Published online before print May 5, 2003, doi: 10.1161/01.CIR.0000065577.60129.F5
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(Circulation. 2003;107:2361.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Evidence for a Major Quantitative Trait Locus on Chromosome 17q21 Affecting Low-Density Lipoprotein Peak Particle Diameter
From the Lipid Research Center, CHUL Research Center (Y.B., J.-P.D., B.L., M.-C.V.), the Department of Food Sciences and Nutrition (Y.B., J.-P.D., M.-C.V.), and the Division of Kinesiology, Department of Social and Preventive Medicine (L.P.), Laval University, Ste-Foy, Québec, Canada; the Quebec Heart Institute (J.-P.D.), Institute on Nutraceutical and Functional Food (B.L., M.-C.V.), and Genetic and Molecular Psychiatric Unit (Y.C.C.), Laval University Robert-Giffard Research Center, Beauport, Québec, Canada; the Division of Biostatistics, Washington University School of Medicine, St Louis, Mo (T.R., D.C.R.); and the Pennington Biomedical Research Center, Baton Rouge, La (C.B.).
Correspondence to Marie-Claude Vohl, PhD, Lipid Research Center, CHUL Research Center, TR-93, 2705, Boulevard Laurier, Sainte-Foy, Quebec, G1V 4G2, Canada. E-mail marie-claude.vohl{at}crchul.ulaval.ca
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Abstract |
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Background— Several lines of evidence suggest that small dense LDL particles are associated with the risk of coronary heart disease. Heritability and segregation studies suggest that LDL particle size is characterized by a large genetic contribution and the presence of a putative major genetic locus. However, association and linkage analyses have thus far been inconclusive in identifying the underlying gene(s).
Methods and Results— An autosomal genome-wide scan for LDL peak particle diameter (LDL-PPD) was performed in the Québec Family Study. A total of 442 markers were genotyped, with an average intermarker distance of 7.2 cM. LDL-PPD was measured by gradient gel electrophoresis in 681 subjects from 236 nuclear families. Linkage was tested by both sib-pair–based and variance components–based linkage methods. The strongest evidence of linkage was found on chromosome 17q21.33 at marker D17S1301, with an LOD score of 6.76 by the variance-components method for the phenotype adjusted for age, body mass index, and triglyceride levels. Similar results were obtained with the sib-pair method (P<0.0001). Other chromosomal regions harboring markers with highly suggestive evidence of linkage (P
0.0023; LOD 
1.75) include 1p31, 2q33.2, 4p15.2, 5q12.3, and 14q31. Several candidate genes are localized under the peak linkages, including apolipoprotein H on chromosome 17q, the apolipoprotein E receptor 2, and members of the phospholipase A2 family on chromosome 1p as well as HMG-CoA reductase on chromosome 5q.
Conclusions— This genome-wide scan for LDL-PPD indicates the presence of a major quantitative trait locus located on chromosome 17q and others interesting loci influencing the phenotype.
Key Words: genome • lipoproteins • genetics • genes
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Introduction |
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Anumber of case-control as well as prospective studies reveal an increased risk of coronary heart disease in patients with small dense LDL compared with those having larger, more buoyant LDL particles.1 Heritability studies based on twins suggested that approximately one third to one half of the variation in the LDL peak particle size can be attributed to genetic influences.2,3 Complex segregation analyses of small dense LDL phenotypes have been performed with data from different types of family structures, different criteria for proband ascertainment, and the use of different techniques to characterize LDL heterogeneity.4–9 Nevertheless, the model providing the best fit to the data included either a dominant, a recessive, or an undetermined mode of inheritance for the trait. Furthermore, the allele frequency determining the small dense LDL phenotype ranges from 19% to 42%, with reduced penetrances in young men and premenopausal women. However, these studies unanimously provided evidence in favor of a gene with a major effect on LDL particle phenotypes.
