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Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:971-978

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:971.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Genome-Wide Linkage Analysis Reveals Evidence of Multiple Regions That Influence Variation in Plasma Lipid and Apolipoprotein Levels Associated With Risk of Coronary Heart Disease

Kathy L. Klos; Sharon L. R. Kardia; Robert E. Ferrell; Stephen T. Turner; Eric Boerwinkle; Charles F. Sing

From the Department of Human Genetics (K.L.K., C.F.S.) and the Department of Epidemiology (S.L.R.K.), University of Michigan, Ann Arbor; the Department of Human Genetics (R.E.F.), University of Pittsburgh, Pittsburgh, Pa; the Division of Hypertension, Department of Medicine, Mayo Clinic (S.T.T.), Rochester, Minn; and the Human Genetics Center, University of Texas Health Science Center (E.B.), Houston.

Correspondence to Dr Charles F. Sing, University of Michigan, Department of Human Genetics, 5928 Buhl Building, 1241 E. Catherine St, Ann Arbor, MI 48109-0618. E-mail csing{at}umich.edu


*    Abstract
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Abstract—Results of genome-wide linkage analyses to identify chromosomal regions that influence interindividual variation in plasma lipid and apolipoprotein levels in the Rochester, Minn, population are reported. Analyses were conducted for total cholesterol (total-C), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, apolipoprotein C-II, apolipoprotein C-III, apolipoprotein E, the total-C/HDL-C ratio, and the TG/HDL-C ratio. Genotypes were measured for 373 genome-wide marker loci on 1484 individuals distributed among 232 multigeneration pedigrees sampled without regard to health status. LOD scores and estimates of additive genetic variance associated with map locations were obtained by using the variance-component method of linkage analysis. No evidence of linkage with genes influencing variation in age served as a negative control. Plasma apolipoprotein E levels and the apolipoprotein E gene served as a positive control (LOD score 4.20). Evidence (LOD score >2.00) was provided that was suggestive of a gene or genes on chromosomes 4 and 5 influencing variation in the apolipoprotein A-II level, on chromosome 12 influencing variation in the apolipoprotein A-I level, and on chromosome 17 influencing variation of total-C/HDL-C. These analyses provide new information about genomic regions in humans that influence interindividual variation in plasma lipid and apolipoprotein levels and serve as a basis for further fine-mapping studies to identify new genes involved in lipid metabolism.


Key Words: genetic linkage • apolipoprotein E • apolipoprotein A-I • apolipoprotein A-II • total cholesterol • high density lipoproteins


*    Introduction
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One of the greatest challenges that the medical and public health communities face is to identify and characterize the genes that influence the risk of coronary artery disease (CAD). Only a small fraction of the genes that are expected to be involved in determining the risk of CAD are known. Measures of lipid metabolism are well-established intermediate traits that translate genetic variation into variation in the risk of CAD. Increased risk of developing CAD has been associated with elevated triglyceride (TG),1 2 total cholesterol (total-C),3 4 5 and LDL cholesterol6 7 levels and with decreased levels of HDL cholesterol (HDL-C).6 8 CAD has also been associated with low levels of plasma apoA-I and apoA-II and high levels of apoB and apoE.9 10 11 12 13 14 Only a fraction of the genetic variation in intermediate measures of lipid metabolism is explained by variation in known candidate genes. For example, the total genetic contribution to variation in total-C, HDL-C, and other lipid traits is estimated to be between 40% and 80%.15 16 However, single polymorphisms typically explain only 5% to 15% of that variation.16 17 18 19 20 The present study is part of an effort to find new genes that influence the genetic architecture of CAD by carrying out genetic studies of intermediate measures of lipid metabolism that translate genetic variation into variation in risk of CAD. The genetic architecture of a trait is defined by the number of genes, the number of alleles per gene and their relative frequencies, and the gene-gene and gene-environment interactions that combine to influence interindividual variation within a population.21 Genome-wide linkage scans have the potential for identifying regions of the genome not previously recognized as sources of interindividual variation in intermediate traits that influence variation in the risk of CAD.22 23 24 25 26

To identify regions of the genome predictive of interindividual variation in plasma lipid levels for the purpose of identifying new candidate genes, we have applied a variance component–based linkage method to phenotypic data in pedigrees ascertained without regard to health status. Evidence of the linkage of marker loci with a gene(s) influencing interindividual variation in plasma apoE level was observed in the region of chromosome 19 containing the apoE gene. LOD scores provided suggestive evidence of the linkage of marker loci with previously unknown genes on chromosomes 4 and 5 influencing apoA-II, on chromosome 12 influencing apoA-I, and on chromosome 17 influencing the total-C/HDL-C ratio.


