High-density lipoprotein and inflammation in cardiovascular disease

Published:January 19, 2016DOI:
      Great advances are being made at the mechanistic level in the understanding of the structural and functional diversity of high-density lipoprotein (HDL). HDL particle subspecies of different sizes are now known to differ in the protein and lipid cargo they transport, conferring on them the ability to perform different functions that in aggregate would be expected to provide protection against the development of atherosclerosis and its downstream clinical consequences. Exacerbating what is already a very complex system is the finding that inflammation, via alteration of the proteomic and lipidomic composition of HDL subspecies, can modulate at least some of their functional activities. In contrast to the progress being made at the mechanistic level, HDL epidemiologic research has lagged behind, largely because the simple HDL biomarkers used (mainly just HDL cholesterol) lack the needed complexity. To address this deficiency, analyses will need to use multiple HDL subspecies and be conducted in such a way as to eliminate potential sources of confounding. To help account for the modulating influence of inflammation, effective use must also be made of inflammatory biomarkers including searching systematically for HDL-inflammation interactions. Using nuclear magnetic resonance (NMR)-measured HDL subclass data and a novel NMR-derived inflammatory biomarker, GlycA, we offer a case study example of the type of analytic approach considered necessary to advance HDL epidemiologic understanding.


      Apo (apolipoprotein), BMI (body mass index), CAD (coronary artery disease), CHD (coronary heart disease), CVD (cardiovascular disease), HDL (high-density lipoprotein), HDL-C (HDL cholesterol), HDL-P (HDL particle concentration), HPS (Heart Protection Study), hsCRP (high-sensitivity C-reactive protein), IRAS (Insulin Resistance Atherosclerosis Study), JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), LDL (low-density lipoprotein), LDL-C (LDL cholesterol), LDL-P (LDL particle concentration), LP-IR (lipoprotein insulin resistance index), MESA (Multi-Ethnic Study of Atherosclerosis), MPO (myeloperoxidase), NMR (nuclear magnetic resonance), PON1 (paraoxonase-1), PREVEND (Prevention of Renal and Vascular End-stage Disease), RA (rheumatoid arthritis), SAA (serum amyloid A), T2D (type 2 diabetes), VLDL (very low-density lipoprotein)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ross R.
        • Glomset J.A.
        Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis.
        Science. 1973; 180: 1332-1339
        • Rohatgi A.
        High-density lipoprotein function measurement in human studies: focus on cholesterol efflux capacity.
        Prog Cardiovasc Dis. 2015; 58: 32-40
        • Favari E.
        • Chroni A.
        • Tietge U.J.
        • et al.
        Cholesterol efflux and reverse cholesterol transport.
        Handb Exp Pharmacol. 2015; 224: 181-206
        • Rothblat G.H.
        • Phillips M.C.
        High-density lipoprotein heterogeneity and function in reverse cholesterol transport.
        Curr Opin Lipidol. 2010; 21: 229-238
        • Soran H.
        • Hama S.
        • Yadav R.
        • et al.
        HDL functionality.
        Curr Opin Lipidol. 2012; 23: 353-366
        • van der Stoep M.
        • Korporaal S.J.
        • Van Eck M.
        High-density lipoprotein as a modulator of platelet and coagulation responses.
        Cardiovasc Res. 2014; 103: 362-371
        • Zhu X.
        • Parks J.S.
        New roles of HDL in inflammation and hematopoiesis.
        Annu Rev Nutr. 2012; 32: 161-182
        • Mineo C.
        • Shaul P.W.
        Novel biological functions of high-density lipoprotein cholesterol.
        Circ Res. 2012; 111: 1079-1090
        • Rosenson R.S.
        • Brewer Jr., H.B.
        • Ansell B.
        • et al.
        Translation of high-density lipoprotein function into clinical practice: current prospects and future challenges.
        Circulation. 2013; 128: 1256-1267
        • Karlsson H.
        • Kontush A.
        • James R.W.
        Functionality of HDL: antioxidation and detoxifying effects.
        Handb Exp Pharmacol. 2015; 224: 207-228
        • Camont L.
        • Lhomme M.
        • Rached F.
        • et al.
        Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities.
        Arterioscler Thromb Vasc Biol. 2013; 33: 2715-2723
        • Mineo C.
        • Deguchi H.
        • Griffin J.H.
        • et al.
        Endothelial and antithrombotic actions of HDL.