Association studies with candidate genes have been inconsistent in finding genes associated with small dense LDL. The -250G
A polymorphism within the hepatic lipase promoter was associated with buoyant LDL particles.10 However, the -514CT polymorphism, which is in complete linkage disequilibrium with the -250GA polymorphism,11 showed no effect on LDL particle size.12,13 The apolipoprotein (apo) E genotype was also associated with the small dense LDL phenotype. However, some studies have reported smaller particles for subjects carrying the E4 allele,14–16 and other studies did for subjects carrying the E2 allele.17,18 In contrast, others have shown that LDL particle size did not differ among the apoE genotypes.19 Additional candidate genes, including cholesteryl ester transfer protein,20 microsomal triglyceride transfer protein,21 cholesterol 7
-hydroxylase,22 apoB-100,23 apoC-III,24 and ACE16 were investigated for potential effects on small dense LDL phenotypes. These studies revealed either the absence of an association or the presence of an association only in particular subgroups.
Results from linkage studies are equivocal. After linkage of small dense LDL with the apoB (the protein moiety of LDL) gene locus on chromosome 2 was excluded,25,26 suggestive linkage to the LDL receptor locus on chromosome 19 has been reported.27,28 However, subsequent sequencing of the entire coding regions of the LDL-receptor gene did not reveal any sequence variants, thus weakening the hypothesis that a mutant LDL-receptor allele is responsible for the dense LDL phenotype.29 Other candidate loci, including hepatic lipase,12 lipoprotein lipase,30 cholesteryl ester transfer protein,28,31,32 apoA1-CIII-AIV complex,28,32 and the manganese superoxide dismutase,28,32 have been shown to be linked with the small dense LDL phenotype. Unfortunately, most of these linkages have not been replicated.33,34 On the basis of these results, Austin et al34 emphasized the necessity of finding new genetic loci, other than those harboring known candidate genes, to identify the genes potentially involved in determining the small dense LDL phenotype. Genome-wide scans are particularly suited for this purpose. Previous genome-wide scans have focused on variation in cholesterol concentrations of LDL size fractions. Rainwater et al35 found 2 quantitative trait loci (QTLs) on chromosome 3 and 4 with logarithm of the odds (LOD) scores >3 for LDL size fraction 3 (LDL-3), a fraction that contains small LDL particles. This study demonstrates the existence of QTLs affecting the concentration of cholesterol within a particular subpopulation of LDL but do not provide evidence of QTLs responsible for the size of the LDL particle by itself. To the best of our knowledge, the only whole-genome scans on LDL particle size were performed on 240 individuals ascertained through 18 unrelated familial combined hyperlipidemic probands.12 Results suggest a locus over the hepatic lipase gene on chromosome 15 with a LOD score of 2.2. Here, we report the results of an autosomal genomic scan for LDL peak particle diameter (LDL-PPD) measured by gradient gel electrophoresis.
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Methods |
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Population
The Québec Family Study is an ongoing project composed of French-Canadian families that has been described previously.36 In the present study, a total of 681 subjects from 236 nuclear families had available data on LDL-PPD. Table 1 presents the characteristics of subjects in each of the sex and generation groups. The Laval University Medical Ethics Committee approved the study, and all subjects provided written informed consent. All the procedures followed were in accordance with institutional guidelines.
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Phenotype
LDL-PPD was measured by gradient gel electrophoresis from plasma obtained after a 12-hour fast. Details on the technique have been provided previously.37
Genotypes
Genomic DNA was prepared by the proteinase K and phenol/chloroform technique. DNA preparation, polymerase chain reaction conditions, and genotyping are described in detail elsewhere.38 Genotypes for each marker were typed by use of automatic DNA sequencers and the computer software SAGA from LICOR. The results were stored in a local dBase IV database, GENEMARK, which inspects results for mendelian inheritance incompatibilities within nuclear families and extended pedigrees. A total of 335 microsatellite markers (dinucleotide, trinucleotide, and tetranucleotide repeats) selected from different sources, but primarily from the Marshfield panel version 8a, were available for this genome scan. The location of markers on the chromosomes in centimorgans (cM) were taken from version 9.0 of the Marshfield Institute map39 and the Location Database map.40 In addition, 107 polymorphisms in 63 candidate genes were included. The average intermarker distance for the whole set of 442 markers was 7.2 cM. The Genome Database41 and the OMIM gene map42 were used to identify candidate genes.