*    Methods
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Sample and Laboratory Methods
As part of the Rochester Family Heart Study, multigeneration pedigrees were ascertained without regard for health through households with >=2 children enrolled in the primary and secondary schools of Rochester, Minn. Sampling details, the clinic examination protocol, and baseline characteristics have been described by Moll et al27 and Turner et al.28 Marker genotype data were obtained for 1484 individuals (779 females and 705 males) of the 4486 individuals identified with 232 pedigrees (see Table 1Down). There was an average of 2.94 children per pedigree. Individuals were genotyped for 373 highly polymorphic microsatellite marker loci located on the 22 human autosomes. The median distance between adjacent markers was 8.3 cM (range 0 to 40.2 cM). Genotyping was performed by standard methods with use of an Applied Biosystems/Perkin Elmer 377 automatic DNA sequencer. The genotype data were analyzed for typings inconsistent with the pedigree structure by use of the Lange and Goradia29 algorithm as implemented by Ped Check.30 Observed discrepancies were evaluated for typing errors in the laboratory. Instances that could not be resolved were treated as missing data.


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  		Table 1. Characteristics of 232 Multigeneration Pedigrees Containing 1484 Individuals From Rochester, Minn., Who Were Genotyped for the Linkage Analysis

Plasma total-C and TG levels were measured by standard enzymatic methods.31 32 LDL particles were precipitated with polyethylene glycol 6000, and an aliquot of the supernatant was used for determination of HDL-C by an enzymatic method as described by Kaprio et al.33 Plasma apoA-I, apoA-II, apoC-II, apoC-III, and apoE were measured by radioimmunoassay.34 Plasma apoB was measured by ELISA.33 Complete lipid and apolipoprotein measurements were available for 778 females and 704 males.

Linkage Analysis
The lipid levels were adjusted for gender-specific age, height, and weight to the third order, as well as body mass index (BMI), before carrying out the linkage analysis. Marker relative allele frequencies were estimated as the sample relative allele frequencies. Genetic map location estimates were taken from the maps prepared by the Center for Medical Genetics at the Marshfield Medical Research Foundation.35 Locations for markers not contained in the Marshfield map were inferred from their map locations in the Genetic Location Database.36

Linkage analyses were conducted by the variance-components method37 with use of the SOLAR computer program. In this method, a linear mixed model was fit to the trait data so that the phenotypic variance about the trait mean is partitioned into a monogenic component ({varsigma}2QTL) representing the contribution of a quantitative trait locus (QTL) linked to the marker locus, a residual familial component ({varsigma}2R) attributable to familial genetic and shared environmental effects, and a component ({varsigma}2E) attributable to environmental effects unique to the individual. With the assumption of no recombination between trait and marker loci, the phenotypic variance-covariance matrix ({Omega}) for individuals in a pedigree may be written as {Omega}={Phi}{varsigma}2QTL+II{varsigma}2R+I{varsigma}2E, where {Phi} is a matrix of the proportion of alleles shared identical by descent (IBD) at a point in the genome estimated from the genotypic data, II is a matrix of the expected proportion of alleles shared IBD for pairs of relatives, and I is an identity matrix. Multipoint estimates of IBD were obtained as a weighted average of the IBD at each individual marker.38 The estimates of IBD for individual markers were obtained by the computer program SOLAR37 by using the relationship information from the 4486 individuals making up the 232 pedigrees and the genotype data for the subset of 1484 individuals who were genotyped for the present study. Missing genotype values in the subset of 1484 were imputed by using information from flanking markers before full multipoint estimation.37

All LOD scores reported below are based on multipoint analyses. The LOD scores were calculated as the difference between the maximum of the log10 likelihood of the full model, including estimates of {varsigma}2QTL, {varsigma}2R, and {varsigma}2E, and the maximum of the log10 likelihood of the reduced model in which {varsigma}2QTL was constrained to equal 0. Twice the difference between the maximum of the loge likelihood of these 2 models is a likelihood ratio test statistic asymptotically distributed as a 1/2:1/2 mixture of a {chi}2 with a point mass at 0 and 1 df. In 3 cases, the linkage analysis yielded evidence of >=1 QTL influencing interindividual variation in a trait (multipoint LOD >2.00). In these cases, a second linkage analysis was performed with the contribution of the first QTL to trait variation fixed in the full and reduced models.39 All linkage analyses were carried out in SOLAR with use of the t distribution function, which provides a better fit to data that do not meet assumptions of normality. We have used a LOD score of >=3.00 to indicate adequate evidence of linkage, a LOD threshold of >=2.00 as suggestive, and a LOD score of >=1.30 as tentative evidence of linkage.40


