The lipoprotein subfraction profile: heritability and identification of quantitative trait loci

The HDL and LDL subclass profile is an emerging cardiovascular risk factor. Yet, the biological and genetic mechanisms controlling the lipoprotein subclass distribution are unclear. Therefore, we aimed 1) to determine the heritability of the entire spectrum of LDL and HDL subclass features and 2) to identify gene loci influencing the lipoprotein subfraction pattern. Using NMR spectroscopy, we analyzed the lipoprotein subclass distribution in 1,275 coronary artery disease patients derived from the Regensburg Myocardial Infarction Family Study. We calculated heritabilities, performed a microsatellite genome scan, and calculated linkage. HDL and LDL subclass profiles showed heritabilities ranging from 23% to 67% (all P < 10−3) of traits using univariate calculation. After multivariate adjustment, we found heritabilities of 27–48% (all P < 0.05) for HDL and 21–44% for LDL traits. The linkage analysis revealed a significant logarithm of the odds (LOD) score (3.3) for HDL particle concentration on chromosome 18 and a highly suggestive signal for HDL particle size on chromosome 12 (2.9). After multivariate adjustment, we found a significant maximum LOD score of 3.7 for HDL size. Our study is the first to analyze heritability and linkage for the entire spectrum of LDL and HDL subclass features. Our findings may lead to the identification of genes controlling the lipoprotein subclass distribution. The HDL and LDL subclass profile is an emerging cardiovascular risk factor. Yet, the biological and genetic mechanisms controlling the lipoprotein subclass distribution are unclear. Therefore, we aimed 1) to determine the heritability of the entire spectrum of LDL and HDL subclass features and 2) to identify gene loci influencing the lipoprotein subfraction pattern. Using NMR spectroscopy, we analyzed the lipoprotein subclass distribution in 1,275 coronary artery disease patients derived from the Regensburg Myocardial Infarction Family Study. We calculated heritabilities, performed a microsatellite genome scan, and calculated linkage. HDL and LDL subclass profiles showed heritabilities ranging from 23% to 67% (all P < 10−3) of traits using univariate calculation. After multivariate adjustment, we found heritabilities of 27–48% (all P < 0.05) for HDL and 21–44% for LDL traits. The linkage analysis revealed a significant logarithm of the odds (LOD) score (3.3) for HDL particle concentration on chromosome 18 and a highly suggestive signal for HDL particle size on chromosome 12 (2.9). After multivariate adjustment, we found a significant maximum LOD score of 3.7 for HDL size. Our study is the first to analyze heritability and linkage for the entire spectrum of LDL and HDL subclass features. Our findings may lead to the identification of genes controlling the lipoprotein subclass distribution. The plasma lipoprotein profile plays a pivotal role in the pathogenesis of atherosclerosis and is a major predictor for coronary artery disease (CAD). In particular, LDL and HDL cholesterol levels have been established as important risk factors for CAD, and the decrease of LDL cholesterol is a principal target in cardiovascular preventive strategies (1.Adult Treatment Panel III.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) final report.Circulation. 2002; 106: 3163-3184Google Scholar). However, it has been known for several years that the major lipoprotein classes can be further characterized into subfractions. Indeed, there is growing evidence that the profile of these subclasses is a crucial prognostic factor for the manifestation and progression of CAD (2.Otvos J.D. Collins D. Freedman D.S. Shalaurova I. Schaefer E.J. McNamara J.R. Bloomfield H.E. Robins S.J. 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: 1556-1563Crossref PubMed Scopus (481) Google Scholar, 3.Freedman D.S. Otvos J.D. Jeyarajah E.J. Barboriak J.J. Anderson A.J. Walker J.A. Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1046-1053Crossref PubMed Scopus (288) Google Scholar, 4.Rosenson R.S. Otvos J.D. Freedman D.S. Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) Trial.Am. J. Cardiol. 2002; 90: 89-94Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar). With respect to the assessment of LDL particles, small dense particles have been shown to be much more atherogenic than large buoyant particles (5.Berneis K.K. Krauss R.M. Metabolic origins and clinical significance of LDL heterogeneity.J. Lipid Res. 2002; 43: 1363-1379Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar). Furthermore, several epidemiological studies demonstrated that mean LDL particle size and particle concentration provide more reliable prognostic information than the routine measurement of LDL cholesterol levels (6.Lamarche B. St-Pierre A.C. Ruel I.L. Cantin B. Dagenais G.R. Despres J.P. A prospective, population-based study of low density lipoprotein particle size as a risk factor for ischemic heart disease in men.Can. J. Cardiol. 