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• W2015015053 abstract "Substantial evidence exists suggesting that small, dense LDL particles are associated with an increased risk of coronary heart disease. This disease-related risk factor is recognized to be under both genetic and environmental influences. Several studies have been conducted to elucidate the genetic architecture underlying this trait, and a review of this literature seems timely. The methods and strategies used to determine its genetic component and to identify the genes have greatly changed throughout the years owing to the progress made in genetic epidemiology and the influence of the Human Genome Project. Heritability studies, complex segregation analyses, candidate gene linkage and association studies, genome-wide linkage scans, and animal models are all part of the arsenal to determine the susceptibility genes. The compilation of these studies clearly revealed the complex genetic nature of LDL particles.This work is an attempt to summarize the growing evidence of genetic control on LDL particle heterogeneity with the aim of providing a concise overview in one read. Substantial evidence exists suggesting that small, dense LDL particles are associated with an increased risk of coronary heart disease. This disease-related risk factor is recognized to be under both genetic and environmental influences. Several studies have been conducted to elucidate the genetic architecture underlying this trait, and a review of this literature seems timely. The methods and strategies used to determine its genetic component and to identify the genes have greatly changed throughout the years owing to the progress made in genetic epidemiology and the influence of the Human Genome Project. Heritability studies, complex segregation analyses, candidate gene linkage and association studies, genome-wide linkage scans, and animal models are all part of the arsenal to determine the susceptibility genes. The compilation of these studies clearly revealed the complex genetic nature of LDL particles. This work is an attempt to summarize the growing evidence of genetic control on LDL particle heterogeneity with the aim of providing a concise overview in one read. LDL cholesterol is a well-known risk factor for coronary heart disease (CHD) and is now recognized as the primary target of lipid-lowering therapy (1Executive 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).J. Am. Med. Assoc. 2001; 285: 2486-2497Crossref PubMed Google Scholar). However, it is known that LDL particles are heterogeneous in terms of size, density, chemical composition, and electric charge (2Shen M.M. Krauss R.M. Lindgren F.T. Forte T.M. Heterogeneity of serum low density lipoproteins in normal human subjects.J. Lipid Res. 1981; 22: 236-244Abstract Full Text PDF PubMed Google Scholar, 3Krauss R.M. Burke D.J. Identification of multiple subclasses of plasma low density lipoproteins in normal humans.J. Lipid Res. 1982; 23: 97-104Abstract Full Text PDF PubMed Google Scholar, 4Ghosh S. Basu M.K. Schweppe J.S. Charge heterogeneity of human low density lipoprotein (LDL).Proc. Soc. Exp. Biol. Med. 1973; 142: 1322-1325Crossref PubMed Scopus (23) Google Scholar). Data from case-control (5Austin M.A. Hokanson J.E. Brunzell J.D. Characterization of low-density lipoprotein subclasses: methodologic approaches and clinical relevance.Curr. Opin. Lipidol. 1994; 5: 395-403Crossref PubMed Google Scholar) and prospective (6Gardner C.D. Fortmann S.P. Krauss R.M. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.J. Am. Med. Assoc. 1996; 276: 875-881Crossref PubMed Google Scholar, 7Stampfer 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, 8Lamarche B. Tchernof A. Moorjani S. Cantin B. Dagenais G.R. Lupien P.J. Despres J.P. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.Circulation. 1997; 95: 69-75Crossref PubMed Google Scholar, 9Lamarche 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) studies have suggested that small, dense LDL particles are associated with increased risk of CHD. The atherogenicity of these particles is attributed to several possible biological mechanisms, including greater susceptibility to oxidation (10Chait A. Brazg R.L. Tribble D.L. Krauss R.M. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B.Am. J. Med. 1993; 94: 350-356Abstract Full Text PDF PubMed Scopus (450) Google Scholar, 11de Graaf J. Hak-Lemmers H.L. Hectors M.P. Demacker P.N. Hendriks J.C. Stalenhoef A.F. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects.Arterioscler. Thromb. 1991; 11: 298-306Crossref PubMed Google Scholar, 12de Graaf J. Hendriks J.C. Demacker P.N. Stalenhoef A.F. Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects. Normalization after clofibrate treatment.Arterioscler. Thromb. 1993; 13: 712-719Crossref PubMed Google Scholar, 13Dejager S. Bruckert E. Chapman M.J. Dense low density lipoprotein subspecies with diminished oxidative resistance predominate in combined hyperlipidemia.J. Lipid Res. 1993; 34: 295-308Abstract Full Text PDF PubMed Google Scholar, 14Tribble D.L. Holl L.G. Wood P.D. Krauss R.M. Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size.Atherosclerosis. 1992; 93: 189-199Abstract Full Text PDF PubMed Scopus (433) Google Scholar), decreased affinity for the LDL receptor (15Campos H. Arnold K.S. Balestra M.E. Innerarity T.L. Krauss R.M. Differences in receptor binding of LDL subfractions.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 794-801Crossref PubMed Google Scholar, 16Chen G.C. Liu W. Duchateau P. Allaart J. Hamilton R.L. Mendel C.M. Lau K. Hardman D.A. Frost P.H. Malloy M.J. Kane J.P. Conformational differences in human apolipoprotein B-100 among subspecies of low density lipoproteins (LDL). Association of altered proteolytic accessibility with decreased receptor binding of LDL subspecies from hypertriglyceridemic subjects.J. Biol. Chem. 1994; 269: 29121-29128Abstract Full Text PDF PubMed Google Scholar, 17Galeano N.F. Milne R. Marcel Y.L. Walsh M.T. Levy E. Ngu'yen T.D. Gleeson A. Arad Y. Witte L. Al-Haideri M. Rumsey S.C. Deckelbaum R.J. Apoprotein B structure and receptor recognition of triglyceride-rich low density lipoprotein (LDL) is modified in small LDL but not in triglyceride-rich LDL of normal size.J. Biol. Chem. 1994; 269: 511-519Abstract Full Text PDF PubMed Google Scholar, 18Nigon F. Lesnik P. Rouis M. Chapman M.J. Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor.J. Lipid Res. 1991; 32: 1741-1753Abstract Full Text PDF PubMed Google Scholar, 19Teng B. Sniderman A. Krauss R.M. Kwiterovich Jr., P.O. Milne R.W. Marcel Y.L. Modulation of apolipoprotein B antigenic determinants in human low density lipoprotein subclasses.J. Biol. Chem. 1985; 260: 5067-5072Abstract Full Text PDF PubMed Google Scholar), increased binding to the arterial wall (20Anber V. Griffin B.A. McConnell M. Packard C.J. Shepherd J. Influence of plasma lipid and LDL-subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans.Atherosclerosis. 1996; 124: 261-271Abstract Full Text PDF PubMed Scopus (188) Google Scholar, 21Anber V. Millar J.S. McConnell M. Shepherd J. Packard C.J. Interaction of very-low-density, intermediate-density, and low-density lipoproteins with human arterial wall proteoglycans.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2507-2514Crossref PubMed Google Scholar, 22Camejo G. Rosengren B. Olson U. Lopez F. Olofson S.O. Westerlund C. Bondjers G. Molecular basis of the association of arterial proteoglycans with low density lipoproteins: its effect on the structure of the lipoprotein particle.Eur. Heart J. 1990; 11: 164-173Crossref PubMed Google Scholar, 23Galeano N.F. Al-Haideri M. Keyserman F. Rumsey S.C. Deckelbaum R.J. Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity.J. Lipid Res. 1998; 39: 1263-1273Abstract Full Text Full Text PDF PubMed Google Scholar), and greater facility to cross the arterial wall (24Bjornheden T. Babyi A. Bondjers G. Wiklund O. Accumulation of lipoprotein fractions and subfractions in the arterial wall, determined in an in vitro perfusion system.Atherosclerosis. 1996; 123: 43-56Abstract Full Text PDF PubMed Scopus (191) Google Scholar, 25Nielsen L.B. Transfer of low density lipoprotein into the arterial wall and risk of atherosclerosis.Atherosclerosis. 