*    Results
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The phenotypic characteristics of the 1482 individuals in 232 pedigrees used in these linkage analyses are summarized in Table 2Down. The average age of males was 36.3 years (range 5.2 to 89.3 years) and of females was 39.0 years (range 5.4 to 90.3 years). The average BMI was 23.4 kg/m2 (range 13.7 to 50.8 kg/m2) for females and 23.7 kg/m2 (range 13.8 to 43.3 kg/m2) for males. On average, 1263 (range 819 to 1392) individuals were genotyped for a marker locus. The average individual was successfully genotyped for 320 markers.


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  		Table 2. Characteristics of the 1484 Participants From Rochester Who Were Genotyped for the Linkage Analysis

The multipoint linkage analysis results of the genome scan are presented in Table 3Down as the highest LOD score observed on each chromosome for each of 11 plasma lipid and apolipoprotein traits. LOD peaks >2.00 are indicated in boldface type; LOD scores >3.00 were observed for the apoE level on chromosome 19 in the region containing the apoE gene. In the analysis of age, we observed no LOD score >0.00 (Table 3Down).


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  		Table 3. Peak Multipoint LOD Scores and Positions on Each Chromosome for 11 Plasma Lipid and Apolipoprotein Traits

Figure 1Down depicts the linkage results for 4 traits (apoA-I, apoA-II, apoE, and total-C/HDL-C) for the chromosomes for which LOD peaks >1.30 were observed. The highest LOD score observed was 4.20, corresponding to a chromosomal region influencing the plasma apoE level on 19q, near the marker D19S246. An interval 40 cM wide between markers D19S245 and D19S254 had LOD scores >2.00. Tentative evidence for linkage to a region influencing variation in apoE was also found on chromosome 12p near the marker GATA91H06 (LOD score 1.50). To test whether the multiple QTLs identified as influencing variation in apoE levels formed a true multilocus system, we ran a multipoint linkage scan of the genome by using full and reduced models, which both included the contribution of the QTL on chromosome 19. A LOD score from this analysis of 1.30 on chromosome 12 near the marker GATA91H06 supports the initially observed evidence of linkage to a QTL in this region that influences variation in apoE levels.



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  		Figure 1. Plot of multipoint LOD scores (calculated at 1-cM intervals) for linkage with regions on chromosomes 4, 5, and 18 influencing variation in plasma apoA-II level, on chromosomes 5 and 17 influencing variation in total-C/HDL-C, on chromosomes 12 and 19 influencing variation in plasma apoE level, and on chromosome 12 influencing variation in plasma apoA-I level.

Suggestive evidence of a QTL near the marker D4S2368 on chromosome 4q (LOD score 2.35) and a QTL on 5p (LOD score 2.13) near the marker D5S2500, which influence variation in apoA-II levels, was detected. Tentative evidence was observed for a third QTL influencing apoA-II variation on chromosome 18 near the marker D18S976 (LOD score 1.53). Linkage analysis in which the full and reduced models included the contribution of the chromosome 4 QTL resulted in a LOD score of 1.55 for a second QTL on chromosome 5 near D5S2500. Suggestive evidence was found of linkage near marker D12S2070 on chromosome 12 (LOD score 2.02) with a QTL influencing plasma apoA-I levels. Evidence suggestive of a QTL near marker D17S928 at the end of the long arm of chromosome 17 (LOD score 2.48) that influences plasma total-C/HDL-C variation was observed. Additional tentative evidence of a QTL influencing variation in total-C/HDL-C was found on chromosome 5q near the marker D5S408 (LOD score 1.57). Linkage analysis with the contribution of the chromosome 17 QTL included in the full and reduced models resulted in a LOD score of 1.26 for a second QTL at the chromosome 5 location.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The purpose of the present study was to identify genomic regions containing genes influencing interindividual variation in plasma lipid and apolipoprotein levels in nonhispanic white families from Rochester, Minn, selected without regard to health status. The results of our linkage scan provide evidence of regions of the genome that may contain previously unknown genes that influence normal interindividual variation in apoA-I, apoA-II, apoE, and total-C/HDL-C. Positional candidate genes in regions identified by multipoint linkage analyses are summarized in Table 4Down.