Statistical Analyses
LDL-PPD was adjusted for covariates by use of a stepwise multiple regression procedure, retaining only terms that were significant at the 5% level. Regression parameters were estimated within 6 age-by-sex (<30, 30 to 50, and 50 years; male versus female) groups after exclusion of outliers (±4 SD), and residuals were computed for all subjects. Residual scores were then standardized to a mean of 0 and an SD of 1. LDL-PPDs were adjusted for 3 different sets of covariates: (1) age up to the cubic polynomial, (2) age and body mass index (BMI), and (3) age, BMI, and triglyceride levels. These adjustments gave 3 phenotypes, arbitrary called LDL-PPD1, LDL-PPD2, and LDL-PPD3, respectively. The phenotypes were adjusted by use of SAS software (version 8.02).
The search for linkage between the phenotypes and the genetic markers was performed by 2 different approaches. First, linkage was tested by the new Haseman-Elston regression-based method, which models the trait covariance between sib-pairs, instead of the squared sib-pair trait difference used in the original method. It regresses the mean-corrected trait cross product on the number of alleles shared identical by descent (IBD). Single-point and multipoint estimates of alleles shared IBD were generated with the GENIBD software, and linkage was tested with the SIBPAL2 software from the SAGE 4.0 statistical package (SAGE, 2001).43 The maximum number of sib-pairs was 352. Linkage was also investigated by the variance components–based approach implemented in the quantitative transmission disequilibrium test (QTDT) computer software.44 By this approach, the phenotypic covariance among members of a family is assumed to result from the additive effects of linkage caused by a major locus (a), a residual familial component resulting from polygenes (g), and a residual nonshared environmental component (e) that represents environmental effects unique to each family member. Linkage is tested by contrasting the null hypothesis of no linkage (
a=0) with the alternative hypothesis (a
0) by use of a likelihood ratio test, as described previously.45 The LOD score was computed as 
2/(2 loge 10). The interpretation of linkage evidence was considered suggestive (P0.01; LOD 1.18), highly suggestive (P0.0023; LOD 1.75), or evidence of linkage (P0.0001; LOD 3.0).46
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Results |
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An overview of the variance components–based linkage results for the 3 LDL-PPD phenotypes is given in Figure 1. Suggestive evidence of linkages (P
0.01 or LOD scores 1.18 for at least one of the phenotypes) is summarized in Table 2. The strongest evidence of linkage, which was confirmed by both linkage methods, was found on chromosome 17q21.33. As shown in Figure 2, the peak linkages were found with marker D17S1301 for LDL-PPD1 (LOD=4.72), LDL-PPD2 (LOD=4.70), and LDL-PPD3 (LOD=6.76). Marker D17S1290, located 1.6 cM from D17S1301, also gave fairly good evidence of linkage for the 3 phenotypes.
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Other chromosomes exhibiting some evidence of linkage by the variance components–based method are displayed in Figure 1. Highly suggestive evidence of linkages was observed at 1p31 (leptin receptor locus), 2q33.2 (marker D2S1384), 4p15.2 (D4S2397), 5q12.3 (D5S1501), and 14q31.1 (D14S53). Markers at the leptin receptor locus and markers D5S1501 and D14S53 also provided evidence of linkage by the sib-pair method (see Table 2).
Other markers gave highly suggestive evidence of linkage (P<0.0023) with at least one of the linkage methods. For instance, marker D16S261 provided evidence of single-point linkage with the 3 phenotypes. The marker VWFP1 on chromosome 22q11.21 provided evidence of single-point and multipoint linkage for the 3 phenotypes. Conversely, marker D4S1627 yielded highly suggestive evidence of linkage for LDL-PPD1 and LDL-PPD2 with the variance component method. D5S1457 at 5p12 shows highly suggestive evidence of linkage in multipoint analysis for the 3 phenotypes and in single-point for LDL-PPD3. Finally, several markers provided highly suggestive evidence of linkage with LDL-PPD3 only, including D1S198, D2S434, IRS1 (2q36.3), ADRB2 (5q31), TNF (6p21.3), D8S1110, D9S1121, D16S410, and ACE (17q23).