        Circ Res. 2006; 98: 1352-1364
        • Thomson R.
        • Samanovic M.
        • Raper J.
        Activity of trypanosome lytic factor: a novel component of innate immunity.
        Future Microbiol. 2009; 4: 789-796
        • Feingold K.R.
        • Grunfeld C.
        Lipids: a key player in the battle between the host and microorganisms.
        J Lipid Res. 2012; 53: 2487-2489
        • Tuteja S.
        • Rader D.J.
        High-density lipoproteins in the prevention of cardiovascular disease: changing the paradigm.
        Clin Pharmacol Ther. 2014; 96: 48-56
        • Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults
        Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).
        JAMA. 2001; 285: 2486-2497
        • Kuivenhoven J.A.
        • Groen A.K.
        Beyond the genetics of HDL: why is HDL cholesterol inversely related to cardiovascular disease?.
        Handb Exp Pharmacol. 2015; 224: 285-300
        • Vickers K.C.
        • Remaley A.T.
        HDL and cholesterol: life after the divorce?.
        J Lipid Res. 2014; 55: 4-12
        • Shah A.S.
        • Tan L.
        • Long J.L.
        • et al.
        Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond.
        J Lipid Res. 2013; 54: 2575-2585
        • Kontush A.
        • Lindahl M.
        • Lhomme M.
        • et al.
        Structure of HDL: particle subclasses and molecular components.
        Handb Exp Pharmacol. 2015; 224: 3-51
        • Vaisar T.
        • Pennathur S.
        • Green P.S.
        • et al.
        Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.
        J Clin Invest. 2007; 117: 746-756
        • Shiflett A.M.
        • Bishop J.R.
        • Pahwa A.
        • et al.
        Human high density lipoproteins are platforms for the assembly of multi-component innate immune complexes.
        J Biol Chem. 2005; 280: 32578-32585
        • Gordon S.M.
        • Deng J.
        • Lu L.J.
        • et al.
        Proteomic characterization of human plasma high density lipoprotein fractionated by gel filtration chromatography.
        J Proteome Res. 2010; 9: 5239-5249
        • Kontush A.
        • Lhomme M.
        • Chapman M.J.
        Unraveling the complexities of the HDL lipidome.
        J Lipid Res. 2013; 54: 2950-2963
        • Jahangiri A.
        High-density lipoprotein and the acute phase response.
        Curr Opin Endocrinol Diabetes Obes. 2010; 17: 156-160
        • Watanabe J.
        • Charles-Schoeman C.
        • Miao Y.
        • et al.
        Proteomic profiling following immunoaffinity capture of high-density lipoprotein: association of acute-phase proteins and complement factors with proinflammatory high-density lipoprotein in rheumatoid arthritis.
        Arthritis Rheum. 2012; 64: 1828-1837
        • Vaisar T.
        • Mayer P.
        • Nilsson E.
        • et al.
        HDL in humans with cardiovascular disease exhibits a proteomic signature.
        Clin Chim Acta. 2010; 411: 972-979
        • Green P.S.
        • Vaisar T.
        • Pennathur S.
        • et al.
        Combined statin and niacin therapy remodels the high-density lipoprotein proteome.
        Circulation. 2008; 118: 1259-1267
        • Alwaili K.
        • Bailey D.
        • Awan Z.
        • et al.
        The HDL proteome in acute coronary syndromes shifts to an inflammatory profile.
        Biochim Biophys Acta. 2012; 1821: 405-415
        • Holzer M.
        • Wolf P.
        • Curcic S.
        • et al.
        Psoriasis alters HDL composition and cholesterol efflux capacity.
        J Lipid Res. 2012; 53: 1618-1624
        • Charles-Schoeman C.
        • Watanabe J.
        • Lee Y.Y.
        • et al.
        Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis.
        Arthritis Rheum. 2009; 60: 2870-2879
        • Farbstein D.
        • Levy A.P.
        HDL dysfunction in diabetes: causes and possible treatments.
        Expert Rev Cardiovasc Ther. 2012; 10: 353-361
        • Yasuda T.
        • Ishida T.
        • Rader D.J.
        Update on the role of endothelial lipase in high-density lipoprotein metabolism, reverse cholesterol transport, and atherosclerosis.
        Circ J. 2010; 74: 2263-2270
        • Sattar N.
        • McCarey D.W.
        • Capell H.