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  		Table 4. Positional Candidate Genes for Plasma ApoA-I, ApoA-II, ApoE, and Total-C/HDL-C in Genomic Regions Identified by Multipoint Linkage Analyses

The genome-wide linkage scan for loci influencing age serves as a negative control for the variance-components linkage method in this population. Figure 2Down contrasts the multipoint linkage results for age with those for plasma apoE on chromosome 19. The fact that no LOD score >0.00 was observed for age on any chromosome is in accord with the low type I error rate (0.0025) estimated for this method in the GAW10 problem set of simulated nuclear families.41



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  		Figure 2. Plot of multipoint LOD scores (calculated at 1-cM intervals) for linkage on chromosome 19 with regions influencing variation in plasma apoE level, apoE adjusted for apoE genotype (apoE/E type), and age.

The apoE gene region on chromosome 19q serves as a positive control for the variance-components linkage method. There is a large body of evidence supporting the major contribution of the apoE gene to variation in plasma apoE level and to the risk of developing CAD.11 14 42 43 44 45 The 3 major apoE isoforms (E2, E3, and E4) account for between 11% and 19% of the interindividual variation in levels of apoE in this and other populations.16 33 46 The highest LOD score observed in the present study (LOD score 4.20, near the marker D19S246) identifies a region of chromosome 19 that includes the apoE/C-I/C-II gene cluster. The width of this peak, covering more than one third of chromosome 19 (LOD score >2.00), may be due to the major effect of the apoE gene on interindividual variation in the apoE level. Alternately, the width of the region with LOD scores suggestive of linkage may indicate overlapping peaks that are due to genes other than apoE within this region with effects on lipid metabolism. To test whether variation in the apoE gene was responsible for the multipoint LOD peak observed on chromosome 19, we adjusted plasma apoE levels for apoE genotype means (after gender-specific adjustment for variation in age, height, and weight to the third order and BMI). The resulting peak multipoint LOD, 1.10 at 78 cM (Figure 2Up), is below our threshold for tentative evidence of linkage but may still reflect variation in the apoE gene not measured by the {epsilon}2, {epsilon}3, and {epsilon}4 alleles47 (J.H. Stengård, personal communication, 2000).

The ability to detect linkage of markers with the apoE gene region, when the plasma apoE level is considered, documents the utility of this method to localize genes influencing interindividual variation in plasma lipid traits of complex inheritance. Simulations by Blangero et al39 indicate that a variance-components linkage analysis of 1000 individuals in randomly ascertained extended pedigrees has a power of 80% to detect a QTL that accounts for as little as 20% of trait variation with a LOD score of >=3.0. However, the pedigrees used in the study of Blangero et al were much larger than the pedigrees used in the present study, and the power of the variance-components method to detect linkage decreases with declining QTL-specific heritability.48 Thus, the many QTLs that are each expected to have considerably smaller effects on genetic variance may not be detected by a linkage analysis performed with this simple model on small randomly ascertained pedigrees.

Polymorphism in the apoE gene has been identified as a predictor of variation in intermediate risk factors for CAD, apart from apoE level, including total-C, TGs, apoB, and HDL-C.33 45 49 For example, the traditional apoE genotypes explain 3% and 23% of variation in TGs in men and women, respectively, in Rochester, Minn.33 Peak multipoint LOD scores on chromosome 19 for TGs did not exceed 2.00, nor did the peak correspond to the position of the apoE gene (Table 3Up). However, the effect of apoE on TG level varies in contexts such as age and measures of body size.50 51 52 53 The context-dependent effects of apoE genotype on other measures of lipid metabolism, and on the correlations among them, are also well known.52 53 Much of the complexity of the genetic architecture of apoE and other plasma lipid and apolipoprotein traits is ignored by the simple additive variance-components model of linkage used in the present study. We chose to initially examine the first-order effects to maximize the power to detect a QTL by using the full sample in this first genome scan. We expect that QTLs with large marginal effects will be detected by this model but that QTLs whose effects are confined to particular strata of the population may be associated with LOD scores below our threshold for linkage.