2001; 17: 859-865PubMed Google Scholar, 7.Stampfer M.J. Krauss R.M. Ma J. Blanche P.J. Holl L.G. Sacks F.M. Hennekens C.H. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.J. Am. Med. Assoc. 1996; 276: 882-888Crossref PubMed Google Scholar, 8.Kuller L. Arnold A. Tracy R. Otvos J. Burke G. Psaty B. Siscovick D. Freedman D.S. Kronmal R. Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the Cardiovascular Health Study.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1175-1180Crossref PubMed Scopus (265) Google Scholar, 9.El Harchaoui K. van der Steeg W.A. Stroes E.S. Kuivenhoven J.A. Otvos J.D. Wareham N.J. Hutten B.A. Kastelein J.J. Khaw K.T. Boekholdt S.M. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study.J. Am. Coll. Cardiol. 2007; 49: 547-553Crossref PubMed Scopus (209) Google Scholar). Similar is true for HDL particles. Accumulating evidence shows that different subclasses have distinct functional properties and prognostic impact (10.Asztalos B.F. Cupples L.A. Demissie S. Horvath K.V. Cox C.E. Batista M.C. Schaefer E.J. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the Framingham Offspring Study.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 2181-2187Crossref PubMed Scopus (262) Google Scholar, 11.Asztalos B.F. Collins D. Cupples L.A. Demissie S. Horvath K.V. Bloomfield H.E. Robins S.J. Schaefer E.J. Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2185-2191Crossref PubMed Scopus (241) Google Scholar, 12.Lamarche B. Moorjani S. Cantin B. Dagenais G.R. Lupien P.J. Despres J.P. Associations of HDL2 and HDL3 subfractions with ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1098-1105Crossref PubMed Scopus (162) Google Scholar). The cholesterol content per particle exhibits large interindividual variation. However, it is unclear which biological mechanisms control the lipoprotein subclass distribution. Specifically, it has not been clarified to what extent genetic factors contribute. Thus, the identification of genes influencing the lipoprotein subfraction profile is an important step toward understanding the underlying biological principles, which in turn may facilitate the development of novel preventive and therapeutic strategies. Therefore, we aimed 1) to determine the heritability of the entire spectrum of LDL and HDL particle subclass features in families with high cardiovascular risk and the presence of CAD and 2) to identify quantitative trait loci (QTLs) influencing the lipoprotein subfraction patterns, which we assessed by genome-wide linkage analysis. The 1,275 patients for this study were derived from 590 families in the Regensburg Myocardial Infarction Family Study that has been described previously (13.Broeckel U. Hengstenberg C. Mayer B. Holmer S. Martin L.J. Comuzzie A.G. Blangero J. Nurnberg P. Reis A. Riegger G.A. et al.A comprehensive linkage analysis for myocardial infarction and its related risk factors.Nat. Genet. 2002; 30: 210-214Crossref PubMed Scopus (283) Google Scholar). Recruitment continued after the mentioned publication, so that in the present study we were able to include 77 additional families not included in our previous work. Briefly, CAD families were ascertained through index patients at 15 cardiac rehabilitation centers distributed throughout Germany. All index patients had suffered from myocardial infarction before 60 years of age. If at least one sibling presented with myocardial infarction or severe CAD before 70 years of age, defined by percutaneous coronary intervention or coronary artery bypass grafting, the entire nuclear family (index patient, available parents, and all affected and unaffected siblings) was contacted and invited to participate in the study. The Ethics Committee of the University of Regensburg approved the study protocol, and all participants gave written, informed consent. The investigation conforms with the principles outlined in the Declaration of Helsinki. We from using a available A microsatellite genome-wide was by the as using the with an of (13.Broeckel U. Hengstenberg C. Mayer B. Holmer S. Martin L.J. Comuzzie A.G. Blangero J. Nurnberg P. Reis A. Riegger G.A. et al.A comprehensive linkage analysis for myocardial infarction and its related risk factors.Nat. Genet. 2002; 30: 210-214Crossref PubMed Scopus (283) Google Scholar). The has been described previously (13.Broeckel U. Hengstenberg C. Mayer B. Holmer S. Martin L.J. Comuzzie A.G. Blangero J. Nurnberg P. Reis A. Riegger G.A. et al.A comprehensive linkage analysis for myocardial infarction and its related risk factors.Nat. Genet. 