        • et al.
        Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis.
        Circulation. 2003; 108: 2957-2963
        • Toms T.E.
        • Panoulas V.F.
        • Kitas G.D.
        Dyslipidaemia in rheumatological autoimmune diseases.
        Open Cardiovasc Med J. 2011; 5: 64-75
        • Chung C.P.
        • Oeser A.
        • Raggi P.
        • et al.
        Lipoprotein subclasses determined by nuclear magnetic resonance spectroscopy and coronary atherosclerosis in patients with rheumatoid arthritis.
        J Rheumatol. 2010; 37: 1633-1638
        • Otocka-Kmiecik A.
        • Mikhailidis D.P.
        • Nicholls S.J.
        • et al.
        Dysfunctional HDL: a novel important diagnostic and therapeutic target in cardiovascular disease?.
        Prog Lipid Res. 2012; 51: 314-324
        • Khovidhunkit W.
        • Kim M.S.
        • Memon R.A.
        • et al.
        Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.
        J Lipid Res. 2004; 45: 1169-1196
        • de la Llera Moya M.
        • McGillicuddy F.C.
        • Hinkle C.C.
        • et al.
        Inflammation modulates human HDL composition and function in vivo.
        Atherosclerosis. 2012; 222: 390-394
        • Fogelman A.M.
        Further evidence that high-density lipoprotein is a chameleon-like lipoprotein.
        Eur Heart J. 2015; 36: 3017-3019
        • Mackness B.
        • Mackness M.
        Anti-inflammatory properties of paraoxonase-1 in atherosclerosis.
        Adv Exp Med Biol. 2010; 660: 143-151
        • Deakin S.
        • Moren X.
        • James R.W.
        HDL oxidation compromises its influence on paraoxonase-1 secretion and its capacity to modulate enzyme activity.
        Arterioscler Thromb Vasc Biol. 2007; 27: 1146-1152
        • Huang Y.
        • Wu Z.
        • Riwanto M.
        • et al.
        Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex.
        J Clin Invest. 2013; 123: 3815-3828
        • Zheng L.
        • Nukuna B.
        • Brennan M.L.
        • et al.
        Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease.
        J Clin Invest. 2004; 114: 529-541
        • Undurti A.
        • Huang Y.
        • Lupica J.A.
        • et al.
        Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle.
        J Biol Chem. 2009; 284: 30825-30835
        • Riwanto M.
        • Rohrer L.
        • Roschitzki B.
        • et al.
        Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling.
        Circulation. 2013; 127: 891-904
        • Vaisar T.
        • Tang C.
        • Babenko I.
        • et al.
        Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity.
        J Lipid Res. 2015; 56: 1519-1530
        • Thomas M.J.
        • Sorci-Thomas M.G.
        SAA: a link between cholesterol efflux capacity and inflammation?.
        J Lipid Res. 2015; 56: 1383-1385
        • G H.B.
        • Rao V.S.
        • Kakkar V.V.
        Friend turns foe: transformation of anti-inflammatory HDL to proinflammatory HDL during acute-phase response.
        Cholesterol. 2011; 2011: 274629
        • Raterman H.G.
        • Levels H.
        • Voskuyl A.E.
        • et al.
        HDL protein composition alters from proatherogenic into less atherogenic and proinflammatory in rheumatoid arthritis patients responding to rituximab.
        Ann Rheum Dis. 2013; 72: 560-565
        • McInnes I.B.
        • Thompson L.
        • Giles J.T.
        • et al.
        Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study.
        Ann Rheum Dis. 2013; 74: 694-702
        • Liao K.P.
        • Playford M.P.
        • Frits M.
        • et al.
        The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis.
        J Am Heart Assoc. 2015; 4
        • Rohatgi A.
        • de Lemos J.A.
        • Shaul P.W.
        HDL cholesterol efflux capacity and cardiovascular events.
        N Engl J Med. 2015; 372: 1871-1872
        • Rosenson R.S.
        • Brewer Jr., H.B.
        • Davidson W.S.
        • et al.
        Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.
        Circulation. 2012; 125: 1905-1919
        • Corsetti J.P.
        • Gansevoort R.T.
        • Sparks C.E.
        • et al.
        Inflammation reduces HDL protection against primary cardiac risk.
        Eur J Clin Invest. 2010; 40: 483-489
        • Saleheen D.
        • Scott R.
        • Javad S.