Despite the limitations of the simple model used in the present study, several regions suggestive of linkage with lipid and apolipoprotein traits within which lie candidate genes for lipid metabolism were identified (Table 4Up). In addition to the evidence for linkage with a QTL influencing variation in apoE level on chromosome 19, tentative evidence for linkage was observed on chromosome 12. This region contains the gene encoding the catalytic polypeptide of the apoB mRNA–editing enzyme (APOBEC1), which is involved in the metabolism of apoE. In LDL receptor knockout mice, inactivation of APOBEC1 resulted in a 60% increase in plasma apoE.54 Thus, variation in the APOBEC1 gene may affect the risk of CAD by influencing variation in the apoE level in particular contexts indexed by the level of LDL receptor expression. Additionally, evidence of a locus on chromosome 12 influencing the risk of Alzheimer’s disease is stronger in families without the apoE {epsilon}4 allele,55 56 57 a risk factor for CAD and Alzheimer’s disease.

Regions on chromosomes 4 and 5 showed suggestive evidence of the influence of QTL on apoA-II variation (LOD score >2.00) (Figure 1Up). ApoA-II is the second most abundant apolipoprotein in HDL (after apoA-I) and may affect the risk of CAD by influencing the rate of cholesterol efflux from peripheral tissues.58 A gene on chromosome 4 that codes for carboxypeptidase E is a positional candidate gene for influencing apoA-II level. Carboxypeptidase E is an enzyme responsible for prohormone sorting and processing, influencing such signaling molecules as pro-opiomelanocortin and insulin, both of which are involved in energy homeostasis.59 60 61 Also near the position of the multipoint LOD peak for apoA-II on chromosome 4 is the gene coding for the fibrinogen-ß polypeptide, which has been associated with increased risk of peripheral atherosclerosis.62 On chromosome 5, positional candidate genes include cholesterologenesis enzymes 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1). Inhibition of HMGCR in humans alters the plasma lipid profile, including a significant reduction in the ratio of cholesterol to HDL-C.63 In rats, administration of tetradecylthioacetic acid decreases apoA-II while increasing HMGCS1 mRNA levels, evidence of a link between HMGCS1 expression and the level of liver apolipoproteins.64 Neither of the 2 regions influencing variation in apoA-II that were identified in this population included the structural gene for apoA-II on chromosome 1q21-q23. Variation in the apoA-II gene can account for 10% to 11% of interindividual variation in the apoA-II level.65 However, in the sample considered here, variation in the apoA-II gene does not contribute to variation in apoA-II at a level detectable by linkage analysis (LOD score <0.50, Table 2Up).

ApoA-I is the most abundant apolipoprotein in HDL-C and is a better predictor of CAD risk than is HDL-C alone.10 13 Studies of the genetic determination of apoA-I have found evidence of 1 major locus,66 2 major loci,67 or polygenes alone68 69 influencing the variation in different populations. The LOD score of 2.02 at 128 cM in the present study suggests that variation in plasma apoA-I may be influenced by a gene on chromosome 12q. A positional candidate gene, scavenger receptor class B type 1 (SRB1), is located near the position of this LOD peak. SRB1, with a binding affinity for multiple apolipoproteins including apoA-I, apoA-II, and apoC-III, acts as a receptor for the selective uptake of HDL cholesteryl ester in the liver and steroidogenic tissues and for the efflux of cholesterol from peripheral cells.70 The overexpression of SRB1 in mice is accompanied by a substantial, but transitory, decrease in HDL-C and apoA-I levels.71 It is possible that changes in SRB1 expression may also influence apoA-I levels in humans.

Evidence suggestive of the influence of a QTL on variation in total-C/HDL-C was observed from the analyses of chromosomes 5 and 17. Regulation of microsomal transfer protein (MTP) expression and activity may influence plasma cholesterol level. There are no obvious candidate genes near this location of the LOD peak on chromosome 5. A positional candidate gene located in the region of the peak LOD score on chromosome 17 is the procollagen proline 2-oxoglutarate 4-dioxygenase cellular thyroid hormone binding protein, a multifunctional protein that is the small subunit of the MTP heterodimer. MTP catalyzes the transport of TGs, cholesteryl esters, and phospholipids between phospholipid surfaces. Defects in the larger subunit of MTP have been previously associated with abetalipoproteinemia.72