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Discussion |
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The primary objective of this study was to identify QTLs affecting LDL-PPD variation. The results provide evidence for a major locus affecting LDL-PPD located on chromosome 17q21. Interestingly, none of the candidate genes located in the area of this QTL were tested previously. The marker D17S1301 located on chromosome 17q21.33 was strongly linked with the LDL-PPD, whether adjusted for covariates or not. However, the evidence for linkage was stronger when the phenotype was adjusted for plasma triglycerides, indicating that triglyceride levels may attenuate the penetrance of the locus. Marker D17S1290, located 1.6 cM from D17S1301, also provided good evidence of linkage (1.34
LOD2.63). The apoH (APOH) gene, also referred to as ß2-glycoprotein I, is encoded under the peak linkage on 17q21. ApoH is a single-chain glycoprotein that exists in plasma both in a free form and in combination with lipoprotein particles. It has been implicated in several physiological pathways, including lipid metabolism, coagulation, and the production of antiphospholipid antibodies. This apolipoprotein activates lipoprotein lipase,47 and genetic variations in this gene have been associated with variation in HDL cholesterol and triglyceride levels.48–50 ACE is also located in this genomic region. This enzyme cleaves the final intravascular step, resulting in the vasoactive peptide angiotensin II. Angiotensin II has been shown to bind specifically to LDL,51 which produces a modified form of LDL that is taken up by macrophages at an enhanced rate, leading to cellular cholesterol accumulation.52 In the present study, the insertion/deletion polymorphism in intron 16 of the ACE gene provided evidence of linkage with LDL-PPD1 (LOD=1.46), LDL-PPD2 (LOD=1.57) and LDL-PPD3 (LOD=2.35). Figure 2 shows the approximate location of candidate genes surrounding the major peak on chromosome 17. Several other chromosomal regions provided highly suggestive (P<0.0023) evidence of linkage. These regions include chromosomes 1p31, 5p12-p12.3, and 14q31.1, which show evidence of linkage with both linkage methods and for all LDL-PPD phenotypes. Some promising candidate genes are located within these regions. First, the strongest evidence of linkage on chromosome 1p comes from a marker located within the leptin receptor (LEPR) gene. By modulating the hypothalamic effects of leptin on food intake and energy expenditure, genetic variants in the LEPR may affect energy balance and the size of LDL particles as a consequence of body fatness alterations. However, adjusting the LDL-PPD for BMI did not affect the strength of the linkage. On 1p, 3 members of the phospholipase A2 (PLA2) gene family are present, namely PLA2 group IID (PLA2G2D), group V (PLA2G5), and group IIA (PLA2G2A). PLA2 is known to hydrolyze the phospholipid monolayers of LDL particles and change their physicochemical properties and size.53 ApoE receptor 2 (APOER2) is also located near the locus of interest. On chromosome 5, 2 markers (D5S1457 and D5S1501) located 20 cM apart provided evidence of linkage with LDL-PPD. This region contains the HMG CoA reductase (HMGCR), which is the rate-limiting enzyme for cholesterol synthesis. A list of other potential candidate genes within the chromosomal regions linked to the LDL-PPD is provided in Table 3.
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Among the panel of markers included in the genome scan, few candidate genes for LDL-PPD were present. First, an apoB marker gave no evidence of linkage with the phenotype. A significant linkage to apoB has been reported in a sib-pair linkage analysis of dizygotic female twins,33 but other linkage studies excluded the hypothesis of linkage for the apoB locus and LDL size.25,26,28 Second, although no linkage was found with the lipoprotein lipase locus in the present study or in 2 others,28,34 a highly significant LOD score of 6.24 was obtained in another study of heterozygous lipoprotein lipase–deficient families.30 Third, the apoE gene gave no evidence of linkage, as reported previously.28,33,34 Finally, consistent with 3 other studies,32–34 the LDL receptor also was not linked to LDL-PPD in the present study. In contrast, 2 previous results linked the LDL receptor locus to LDL subclass in families ascertained through probands with the atherogenic lipoprotein phenotype27 and in families with coronary heart disease.28 However, no amino acid sequence changes in the LDL receptor were found in the former study,27 making it unlikely that a mutant allele in the LDL receptor gene was responsible for the linkage.29 In the present study, negative results were also obtained with other candidate genes, including paraoxonase, hormone-sensitive lipase, CD36, and the intestinal fatty acid-binding protein.
In conclusion, the results of this study reveal the presence of a major locus located on chromosome 17q21.33 influencing LDL-PPD. This finding supports results from a handful of segregation analyses indicating the presence of a putative major locus for LDL particle size. Evidence of linkage was also found on chromosomes 1p31, 2q33.2, 4p15.2, 5q12.3, and 14q31.1. These QTLs harbor a good number of candidate genes that have not previously been tested in association studies with LDL-PPD.