        • et al.
        Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study.
        Lancet Diabetes Endocrinol. 2015; 3: 507-513
        • Rohatgi A.
        • Khera A.
        • Berry J.D.
        • et al.
        HDL cholesterol efflux capacity and incident cardiovascular events.
        N Engl J Med. 2014; 371: 2383-2393
        • Nobecourt E.
        • Jacqueminet S.
        • Hansel B.
        • et al.
        Defective antioxidative activity of small dense HDL3 particles in type 2 diabetes: relationship to elevated oxidative stress and hyperglycaemia.
        Diabetologia. 2005; 48: 529-538
        • Morgantini C.
        • Natali A.
        • Boldrini B.
        • et al.
        Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes.
        Diabetes. 2011; 60: 2617-2623
        • Charles-Schoeman C.
        • Lee Y.Y.
        • Grijalva V.
        • et al.
        Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis.
        Ann Rheum Dis. 2012; 71: 1157-1162
        • O'Neill F.
        • Riwanto M.
        • Charakida M.
        • et al.
        Structural and functional changes in HDL with low grade and chronic inflammation.
        Int J Cardiol. 2015; 188: 111-116
        • Ahmed U.
        • Tanwir F.
        Association of periodontal pathogenesis and cardiovascular diseases: a literature review.
        Oral Health Prev Dent. 2015; 13: 21-27
        • Pirillo A.
        • Catapano A.L.
        • Norata G.D.
        HDL in infectious diseases and sepsis.
        Handb Exp Pharmacol. 2015; 224: 483-508
        • Brousseau M.E.
        • Schaefer E.J.
        • Wolfe M.L.
        • et al.
        Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.
        N Engl J Med. 2004; 350: 1505-1515
        • Jafri H.
        • Alsheikh-Ali A.A.
        • Mooney P.
        • et al.
        Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD.
        J Clin Lipidol. 2009; 3: 45-50
        • Bays H.
        • Giezek H.
        • McKenney J.M.
        • et al.
        Extended-release niacin/laropiprant effects on lipoprotein subfractions in patients with type 2 diabetes mellitus.
        Metab Syndr Relat Disord. 2012; 10: 260-266
        • Toth P.P.
        • Thakker K.M.
        • Jiang P.
        • et al.
        Niacin extended-release/simvastatin combination therapy produces larger favorable changes in high-density lipoprotein particles than atorvastatin monotherapy.
        Vasc Health Risk Manag. 2012; 8: 39-44
        • Gauthamadasa K.
        • Rosales C.
        • Pownall H.J.
        • et al.
        Speciated human high-density lipoprotein protein proximity profiles.
        Biochemistry. 2010; 49: 10656-10665
        • Jeyarajah E.J.
        • Cromwell W.C.
        • Otvos J.D.
        Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy.
        Clin Lab Med. 2006; 26: 847-870
        • Kingwell B.A.
        • Chapman M.J.
        • Kontush A.
        • et al.
        HDL-targeted therapies: progress, failures and future.
        Nat Rev Drug Discov. 2014; 13: 445-464
        • Otvos J.D.
        The surprising AIM-HIGH results are not surprising when viewed through a particle lens.
        J Clin Lipidol. 2011; 5: 368-370
        • Matyus S.P.
        • Braun P.J.
        • Wolak-Dinsmore J.
        • et al.
        NMR measurement of LDL particle number using the Vantera® Clinical Analyzer.
        Clin Biochem. 2014; 47: 203-210
        • Otvos J.D.
        • Mora S.
        • Shalaurova I.
        • et al.
        Clinical implications of discordance between low-density lipoprotein cholesterol and particle number.
        J Clin Lipidol. 2011; 5: 105-113
        • Mora S.
        • Buring J.E.
        • Ridker P.M.
        Discordance of low-density lipoprotein (LDL) cholesterol with alternative LDL-related measures and future coronary events.
        Circulation. 2014; 129: 553-561
        • Mackey R.H.
        • Greenland P.
        • Goff Jr., D.C.
        • et al.
        High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis).
        J Am Coll Cardiol. 2012; 60: 508-516
        • Parish S.
        • Offer A.
        • Clarke R.
        • et al.
        Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study.
        Circulation. 2012; 125: 2469-2478
        • Milionis H.
        • Liamis G.
        • Elisaf M.
        Proprotein convertase subtilisin kexin 9 inhibitors: next generation in lipid-lowering therapy.