Three regions identified in our genome-wide linkage scan, although associated with LOD scores <2.00, are worthy of further mention as supporting evidence for previously published reports of linkage. Aouizerat et al23 found suggestive evidence of linkage on chromosome 11p with a gene contributing to familial combined hyperlipidemia in Dutch pedigrees. The region, near the marker D11S1324 (35 cM), was associated with a combined lipid phenotype that included elevated total-C (>90th percentile). Tentative evidence for linkage (LOD score 1.84 at 34 cM) with a gene(s) on chromosome 11p (34 cM) influencing plasma total-C level was observed in the present study. Knoblauch et al25 observed strong evidence of linkage with a region of chromosome 13q near the markers D13S1241 and D13S786 (76 to 77 cM) influencing HDL-C, LDL, total-C, and BMI in an Arab family from Israel ascertained for familial hypercholesterolemia and in an independent sample of healthy white monozygotic and dizygotic twins from Germany. This region of 13q is very near the QLTs identified in the present study, which may influence TG (LOD score 1.64 at 86 cM) and TG/HDL-C (LOD score 1.37 at 64 cM) levels.

The results of our genome-wide linkage analyses of 11 lipid and apolipoprotein traits provide a focus for future genetic studies. This scan has identified chromosomal regions hypothesized to contain new genes influencing interindividual variation in apoA-I, apoA-II, and total-C/HDL-C and has provided supporting evidence of regions that may contain genes influencing variation in apoE, total-C, TGs, and TG/HDL-C. These results suggest a list of positional candidate genes for detailed DNA sequence analysis aimed at identifying functional mutations that affect variation in the plasma lipid profile. Identification of genes that influence lipid metabolism will lead to a better understanding of the etiology of CAD and provide suggestions for the development of new therapies for the treatment and prevention of disease. Finally, a comparison of our results with the findings of other studies suggests to us the importance of gene-environment interactions and the need for context-dependent linkage analyses to identify regions of the genome that contain genes that influence interindividual variation in plasma lipid and apolipoprotein levels only in particular subdivisions of the population at large.


*    Acknowledgments
 
Funding for this research was provided by National Institutes of Health grants HL-39107, HL-51021, and HD-32197. We would like to thank Paul Kopec, Ken Weiss, and Sara Hamon at the University of Michigan and Terry Bertin and Kim Lawson at the University of Texas for their technical assistance and critical input.

Received February 9, 2001; accepted February 26, 2001.


*    References
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 *References
 