1996; 123: 1-15Abstract Full Text PDF PubMed Scopus (137) Google Scholar) as well as having negative effects on the endothelium function (26Vakkilainen J. Makimattila S. Seppala-Lindroos A. Vehkavaara S. Lahdenpera S. Groop P.H. Taskinen M.R. Yki-Jarvinen H. Endothelial dysfunction in men with small LDL particles.Circulation. 2000; 102: 716-721Crossref PubMed Google Scholar). Additional evidence for the relevance of the small, dense LDL on atherosclerotic lesion development and CHD progression is derived from an animal model (27Veniant M.M. Withycombe S. Young S.G. Lipoprotein size and atherosclerosis susceptibility in Apoe(−/−) and Ldlr(−/−) mice.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1567-1570Crossref PubMed Google Scholar) and lipid-lowering trials in humans (28Miller B.D. Alderman E.L. Haskell W.L. Fair J.M. Krauss R.M. Predominance of dense low-density lipoprotein particles predicts angiographic benefit of therapy in the Stanford Coronary Risk Intervention Project.Circulation. 1996; 94: 2146-2153Crossref PubMed Google Scholar, 29Zambon A. Hokanson J.E. Brown B.G. Brunzell J.D. Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density.Circulation. 1999; 99: 1959-1964Crossref PubMed Google Scholar). On the other hand, recent findings from the Cholesterol and Recurrent Events trial (30Campos H. Moye L.A. Glasser S.P. Stampfer M.J. Sacks F.M. Low-density lipoprotein size, pravastatin treatment, and coronary events.J. Am. Med. Assoc. 2001; 286: 1468-1474Crossref PubMed Google Scholar) support earlier case-control (31Campos H. Roederer G.O. Lussier-Cacan S. Davignon J. Krauss R.M. Predominance of large LDL and reduced HDL2 cholesterol in normolipidemic men with coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1043-1048Crossref PubMed Google Scholar, 32Gray R.S. Robbins D.C. Wang W. Yeh J.L. Fabsitz R.R. Cowan L.D. Welty T.K. Lee E.T. Krauss R.M. Howard B.V. Relation of LDL size to the insulin resistance syndrome and coronary heart disease in American Indians. The Strong Heart Study.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2713-2720Crossref PubMed Google Scholar, 33Ruotolo G. Tettamanti C. Garancini M.P. Ragogna F. Derosa G. Nardecchia L. Parlato F. Pozza G. Smaller, denser LDL particles are not a risk factor for cardiovascular disease in healthy nonagenarian women of the Cremona Population Study.Atherosclerosis. 1998; 140: 65-70Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 34Wahi S. Gatzka C.D. Sherrard B. Simpson H. Collins V. Dowse G. Zimmet P. Jennings G. Dart A.M. Risk factors for coronary heart disease in a population with a high prevalence of obesity and diabetes: a case-control study of the Polynesian population of Western Samoa.J. Cardiovasc. Risk. 1997; 4: 173-178Crossref PubMed Scopus (15) Google Scholar) and prospective (35Mykkanen L. Kuusisto J. Haffner S.M. Laakso M. Austin M.A. LDL size and risk of coronary heart disease in elderly men and women.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2742-2748Crossref PubMed Google Scholar) studies showing that small, dense LDLs are not risk factors for CHD. In fact, some of these studies have shown that larger LDL particles are associated with CHD. Although these studies disagree on which LDL particle size (small or large) is related to CHD risk (36Krauss R.M. Is the size of low-density lipoprotein particles related to the risk of coronary heart disease?.J. Am. Med. Assoc. 2002; 287: 712-713Crossref PubMed Google Scholar), defining the genetic and environmental factors that modulate LDL particle properties may be helpful in understanding its relationship with CHD. Multiple approaches have been used to determine the genes involved in complex human diseases and disease-related risk factors. Through the years, methods and strategies have evolved following the progress made in genetic epidemiology and the completion of the Human Genome Project. Genetic studies on LDL particles represent a perfect example of this phenomenon. Several studies have investigated the genetics of LDL particle heterogeneity. Heritability studies, complex