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Acknowledgments |
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This study was supported by the Canadian Institutes of Health Research (MT-13960 and GR-15187). Y. Bossé is the recipient of a studentship from the Fonds pour la formation de chercheurs et l’aide à la recherche (FCAR) et le Fonds de la recherche en santé du Québec (FRSQ). Dr Vohl is a research scholar of the FRSQ. Dr Bouchard was supported in part by the George A. Bray Chair in Nutrition. Dr Després is chair professor of human nutrition, lipidology, and prevention of cardiovascular disease, supported by Provigo and Pfizer Canada. Dr Lamarche is the recipient of the Canada Research Chair in Nutrition, Functional Foods, and Cardiovascular Health. The results of this study were obtained by use of the program package SAGE, which is supported by a US Public Health Service Resource Grant (1-P41-RR-03655) from the National Center for Research Resources. The authors would like to express their gratitude to the subjects for their excellent collaboration and to the staff of the Physical Activity Sciences Laboratory for their contribution to the study.
Received December 6, 2002; revision received February 13, 2003; accepted February 18, 2003.
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K. E. North, H. H. H. Goring, S. A. Cole, V. P. Diego, L. Almasy, S. Laston, T. Cantu, B. V. Howard, E. T. Lee, L. G. Best, et al. Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study J. Lipid Res., January 1, 2006; 47(1): 59 - 66. [Abstract] [Full Text] [PDF]
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Y. Yu, D. F. Wyszynski, D. M. Waterworth, S. D. Wilton, P. J. Barter, Y. A. Kesaniemi, R. W. Mahley, R. McPherson, G. Waeber, T. P. Bersot, et al. Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia J. Lipid Res., October 1, 2005; 46(10): 2202 - 2213. [Abstract] [Full Text] [PDF]
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A. M. Shearman, S. Demissie, L. A. Cupples, I. Peter, C. H. Schmid, J. M. Ordovas, M. E. Mendelsohn, and D. E. Housman Tobacco smoking, estrogen receptor {alpha} gene variation and small low density lipoprotein level Hum. Mol. Genet., August 15, 2005; 14(16): 2405 - 2413. [Abstract] [Full Text] [PDF]
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Y. Bosse, Y. C. Chagnon, J.-P. Despres, T. Rice, D. C. Rao, C. Bouchard, L. Perusse, and M.-C. Vohl Compendium of genome-wide scans of lipid-related phenotypes: adding a new genome-wide search of apolipoprotein levels J. Lipid Res., December 1, 2004; 45(12): 2174 - 2184. [Abstract] [Full Text] [PDF]
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M. D. Badzioch, R. P. Igo Jr, F. Gagnon, J. D. Brunzell, R. M. Krauss, A. G. Motulsky, E. M. Wijsman, and G. P. Jarvik Low-Density Lipoprotein Particle Size Loci in Familial Combined Hyperlipidemia: Evidence for Multiple Loci From a Genome Scan Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1942 - 1950. [Abstract] [Full Text] [PDF]
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J.-C. Hogue, B. Lamarche, D. Gaudet, M. Lariviere, A. J. Tremblay, J. Bergeron, I. Lemieux, J.-P. Despres, C. Gagne, and P. Couture Relationship between cholesteryl ester transfer protein and LDL heterogeneity in familial hypercholesterolemia J. Lipid Res., June 1, 2004; 45(6): 1077 - 1083. [Abstract] [Full Text] [PDF]
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Y. Bosse, L. Perusse, and M.-C. Vohl Genetics of LDL particle heterogeneity: from genetic epidemiology to DNA-based variations J. Lipid Res., June 1, 2004; 45(6): 1008 - 1026. [Abstract] [Full Text] [PDF]
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C.C. Shoulders, E.L. Jones, and R.P. Naoumova Genetics of familial combined hyperlipidemia and risk of coronary heart disease Hum. Mol. Genet., April 1, 2004; 13(90001): R149 - 160. [Abstract] [Full Text] [PDF]
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M. A. Austin, K. L. Edwards, S. A. Monks, K. M. Koprowicz, J. D. Brunzell, A. G. Motulsky, M. C. Mahaney, and J. E. Hixson Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia J. Lipid Res., November 1, 2003; 44(11): 2161 - 2168. [Abstract] [Full Text] [PDF]
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