2002; 30: 210-214Crossref PubMed Scopus (283) Google Scholar). In to a were by information was by of from and all patients a a at Myocardial infarction was and as described previously (13.Broeckel U. Hengstenberg C. Mayer B. Holmer S. Martin L.J. Comuzzie A.G. Blangero J. Nurnberg P. Reis A. Riegger G.A. et al.A comprehensive linkage analysis for myocardial infarction and its related risk factors.Nat. Genet. 2002; 30: 210-214Crossref PubMed Scopus (283) Google Scholar). was defined by the of or by of was in a from were assessed the of the Myocardial Infarction Family Study. cholesterol and HDL cholesterol were measured using a HDL cholesterol was after with and LDL cholesterol was after with in the NMR spectroscopy was at from at The was Briefly, NMR of plasma were which to profiles of the lipoprotein Using the ranging from to were into a of 15 lipoprotein lipoprotein subfractions were to and properties of lipoprotein density in a LDL and HDL levels by NMR spectroscopy showed with the by routine LDL and HDL the mean were and and the of the were and and that the are not the be genetic were using the maximum L. Blangero J. linkage analysis in J. Genet. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The of a trait is into genetic and is defined as the that the genetic to the linkage analysis was as described previously (13.Broeckel U. Hengstenberg C. Mayer B. Holmer S. Martin L.J. Comuzzie A.G. Blangero J. Nurnberg P. Reis A. Riegger G.A. et al.A comprehensive linkage analysis for myocardial infarction and its related risk factors.Nat. Genet. 2002; 30: 210-214Crossref PubMed Scopus (283) Google to the linkage loci and a which was on the genetic of as a of by at a to a L. Blangero J. linkage analysis in J. Genet. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). were using the for cholesterol was performed in a and as described previously A. S. Hengstenberg C. Mayer B. Holmer S. Riegger G. to LDL cholesterol levels by therapy to cardiac J. Cardiol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). linkage analysis was to the additional information in the quantitative traits. The of the linkage to the the of linkage of particle size and to a genetic L. Blangero J. quantitative trait linkage 1997; PubMed Scopus Google Scholar, L. Blangero J. linkage analysis of multivariate and quantitative traits. I. and J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). The clinical and of the study are described in and the previously described risk factor profile of our myocardial infarction families (13.Broeckel U. Hengstenberg C. Mayer B. Holmer S. Martin L.J. Comuzzie A.G. Blangero J. Nurnberg P. Reis A. Riegger G.A. et al.A comprehensive linkage analysis for myocardial infarction and its related risk factors.Nat. Genet. 2002; 30: 210-214Crossref PubMed Scopus (283) Google and of the study of cholesterol cholesterol cholesterol CAD CAD CAD therapy coronary artery are or in a CAD, coronary artery are or The heritability of trait was calculated using analysis. We heritability in different first by univariate and in an as age, and The heritabilities are in In the heritabilities from to 67% for HDL (all P < and from 23% to for LDL traits (all P < After multivariate adjustment, we found heritability of 27–48% for HDL (all P < 0.05) and 21–44% for LDL traits < in LDL and particle The of to the of the was found to be in HDL and in LDL traits not identify gene loci the lipoprotein subclass we a genome-wide linkage for underlying lipoprotein subclasses as as the mean size and concentration of LDL and HDL particles. Using univariate we found a highly suggestive signal for HDL size of the odds (LOD) score of on chromosome 12 as as significant linkage for HDL particle number on chromosome 18 score of The maximum LOD of all assessed lipoprotein traits univariate are in LOD for all assessed lipoprotein traits in univariate LDL were from NMR LDL particle LDL particle LDL A LDL LDL LDL LDL HDL were from NMR HDL particle HDL particle HDL A HDL HDL HDL of the odds (LOD) in Cholesterol were from NMR in a of the odds (LOD) in After for and the signal for HDL size a significant LOD score of the for HDL particle concentration on chromosome 18 was significant with a LOD score of for and we found LOD of 3.7 for HDL size on chromosome 12 and for HDL particle concentration on chromosome 18 After additional for the on chromosome 12 to the signal for HDL particle concentration on chromosome 18 was not We the traits HDL size and particle concentration are on showed that HDL size of HDL concentration HDL particle concentration for of HDL size the of this has a genetic we performed a genetic analysis. We found a significant genetic P and a significant P HDL size and Therefore, a of genes to the of HDL size and HDL