segregation analyses, linkage and association studies with candidate genes, and genome-wide linkage scans are all part of the arsenal used to dissect the genetic architecture of this trait. Cumulative evidence is growing rapidly, and a review of these studies seems timely. Several studies have shown that small, dense LDLs are associated with a constellation of other well-recognized lipoprotein-related risk factors, including increased plasma triglyceride and apolipoprotein B (apoB) levels as well as decreased HDL cholesterol concentrations. Furthermore, small, dense LDL particles coexist in the same subjects as part of multifaceted phenotypes, including the metabolic syndrome, the atherogenic lipoprotein phenotype (LDL subclass pattern B), and familial combined hyperlipidemia (FCHL) (37Kwiterovich Jr., P.O. Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity.Am. J. Cardiol. 2002; 90: 30i-47iAbstract Full Text Full Text PDF PubMed Google Scholar). Thus, small, dense LDL may be a qualitative trait representing a common atherogenic lipoprotein/metabolic profile, and the proposed genetic loci responsible for small, dense LDL may in fact be responsible for a more extensive syndrome. However, throughout this review, we have chosen to adopt a more narrow view on the phenotypes that characterize LDL particle heterogeneity. These phenotypes are the central focus of this paper, and we summarize the published genetic studies surrounding them. A number of analytical techniques are available for characterizing LDL heterogeneity, and it is beyond the scope of the present paper to describe them in detail. However, some technicality must be addressed before going through genetic ground. LDL heterogeneity was first described using analytical ultracentrifugation (38Lindgren F.T. Jensen L.C. Wills R.D. Freeman N.K. Flotation rates, molecular weights and hydrated densities of the low-density lipoproteins.Lipids. 1969; 4: 337-344Crossref PubMed Scopus (72) Google Scholar). Over the years, this technique was replaced by others, including density gradient ultracentrifugation (DGU), gradient gel electrophoresis (GGE), and, more recently, NMR spectroscopy. The phenotypes derived from these techniques are those used in the genetics studies performed to date. Based on GGE, a continuous variable can be defined as LDL peak particle diameter (LDL-PPD), reflecting the size of the major LDL subclass in an individual subject. A dichotomous classification can also be defined based on GGE; it is referred to as LDL subclass patterns, or phenotypes, A and B. LDL subclass phenotype A is characterized by a predominance of large LDL particles and skewing of the densitometric scan toward small particles, whereas LDL subclass phenotype B is characterized by a predominance of small LDL particles and skewing of the curve toward large particles (39Austin M.A. Breslow J.L. Hennekens C.H. Buring J.E. Willett W.C. Krauss R.M. Low-density lipoprotein subclass patterns and risk of myocardial infarction.J. Am. Med. Assoc. 1988; 260: 1917-1921Crossref PubMed Google Scholar). Other phenotypes can be constructed using GGE, including LDL score, which is calculated using the migration distance (in millimeters) of each peak multiplied by its respective relative area (40Tchernof A. Lamarche B. Prud'Homme D. Nadeau A. Moorjani S. Labrie F. Lupien P.J. Despres J.P. The dense LDL phenotype. Association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in men.Diabetes Care. 1996; 19: 629-637Crossref PubMed Google Scholar), and LDL type, which is a weighted average of seven possible categories of LDL, resulting in a variable ranging from 1 (largest) to 7 (smallest) (41Campos H. Genest J.J. Blijlevens E. McNamara J.R. Jenner J.L. Ordovas J.M. Wilson P.W. Schaefer E.J. Low density lipoprotein particle size and coronary artery disease.Arterioscler. Thromb. 1992; 12: 187-195Crossref PubMed Google Scholar). For a detailed description of these techniques, the reader is referred to previously published reviews (5Austin M.A. Hokanson J.E. Brunzell J.D. Characterization of low-density lipoprotein subclasses: methodologic approaches and clinical relevance.Curr. Opin. Lipidol. 