        Expert Opin Biol Ther. 2015; 15: 287-298
        • Mora S.
        • Glynn R.J.
        • Ridker P.M.
        High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy.
        Circulation. 2013; 128: 1189-1197
        • McGarrah R.W.
        • Craig D.M.
        • Haynes C.
        • Dowdy Z.E.
        • Shah S.H.
        • Kraus W.E.
        High-density lipoprotein particle concentration has a stronger inverse association with cardiovascular events than high density lipoprotein cholesterol in a coronary catheterization population.
        Circulation. 2013; 128: A17332
        • May H.T.
        • Anderson J.L.
        • Winegar D.A.
        • et al.
        Utility of high density lipoprotein (HDL) cholesterol, particle concentration, and size in predicting future major adverse cardiovascular events among patients undergoing angiography.
        J Am Coll Cardiol. 2014; 63: A1318
        • Matyus S.P.
        • Braun P.J.
        • Wolak-Dinsmore J.
        • et al.
        HDL particle number measured on the Vantera®, the first clinical NMR analyzer.
        Clin Biochem. 2015; 48: 148-155
        • Kontush A.
        HDL particle number and size as predictors of cardiovascular disease.
        Front Pharmacol. 2015; 6: 218-223
        • Martin S.S.
        • Jones S.R.
        • Toth P.P.
        High-density lipoprotein subfractions: current views and clinical practice applications.
        Trends Endocrinol Metab. 2014; 25: 329-336
        • Rizzo M.
        • Otvos J.
        • Nikolic D.
        • et al.
        Subfractions and subpopulations of HDL: an update.
        Curr Med Chem. 2014; 21: 2881-2891
        • Rosenson R.S.
        • Brewer Jr., H.B.
        • Chapman M.J.
        • et al.
        HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events.
        Clin Chem. 2011; 57: 392-410
        • Otvos J.D.
        • Collins D.
        • Freedman D.S.
        • et al.
        Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial.
        Circulation. 2006; 113: 1556-1563
        • Otvos J.D.
        • Shalaurova I.
        • Wolak-Dinsmore J.
        • et al.
        GlycA: a composite nuclear magnetic resonance biomarker of systemic inflammation.
        Clin Chem. 2015; 61: 714-723
        • Dungan K.
        • Binkley P.
        • Osei K.
        GlycA is a novel marker of inflammation among non-critically ill hospitalized patients with type 2 diabetes.
        Inflammation. 2015; 38: 1357-1363
        • Ormseth M.J.
        • Chung C.P.
        • Oeser A.M.
        • et al.
        Utility of a novel inflammatory marker, GlycA, for assessment of rheumatoid arthritis disease activity and coronary atherosclerosis.
        Arthritis Res Ther. 2015; 17: 117
        • Dullaart R.P.
        • Gruppen E.G.
        • Connelly M.A.
        • et al.
        A pro-inflammatory glycoprotein biomarker is associated with lower bilirubin in metabolic syndrome.
        Clin Biochem. 2015; 48: 1045-1047
        • Dullaart R.P.
        • Gruppen E.G.
        • Connelly M.A.
        • et al.
        GlycA, a biomarker of inflammatory glycoproteins, is more closely related to the leptin/adiponectin ratio than to glucose tolerance status.
        Clin Biochem. 2015; 48: 811-814
        • Bell J.D.
        • Brown J.C.
        • Nicholson J.K.
        • et al.
        Assignment of resonances for ‘acute-phase’ glycoproteins in high resolution proton NMR spectra of human blood plasma.
        FEBS Lett. 1987; 215: 311-315
        • Gruppen E.G.
        • Connelly M.A.
        • Otvos J.D.
        • et al.
        A novel protein glycan biomarker and LCAT activity in metabolic syndrome.
        Eur J Clin Invest. 2015; 45: 850
        • Dijk W.
        • Turner G.
        • Mackiewicz A.
        Changes in glycosylation of acute-phase proteins in health and disease: occurrence, regulation and function.
        Glycoconj J. 1994; 1: 5-14
        • Ceciliani F.
        • Pocacqua V.
        The acute phase protein alpha1-acid glycoprotein: a model for altered glycosylation during diseases.
        Curr Protein Pept Sci. 2007; 8: 91-108
        • Lauridsen M.B.
        • Bliddal H.
        • Christensen R.
        • et al.