particle linkage analysis was performed to and influencing in HDL size and particle However, the linkage not significant LOD score In the present we the heritability of the LDL and HDL subclass profile and performed genome-wide linkage The heritability of the major lipoprotein classes is quantitative results G. and on levels in J. Med. PubMed Scopus Google Scholar). is known the genetic on lipoprotein subclass distribution and for have been on mean or LDL particle heritabilities of L. M.C. of LDL particle from genetic to Lipid Res. 2004; Full Text Full Text PDF PubMed Scopus Google in with our the of HDL HDL can been into major large HDL2 to HDL in our and dense HDL3 to HDL Using this et J.R. D. study of genetic and on PubMed Scopus Google heritabilities of for HDL2 and for HDL3 on the in a study of et S. P. L. G. of cardiovascular risk in with to 1997; PubMed Scopus Google found heritabilities of for HDL2 and for HDL3 in et of high density lipoprotein and lipoprotein and PubMed Google heritability of for HDL2 and for HDL3 in the results of these studies the of our the heritabilities in our study are in with the However, to our our study is the first to the heritability of the entire spectrum of LDL and HDL subclasses in the large After we aimed to identify gene loci influencing the lipoprotein subfraction which we assessed by a genome-wide linkage for on lipoprotein subclass as as particle concentration and mean size. We found significant linkage for HDL particle concentration on chromosome 18 and for HDL size on chromosome a large number of studies provide linkage for lipoprotein traits by et Despres J.P. C. L. M.C. of genome-wide of a genome-wide of Lipid Res. 2004; Full Text Full Text PDF PubMed Scopus Google there is distinct HDL particle features. Using gene the HDL subclass profile has been with in the genes for of high density lipoprotein and lipoprotein and PubMed Google Scholar, P. Otvos J.D. Cupples L.A. C. Schaefer E.J. of the in the gene with in lipoprotein subclass the Framingham Offspring Study.Arterioscler. Thromb. Vasc. Biol. PubMed Scopus Google Scholar, C. D. K. et and genetic of HDL and in Lipid Res. Full Text Full Text PDF PubMed Google Scholar, D. Demissie S. Cupples L.A. P. Schaefer E.J. the of a in the gene on high-density lipoprotein evidence of a in this in the Framingham 2002; 106: PubMed Scopus Google F.M. M.J. of gene with high-density lipoprotein cholesterol subfractions and plasma levels in 2006; Full Text Full Text PDF PubMed Scopus Google A. D. B. J.P. G. P. P. et impact of the highly of the gene on the plasma and HDL the J. Med. Genet. 2002; PubMed Scopus Google S. C.E. genetic and its impact on quantitative traits in and from the Biol. Google Cupples L.A. Demissie S. Otvos J.D. C. D. P. et of the at the gene with in lipoprotein subclass profiles and coronary heart disease the Framingham Offspring 2001; Full Text Full Text PDF PubMed Scopus Google M.C. S.J. J.D. of lipoprotein and to LDL and HDL in healthy Thromb. Vasc. Biol. 2002; 22: PubMed Scopus Google S. Otvos J.D. L. is with an lipoprotein profile in the University 106: PubMed Scopus Google and Blangero J. S. A for is with and high density lipoprotein size in Thromb. PubMed Scopus Google Scholar). showed of on HDL size A. and to high density lipoprotein particle and in PubMed Scopus Google Scholar). genome-wide linkage et L. S. M.C. Blangero J. of genes influencing J. Genet. Full Text Full Text PDF PubMed Scopus Google described a on chromosome influencing a of HDL and a on chromosome 15 HDL size pattern. et L. Cupples L.A. et linkage and gene for HDL3 the Framingham Study.J. Lipid Res. 2005; Full Text Full Text PDF PubMed Scopus Google linkage HDL3 and a on chromosome in which of genes the revealed a significant in the to our the gene loci in our study have not been before in the of the HDL subfraction the on chromosome 12 was described previously by et S.J. J.D. C.E. et linkage for loci and the Family Blood Genet. 2006; PubMed Scopus Google Scholar). found significant linkage to HDL cholesterol in a of A gene that is the the of which is crucial in and is a gene that plays a pivotal role in more and with Furthermore, are to and to and have levels a with L. P. S.J. and in of 2005; PubMed Scopus Google Scholar). findings to the development of as a of the the 2005; PubMed Scopus Google Scholar). the on chromosome we not in the of However, there is evidence that the be in et C.H. A genome-wide using analysis for loci related to plasma Genet. 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Low-density lipoprotein size and cardiovascular risk 2006; PubMed Scopus Google this trait has been as an emerging cardiovascular risk factor (1.Adult Treatment Panel III.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) final report.Circulation. 