1994; 5: 395-403Crossref PubMed Google Scholar, 42Krauss R.M. Blanche P.J. Detection and quantitation of LDL subfractions.Curr. Opin. Lipidol. 1992; 3: 377-383Crossref Scopus (118) Google Scholar, 43Otvos J.D. Measurement of lipoprotein subclass profiles by nuclear magnetic resonance spectroscopy.Clin. Lab. 2002; 48: 171-180PubMed Google Scholar). The first evidence for a genetic determination of LDL properties was reported by Fisher et al. in 1975 (44Fisher W.R. Hammond M.G. Mengel M.C. Warmke G.L. A genetic determinant of the phenotypic variance of the molecular weight of low density lipoprotein.Proc. Natl. Acad. Sci. USA. 1975; 72: 2347-2351Crossref PubMed Scopus (39) Google Scholar). Five families, including 11 couples and 16 offspring, were examined for their LDL molecular weights. Only subjects having monodisperse LDL (i.e., LDL that is found to be present as a single, essentially homogeneous population of macromolecules) were included in the study. Correlation coefficients between pairs of relatives revealed a significant parent-offspring correlation (0.82; P < 0.01) but absence of correlation between fathers and mothers (0.32; P = NS). These results provided evidence for the genetic contribution of LDL molecular weight. To further determine the degree of resemblance of the offspring to their parents, a regression coefficient of the mean molecular weight of the offspring on the mean parental molecular weight was calculated. The regression coefficient was 0.30 (P < 0.01), which made the authors conclude that ∼30% of the observed LDL molecular weight variance is attributable to additive gene action. In addition, based on the five families, the authors postulated a model consistent with a single-gene (two-allele) locus genetic mode of inheritance without dominance. Although the sample size used in this study was relatively small, it demonstrated for the first time that LDL characteristics segregate within families. Since this earlier report, accumulating evidence of familial and ethnic aggregation of LDL subclasses has emerged in the literature. Haffner et al. (45Haffner S.M. D'Agostino Jr., R. Goff D. Howard B. Festa A. Saad M.F. Mykkanen L. LDL size in African Americans, Hispanics, and non-Hispanic whites: the insulin resistance atherosclerosis study.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2234-2240Crossref PubMed Google Scholar, 46Haffner S.M. Mykkanen L. Valdez R.A. Paidi M. Stern M.P. Howard B.V. LDL size and subclass pattern in a biethnic population.Arterioscler. Thromb. 1993; 13: 1623-1630Crossref PubMed Google Scholar) demonstrated a significant difference between ethnic groups in LDL size among 1,571 subjects from the Insulin Resistance Atherosclerosis Study and 466 subjects from the San Antonio Family Heart Study. These studies cannot distinguish the effect of the genetic background from the effect mediated by the difference in lifestyles between ethnic groups, but they clearly motivated genetic studies in the field. More recently, the familial resemblance of LDL-PPD was evaluated in 681 individuals participating in the Québec Family Study (QFS) (47Bossé Y. Vohl M.C. Despres J.P. Lamarche B. Rice T. Rao D.C. Bouchard C. Perusse L. Heritability of LDL peak particle diameter in the Quebec Family Study.Genet. Epidemiol. 2003; 25: 375-381Crossref PubMed Scopus (0) Google Scholar). An ANOVA comparing between-family and within-family variance indicated that there was approximately two times more variance between families than within families. Thus, results from the QFS suggested that the family lines accounted for close to 50% (47–49% depending on covariate adjustment) of the variance in LDL-PPD phenotype. In addition, the pattern of familial correlations revealed no spouse correlation but significant parent-offspring and sibling correlations for the LDL-PPD phenotypes, suggesting that genetic factors are the major determinants of the familial aggregation. The same pattern of correlations was observed among Finnish families with FCHL (48Vakkilainen J. Pajukanta P. Cantor R.M. Nuotio I.O. Lahdenpera S. Ylitalo K. Pihlajamaki J. Kovanen P.T. Laakso M. Viikari J.S. Peltonen L. Taskinen M.R. Genetic influences contributing to LDL particle size in familial combined hyperlipidaemia.Eur. J. Hum. Genet. 