  1. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B–12B.[Medline] [Order article via Infotrieve]
  2. Davignon J, Cohn JS. Triglycerides: a risk factor for coronary heart disease. Atherosclerosis. 1996;124:S57–S64.
  3. Brunzell JD, Miller NE. Atherosclerosis in inherited and acquired disorders of plasma lipoprotein metabolism. In: NE Miller, Lewis B, eds. Lipoproteins, Atherosclerosis and Coronary Heart Disease. Amsterdam, Netherlands: Elsevier/North-Holland Biomedical Press; 1981:73–78.
  4. Dawber TR. The Framingham Study. Cambridge, Mass: Harvard University Press; 1980.
  5. Kannel WB, Garcia MJ, McNamara PN, Pearson G. Serum lipid precursors of coronary heart disease. Hum Pathol. 1971;2:129–151.[Medline] [Order article via Infotrieve]
  6. Castelli WP, Doyle JP, Gordon T. HDL cholesterol and other lipids in coronary heart disease: the Cooperative Lipoprotein Phenotyping Study. Circulation. 1977;55:767–772.[Abstract/Free Full Text]
  7. Gofman JW, Lingren F, Elliott H, Mantz W, Hewitt J, Strisower B, Herring V. The role of lipids and lipoproteins in atherosclerosis. Science. 1950;111:166–171, 186.[Free Full Text]
  8. Miller GJ, Miller NE. Plasma-high-density-lipoprotein concentration and development of ischaemic heart disease. Lancet. 1975;1:16–19.[Medline] [Order article via Infotrieve]
  9. Brunzell JD, Sniderman AD, Albers JJ, Kwiterovich PO Jr. Apolipoproteins B and A-I and coronary artery disease in humans. Arteriosclerosis. 1984;4:79–83.[Free Full Text]
  10. Buring JE, O’Connor GT, Goldhaber SZ, Rosner B, Herbert PN, Blum CB, Breslow JL, Hennekens CH. Decreased HDL2 and HDL3 cholesterol, Apo A-I and Apo A-II, and increased risk of myocardial infarction. Circulation. 1992;85:22–29.[Abstract/Free Full Text]
  11. Davignon J. Apolipoprotein E polymorphism and atherosclerosis. In: Born G, Schwartz C, eds. New Horizons in Coronary Heart Disease. London, UK: Current Science; 1993:5.1–5.21.
  12. Fager G, Wiklund O, Olafsson S, Wilhelmsen L, Bondjers G. Multivariate analyses of serum apolipoproteins and risk factors in relation to acute myocardial infarction. Arteriosclerosis. 1981;1:273–279.[Abstract/Free Full Text]
  13. Kottke BA, Holmes DR, Mao SJT, Kneller RW, Hallaway BJ, Zinsmeister AR. Apolipoproteins and coronary heart disease. Circulation.. 1985;71:415A. Abstract.
  14. Stengård JH, Zerba KE, Pekkanen J, Ehnholm C, Nissinen A, Sing CF. Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation. 1995;91:265–269.[Abstract/Free Full Text]
  15. Iselius L. Genetic epidemiology of common diseases in humans. In: Weir BS, Eisen EJ, Goodman MM, Namkoong G, eds. Quantitative Genetics. 1988:341–352.
  16. Neale MC, deKnijff P, Havekes LM, Bloomsma DI. ApoE polymorphism accounts for only part of the genetic variation in quantitative ApoE levels. Genet Epidemiol. 2000;18:331–340.[Medline] [Order article via Infotrieve]
  17. Menzel HJ, Kladetsky RG, Assman G. Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis. 1983;3:310–322.[Abstract/Free Full Text]
  18. Humphries SE, Talmud PJ, Kessling AM. Use of DNA polymorphisms of the apolipoprotein genes to study the role of genetic variation in the determination of serum lipid levels. In: Bock G, Collins GM, eds. Molecular Approaches to Human Polygenic Disease. Chichester, UK: John Wiley & Sons Ltd; 1987:128–149.
  19. Boerwinkle E, Visvikis S, Welsh D, Steinmetz MS, Hanash SM, Sing CF. The use of measured genotype information in the analysis of quantitative phenotypes in man, II: the role of the apolipoprotein E polymorphism in determining levels, variability and covariability of cholesterol, betalipoprotein and triglycerides in a sample of unrelated individuals. Am J Med Genet. 1987;27:567–582.[Medline] [Order article via Infotrieve]
  20. Sing CF, Boerwinkle EA. Genetic architecture of inter-individual variability in apolipoprotein, lipoprotein and lipid phenotypes. In: Bock G, Collins GM, eds. Molecular Approaches to Human Polygenic Disease. Chichester, UK: John Wiley & Sons, Ltd; 1987:99–127.
  21. Boerwinkle E, Chakraborty R, Sing CF. The use of measured genotype information in the analysis of quantitative phenotypes in man, I: models and analytical methods. Ann Hum Genet. 1986;50:81–94.
  22. Almasy L, Hixson JE, Rainwater DL, Cole S, Williams JT, Mahaney MC, VandeBerg JL, Stern MP, MacCluer JW, Blangero J. Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism. Am J Hum Genet. 1999;64:1686–1693.[Medline] [Order article via Infotrieve]
  23. Aouizerat BE, Allayee H, Cantor RM, Davis RC, Lanning CD, Wen P-Z, Dallinga-Thie GM, deBruin TWA, Rotter JI, Lusis AJ. A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11. Am J Hum Genet. 1999;65:397–412.[Medline] [Order article via Infotrieve]