2002; 106: 3163-3184Google Scholar). the is more the on the prognostic impact of HDL subclasses were described a major of dense HDL3 particles M.J. Sacks F.M. S. Hennekens C.H. A prospective study of and the risk of myocardial J. Med. PubMed Scopus Google Scholar, C.H. D. Associations of the HDL2 and HDL3 cholesterol subfractions with the development of ischemic heart disease in men. The and 90: PubMed Scopus Google Scholar, van R. B. of cholesterol in low-density high-density and high-density lipoprotein and of and with coronary and Med. Google found the properties in large HDL2 particles S. J. Krauss R.M. of large LDL and HDL2 cholesterol in men with coronary artery disease.Arterioscler. Thromb. Vasc. Biol. PubMed Scopus Google or a small HDL particles and CAD D.S. Otvos J.D. Jeyarajah E.J. Barboriak J.J. Anderson A.J. Walker J.A. Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1046-1053Crossref PubMed Scopus (288) Google Scholar). However, in the there to be growing epidemiological evidence that large HDL particles the properties of HDL HDL particles be with cardiovascular events R.S. Otvos J.D. Freedman D.S. Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) Trial.Am. J. Cardiol. 2002; 90: 89-94Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 8.Kuller L. Arnold A. Tracy R. Otvos J. Burke G. Psaty B. Siscovick D. Freedman D.S. Kronmal R. Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the Cardiovascular Health Study.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1175-1180Crossref PubMed Scopus (265) Google Scholar, 11.Asztalos B.F. Collins D. Cupples L.A. Demissie S. Horvath K.V. Bloomfield H.E. Robins S.J. Schaefer E.J. Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2185-2191Crossref PubMed Scopus (241) Google Scholar, 12.Lamarche B. Moorjani S. Cantin B. Dagenais G.R. Lupien P.J. Despres J.P. Associations of HDL2 and HDL3 subfractions with ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1098-1105Crossref PubMed Scopus (162) Google Scholar, S.J. P.J. High-density lipoproteins as therapeutic 2005; PubMed Scopus Google Scholar, Otvos J. Lipoprotein subclass by nuclear magnetic resonance spectroscopy the of coronary artery disease in A prospective report from the of PubMed Scopus Google Scholar). of the present study be Our heritability may the true genetic we not for family in our in from one and parents, it is that a in to in the of NMR spectroscopy be NMR spectroscopy particle and it is not of the cholesterol content of lipoprotein particles. Therefore, the of LDL and HDL cholesterol is performed by an cholesterol content for particle these by the particle number for and all of the subclass cholesterol in can be in as the cholesterol content of lipoprotein subclasses these at least the LDL and HDL cholesterol not with the by routine to be is the that the families were ascertained for myocardial that we have on healthy However, we have to that the heritability of lipoprotein particle features is affected by a myocardial infarction in the Furthermore, the of therapy has to be of our study was on HDL cholesterol which have to an HDL particle an mean particle size M.J. G.A. K. The of on lipoproteins and NMR spectroscopy defined lipoprotein subclasses in patients with heart Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. J.P. The of high therapy on and lipoprotein subfractions in patients with 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. Shalaurova I. Freedman D.S. R.S. of on lipoprotein subclass profiles and particle size in the 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In our therapy had a on HDL particle size and particle of the of the traits and further the of we calculated heritabilities all patients on the results were to from the entire not In our multivariate we for the of in a and this may the for be lipoproteins are not by a number of factors as age, and are highly on We for triglyceride levels to for the that our were from We not to for in the of the lipoprotein profile the of genetic is to be Therefore, for traits genetic than the for may an as triglyceride levels have a as P.J. of features of the in a study of healthy Med. 2002; PubMed Scopus Google Scholar). We present the first study to the heritability of the entire LDL and HDL subfraction profile using NMR we found significant evidence of linkage for HDL size on chromosome 12 and for HDL particle concentration on chromosome the has been previously in the of plasma the has been described as a influencing HDL Therefore, loci are to genes influencing traits. these genes may provide into the biological mechanisms underlying the lipoprotein subfraction profile and may the development of novel therapeutic and preventive strategies.

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