2002; 10: 547-552Crossref PubMed Scopus (13) Google Scholar). Studies using identical [monozygotic (MZ)] and fraternal [dizygotic (DZ)] twins have been used to assess the heritability of LDL size (Table 1). The first study on this issue was based on 119 MZ and 113 DZ twin pairs participating in the third examination of the National Heart, Lung, and Blood Institute Twin Study (49Lamon-Fava S. Jimenez D. Christian J.C. Fabsitz R.R. Reed T. Carmelli D. Castelli W.P. Ordovas J.M. Wilson P.W. Schaefer E.J. The NHLBI Twin Study: heritability of apolipoprotein A-I, B, and low density lipoprotein subclasses and concordance for lipoprotein(a).Atherosclerosis. 1991; 91: 97-106Abstract Full Text PDF PubMed Google Scholar). In this study, the LDL subfractions were separated by GGE and the heritability analysis used LDL type. The LDL type intraclass correlation coefficient in MZ twins was significantly higher than the correlation coefficient in DZ twins (0.58 vs. 0.32; P < 0.005), with a heritability of 0.52 before controlling for covariate effects. After adjustment for body mass index (BMI), alcohol consumption, cigarette smoking, and physical activity, the heritability decreased to 0.39. Despite being of great magnitude, these estimates were not statistically significant, suggesting the lack of heritability for LDL type. Similar results were obtained when only the major LDL band (LDL-PPD) was used as a variable. Thus, the authors concluded that LDL particle size is not greatly influenced by genetic factors within this population. It is noteworthy that the authors used the more conservative among-component (50Christian J.C. Kang K.W. Norton Jr., J.J. Choice of an estimate of genetic variance from twin data.Am. J. Hum. Genet. 1974; 26: 154-161PubMed Google Scholar) estimate of heritability because there was some indication of unequal total variance between zygosities. Although this procedure is considered more suitable in such cases, the power to detect significant heritability is substantially reduced.TABLE 1Heritability analyses on LDL particle characteristicsReferenceStudySubject CharacteristicsPhenotypeHeritabilityMethodsCovariates or AssortmentResultsLamon-Fava et al. (49)The third examination of the National Heart, Lung, and Blood Institute Twin Study119 MZ and 113 DZ male twin pairs aged 59–70 yearsLDL typeANOVA (among component0.52 (P = 0.12)ANOVA (among component)BMI, alcohol consumption, cigarette smoking, and physical activity0.39 (P = 0.39)Austin et al. (51)The second examination of the Kaiser Permanente Women Twins Study203 MZ and 145 DZ female twin pairs with a median age of 51 years; 90% were whiteLDL-PPDClassicAll pairs0.54 (P < 0.001)Postmenopausal pairs0.55 (P < 0.003)Nondiabetic pairs0.35 (P < 0.016)Non β-blocker-user pairs0.45 (P < 0.002)Caucasian pairs0.51 (P < 0.001)ANOVA (within pair)All pairs Postmenopausal pairs0.48 (P < 0.001) 0.34 (P < 0.021)Nondiabetic pairs0.44 (P < 0.001)Non β-blocker-user pairs0.52 (P < 0.001)Caucasian pairs0.43 (P < 0.001)Edwards et al. (52)The GET Study85 families at high risk for cardiovascular disease including 780 individuals, primarily whiteLDL-PPDMaximum likelihood-based approachAge and sex0.34 (P < 0.001)Bossé et al. (47)The Québec Family Study681 French CaucasiansLDL-PPDFamilial correlations under the most parsimonious modelAge, age2, and age30.59 (95% CI 0.43–0.75)Age, age2, age3, and BMI0.58 (95% CI 0.42–0.75)Age, age2, age3, BMI, and triglyceride0.52 (95% CI 0.46–0.58)Barzilai et al. (53)The Longevity Genes Project429 Ashkenazi Jews with exceptional longevityLDL size (NMR)Linear regressionMen0.60 (P = 0.006)Women0.46 (P = 0.003)Rainwater, Martin, and Comuzzie (54)The San Antonio Heart Study1,157 Mexican AmericansΔLDLaΔLDL is a metrics for particle size phenotype to optimally reflect the size correlations between LDL and HDL particles.Maximum likelihood-based approachSex, age, age2, diabetes status, contraceptive