourinary system diseases (renal failure), and hematologic diseases (including different types of anemia). Two-sample MR analysis supported the association between Lp(a) and risk of anemia, showed a suggestive association with type 2 diabetes, but found no association with renal failure. Disease-trajectory and comorbidity analyses identified 3 major sequential patterns of multiple morbidities, mainly in the cardiovascular, metabolic, and mental disorders, related to high circulating Lp(a) levels.

      Conclusions

      Genetically predicted higher circulating Lp(a) levels were associated with increased risk of many circulatory system diseases and anemia. Additionally, this study identified three major sequential patterns of multiple morbidities related to high Lp(a).

      Keywords

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      References

        • Tsimikas S.
        A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies.
        J Am Coll Cardiol. 2017; 69: 692-711
        • Burgess S.
        • Ference B.A.
        • Staley J.R.
        • Freitag D.F.
        • Mason A.M.
        • Nielsen S.F.
        • et al.
        Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis.
        JAMA Cardiol. 2018; 3: 619-627
        • Gudbjartsson D.F.
        • Thorgeirsson G.
        • Sulem P.
        • Helgadottir A.
        • Gylfason A.
        • Saemundsdottir J.
        • et al.
        Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes.
        J Am Coll Cardiol. 2019; 74: 2982-2994
        • Emdin C.A.
        • Khera A.V.
        • Natarajan P.
        • Klarin D.
        • Won H.H.
        • Peloso G.M.
        • et al.
        Phenotypic characterization of genetically lowered human lipoprotein(a) levels.
        J Am Coll Cardiol. 2016; 68: 2761-2772
        • Larsson S.C.
        • Gill D.
        • Mason A.M.
        • Jiang T.
        • Back M.
        • Butterworth A.S.
        • et al.
        Lipoprotein(a) in alzheimer, atherosclerotic, cerebrovascular, thrombotic, and valvular disease: Mendelian randomization investigation.
        Circulation. 2020; 141: 1826-1828
        • Satterfield B.A.
        • Dikilitas O.
        • Safarova M.S.
        • Clarke S.L.
        • Tcheandjieu C.
        • Zhu X.
        • et al.
        Associations of genetically predicted Lp(a) (Lipoprotein [a]) levels with cardiovascular traits in individuals of European and African ancestry.
        Circ Genom Precis Med. 2021; 14e003354
        • Thanassoulis G.
        • Campbell C.Y.
        • Owens D.S.
        • Smith J.G.
        • Smith A.V.
        • Peloso G.M.
        • et al.
        Genetic associations with valvular calcification and aortic stenosis.
        N Engl J Med. 2013; 368: 503-512
        • Kamstrup P.R.
        • Nordestgaard B.G.
        Elevated lipoprotein(a) levels, LPA risk genotypes, and increased risk of heart failure in the general population.
        JACC Heart Fail. 2016; 4: 78-87
        • Pan Y.
        • Li H.
        • Wang Y.
        • Meng X.
        • Wang Y.
        Causal effect of Lp(a) [lipoprotein(a)] level on ischemic stroke and Alzheimer disease: a Mendelian randomization study.
        Stroke. 2019; 50: 3532-3539
        • Ye Z.
        • Haycock P.C.
        • Gurdasani D.
        • Pomilla C.
        • Boekholdt S.M.
        • Tsimikas S.
        • et al.
        The association between circulating lipoprotein(a) and type 2 diabetes: is it causal?.
        Diabetes. 2014; 63: 332-342
        • Kamstrup P.R.
        • Nordestgaard B.G.
        Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study.
        Lancet Diabetes Endocrinol. 2013; 1: 220-227
        • Buchmann N.
        • Scholz M.
        • Lill C.M.
        • Burkhardt R.
        • Eckardt R.
        • Norman K.
        • et al.
        Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin.
        Acta Diabetol. 2017; 54: 1031-1038
        • Yuan S.
        • Wang L.
        • Sun J.
        • Yu L.
        • Zhou X.
        • Yang J.
        • et al.
        Genetically predicted sex hormone levels and health outcomes: phenome-wide Mendelian randomization investigation.
        Int J Epidemiol. 2022; dyac036
        • Denny J.C.
        • Bastarache L.
        • Ritchie M.D.
        • Carroll R.J.
        • Zink R.
        • Mosley J.D.
        • et al.
        Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data.
        Nat Biotechnol. 2013; 31: 1102-1110
        • Verma A.
        • Bradford Y.
        • Dudek S.
        • Lucas A.M.
        • Verma S.S.
        • Pendergrass S.A.
        • et al.
        A simulation study investigating power estimates in phenome-wide association studies.
        BMC Bioinformatics. 2018; 19: 120
      1. FinnGen study. Data freeze 7 results and summary statistics. Available online: https://finngen.gitbook.io/documentation/ (accessed on October 1, 2022).

        • Verma A.
        • Bradford Y.
        • Dudek S.
        • Lucas A.M.
        • Verma S.S.
        • Pendergrass S.A.
        • et al.
        A simulation study investigating power estimates in phenome-wide association studies.
        BMC Bioinformatics. 2018; 19: 120
        • Benjamini Y.
        • Hochberg Y.
        Controlling the false discovery rate: a practical and powerful approach to multiple testing.
        J R Stat Soc B Methodol. 1995; 57: 289-300
        • Burgess S.
        • Small D.S.
        • Thompson S.G.
        A review of instrumental variable estimators for Mendelian randomization.
        Stat Methods Med Res. 2017; 26: 2333-2355
        • Carroll R.J.
        • Bastarache L.
        • Denny J.C.
        R PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment.
        Bioinformatics. 2014; 30: 2375-2376
        • Serrano-Pozo A.
        • Das S.
        • Hyman B.T.
        APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches.
        Lancet Neurol. 2021; 20: 68-80