        1H NMR spectroscopy-based interventional metabolic phenotyping: a cohort study of rheumatoid arthritis patients.
        J Proteome Res. 2010; 9: 4545-4553
        • Chung C.P.
        • Ormseth M.J.
        • Connelly M.A.
        • et al.
        GlycA, a novel marker of inflammation, is elevated in systemic lupus erythematosus.
        Lupus. 2015; ([Epub ahead of print])
        • Akinkuolie A.O.
        • Buring J.E.
        • Ridker P.M.
        • et al.
        A novel protein glycan biomarker and future cardiovascular disease events.
        J Am Heart Assoc. 2014; 3: e001221
        • Gruppen E.G.
        • Riphagen I.J.
        • Connelly M.A.
        • et al.
        GlycA, a pro-inflammatory glycoprotein biomarker, and incident cardiovascular disease: relationship with C-reactive protein and renal function.
        PLoS One. 2015; 10: e0139057
        • Akinkuolie A.O.
        • Glynn R.J.
        • Ridker P.M.
        • Mora S.
        Protein glycan side-chains, rosuvastatin therapy, and incident vascular events: an analysis from the JUPITER trial.
        Circulation. 2014; 130: A17731
        • Muhlestein J.B.
        • Mays H.
        • Winegar D.A.
        • et al.
        GlycA and GlycB, novel NMR biomarkers of inflammation, strongly predict future cardiovascalar events, but not the presence of coronary artery disease (CAD), among patients undergoing, coronary angiography: the Intermountain Heart Collaborative Study.
        J Am Coll Cardiol. 2014; 63: 61389
        • Fischer K.
        • Kettunen J.
        • Wurtz P.
        • et al.
        Biomarker profiling by nuclear magnetic resonance spectroscopy for the prediction of all-cause mortality: an observational study of 17,345 persons.
        PLoS Med. 2014; 11: e1001606
        • Ritchie S.C.
        • Wurtz P.
        • Nath A.P.
        • et al.
        Systems medicine links microbial inflammatory response with glycoprotein-associated mortality risk.
        Cell Systems. 2015; 1: 293-301
        • Akinkuolie A.O.
        • Pradhan A.D.
        • Buring J.E.
        • et al.
        Novel protein glycan side-chain biomarker and risk of incident type 2 diabetes mellitus.
        Arterioscler Thromb Vasc Biol. 2015; 35: 1544-1550
        • Connelly M.A.
        • Gruppen E.G.
        • Wolak-Dinsmore J.
        • et al.
        GlycA, a marker of acute phase glycoproteins, and the risk of incident type 2 diabetes mellitus: PREVEND study.
        Clin Chim Acta. 2015; 452: 10-17
        • Kim K.I.
        • Oh S.W.
        • Ahn S.
        • et al.
        CRP level and HDL cholesterol concentration jointly predict mortality in a Korean population.
        Am J Med. 2012; 125: 787-795.e4
        • Zewinger S.
        • Drechsler C.
        • Kleber M.E.
        • et al.
        Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk.
        Eur Heart J. 2015; 36: 3007-3016
        • Festa A.
        • Williams K.
        • Hanley A.J.
        • et al.
        Nuclear magnetic resonance lipoprotein abnormalities in prediabetic subjects in the Insulin Resistance Atherosclerosis Study.
        Circulation. 2005; 111: 3465-3472
        • Ferrannini E.
        • Nannipieri M.
        • Williams K.
        • et al.
        Mode of onset of type 2 diabetes from normal or impaired glucose tolerance.
        Diabetes. 2004; 53: 160-165
        • Drew B.G.
        • Rye K.A.
        • Duffy S.J.
        • et al.
        The emerging role of HDL in glucose metabolism.
        Nat Rev Endocrinol. 2012; 8: 237-245
        • Shalaurova I.
        • Connelly M.A.
        • Garvey W.T.
        • et al.
        Lipoprotein insulin resistance index: a lipoprotein particle-derived measure of insulin resistance.
        Metab Syndr Relat Disord. 2014; 12: 422-429
        • Ridker P.M.
        • Luscher T.F.
        Anti-inflammatory therapies for cardiovascular disease.
        Eur Heart J. 2014; 35: 1782-1791
        • Voight B.F.
        • Peloso G.M.
        • Orho-Melander M.
        • et al.
        Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomization study.
        Lancet. 2012; 380: 572-580