use, and hypertension medications0.44 (P < 0.001)Sex, age, age2, diabetes status, contraceptive use, hypertension medications, and triglyceride0.30Austin et al. (81)The GET Study140 subjects, members of 26 kindredsLDL-PPDMaximum likelihood-based approachSex, age, oral contraceptive use, menopausal status, and hormone replacement therapy0.26 (P = 0.025)Primarily Caucasians+ triglyceride0.12 (P = 0.168)+ HDL-C0.15 (P = 0.121)+ triglyceride and HDL-C0.10 (P = 0.213)BMI, body mass index; CI, confidence interval; DZ, dizygotic; GET, Genetic Epidemiology of Hypertriglyceridemia; HDL-C, HDL cholesterol; LDL-PPD, low density lipoprotein peak particle size; MZ, monozygotic.a ΔLDL is a metrics for particle size phenotype to optimally reflect the size correlations between LDL and HDL particles. Open table in a new tab BMI, body mass index; CI, confidence interval; DZ, dizygotic; GET, Genetic Epidemiology of Hypertriglyceridemia; HDL-C, HDL cholesterol; LDL-PPD, low density lipoprotein peak particle size; MZ, monozygotic. The heritability estimates were also analyzed based on 203 MZ and 145 DZ pairs of adult female twins who participated in the second examination of the Kaiser Permanente Women Twins Study (51Austin M.A. Newman B. Selby J.V. Edwards K. Mayer E.J. Krauss R.M. Genetics of LDL subclass phenotypes in women twins. Concordance, heritability, and commingling analysis.Arterioscler. Thromb. 1993; 13: 687-695Crossref PubMed Google Scholar). The classic heritability estimate for LDL-PPD was 0.54, and the within-pair estimate was 0.48. These estimates were not changed substantially when the analyses were restricted to postmenopausal, nondiabetic, non-β-blocker users or Caucasian pairs, with heritability ranging from 0.34 to 0.5. Thus, the authors suggested that between one-third and one-half of the variability in LDL size appears to be attributable to genetic influences in this sample of female twins. Heritability estimates of LDL-PPD were also evaluated using family data. The first family study on this issue was based on 780 individual members of 85 families participating in the Genetic Epidemiology of Hypertriglyceridemia (GET) Study (52Edwards K.L. Mahaney M.C. Motulsky A.G. Austin M.A. Pleiotropic genetic effects on LDL size, plasma triglyceride, and HDL cholesterol in families.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2456-2464Crossref PubMed Google Scholar). The GET Study is based on two family studies, one ascertained through hyperlipidemic probands surviving a myocardial infarction and the second through hypertriglyceridemic probands without CHD. After accounting for age and sex effects, results suggested that approximately one-third of the residual variance in LDL-PPD (heritability = 0.34) was attributable to additive genetic effects. The heritability estimate for LDL-PPD from the QFS was slightly higher (47Bossé Y. Vohl M.C. Despres J.P. Lamarche B. Rice T. Rao D.C. Bouchard C. Perusse L. Heritability of LDL peak particle diameter in the Quebec Family Study.Genet. Epidemiol. 2003; 25: 375-381Crossref PubMed Scopus (0) Google Scholar). In this study, three LDL-PPD phenotypes based on three different adjustment procedures were constructed: LDL-PPD1 adjusted for age, LDL-PPD2 adjusted for age and BMI, and LDL-PPD3 adjusted for age, BMI, and triglyceride levels. Heritability estimates for the three phenotypes were 58.8, 58.4, and 52.0%, respectively. The high heritabilities obtained may be explained by the design of the study. Indeed, in this case, heritability is defined as the proportion of variance attributable to additive familial effects, including both genetic and nongenetic sources of variance. Although the pattern of familial correlations in the QFS suggested that the familial resemblance is mostly attributable to genetic fact" @default.
• W2015015053 created "2016-06-24" @default.
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• W2015015053 date "2004-06-01" @default.
• W2015015053 modified "2023-10-16" @default.
• W2015015053 title "Genetics of LDL particle heterogeneity" @default.
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