  24. Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, O’Connell P, Stern MP. A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans. Am J Hum Genet. 2000;66:1237–1245.[Medline] [Order article via Infotrieve]
  25. Knoblauch H, Muller-Myhsok B, Busjahn A, Ben Avi L, Bahring S, Baron H, Heath SC, Uhlmann R, Faulhaber H-D, Shpitzen S, et al. A cholesterol-lowering gene maps to chromosome 13q. Am J Hum Genet. 2000;66:157–166.[Medline] [Order article via Infotrieve]
  26. Pajukanta P, Terwilliger JD, Perola M, Hiekkalinna T, Nuotio I, Ellonen P, Parkkonen M, Hartiala J, Ylitalo K, Pihlajamaki J, et al. Genomewide scan for familial combined hyperlipidemia genes in Finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels. Am J Hum Genet. 1999;64:1453–1463.[Medline] [Order article via Infotrieve]
  27. Moll PP, Sing CF, Weidman WH, Gordon H, Ellefson RD, Hodgson PA, Kottke BA. Total cholesterol and lipoproteins in school children: prediction of coronary heart disease. Prev Med. 1986;15:292–303.[Medline] [Order article via Infotrieve]
  28. Turner S, Weidman W, Michels V, Reed T, Ormson C, Fuller T, Sing CF. Distribution of sodium-lithium countertransport and blood pressure in Caucasians five to eighty-nine years of age. Hypertension. 1989;13:378–391.[Abstract/Free Full Text]
  29. Lange K, Goradia TM. An algorithm for automatic genotype elimination. Am J Hum Genet. 1987;40:250–256.[Medline] [Order article via Infotrieve]
  30. O’Connell JR, Weeks DE. Ped Check: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet. 1998;63:259–266.[Medline] [Order article via Infotrieve]
  31. Barr SE, Kottke BA, Mao SJT. Improved method for determination of triglycerides in plasma lipoproteins by an enzymic kit method. Clin Chem. 1981;27:1142–1144.[Medline] [Order article via Infotrieve]
  32. National Institutes of Health. Lipid Research Clinics Program Manual of Laboratory Operations. Washington, DC: Department of Health Education and Welfare; 1974. Publication No. 75–628.
  33. Kaprio J, Ferrell RE, Kottke BA, Kamboh MI, Sing CF. Effects of polymorphisms in apolipoproteins E, A-IV, and H on quantitative traits related to risk for cardiovascular disease. Arterioscler Thromb. 1991;11:1330–1348.[Abstract/Free Full Text]
  34. Kottke BA, Moll PP, Michels VV, Weidman WH. Levels of lipids, lipoproteins, and apolipoproteins in a defined population. Mayo Clin Proc. 1991;66:1198–1208.[Medline] [Order article via Infotrieve]
  35. Broman KW, Murray JC, Sheffield VC, White RL, Weber JL. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998;63:861–869.[Medline] [Order article via Infotrieve]
  36. Collins A, Frezal J, Teague J, Morton N. A metric map of humans: 23,500 loci in 850 bands. Proc Natl Acad Sci U S A. 1996;93:14771–14775.[Abstract/Free Full Text]
  37. Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998;62:1198–1211.[Medline] [Order article via Infotrieve]
  38. Fulker DW, Cherny SS, Cardon LR. Multipoint interval mapping of quantitative trait loci, using sib pairs. Am J Hum Genet. 1995;56:1224–1233.[Medline] [Order article via Infotrieve]
  39. Blangero B, Williams JT, Almasy L. Quantitative trait locus mapping using human pedigrees. Hum Biol. 2000;72:35–62.[Medline] [Order article via Infotrieve]
  40. Morton NE. Significance levels in complex inheritance. Am J Hum Genet. 1998;62:690–697.[Medline] [Order article via Infotrieve]
  41. Williams JT, Duggirala R, Blangero J. Statistical properties of a variance components method for quantitative trait linkage analysis in nuclear families and extended pedigrees. Genet Epidemiol. 1997;14:1065–1070.[Medline] [Order article via Infotrieve]
  42. Davignon J, Cohn JS. Mabile L, Bernier L. Apolipoprotein E and atherosclerosis: insight from animal and human studies. Clin Chim Acta. 1999;286:115–143.[Medline] [Order article via Infotrieve]
  43. Lambert J-C, Brousseau T, Defosse V, Evans A, Arveiler D, Ruidavets J-B, Haas B, Cambou J-P, Luc G, Ducimetiere P, et al. Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations: the ECTIM Study. Hum Mol Genet. 2000;9:57–61.[Abstract/Free Full Text]
  44. Larson IA, Ordovas JM, DeLuca C, Barnard JR, Feussner G, Schaefer EJ. Association of apolipoprotein (Apo) E genotype with plasma apo E levels. Atherosclerosis. 2000;148:327–335.[Medline] [Order article via Infotrieve]
  45. Sing CF, Davignon J. Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet. 1985;37:268–285.[Medline] [Order article via Infotrieve]
  46. Smit M, deKnijff P, Rosseneu M, Bury J, Klasen E, Frants RR, Havekes L. Apolipoprotein E polymorphism in the Netherlands and its effect on plasma lipid and apolipoprotein levels. Hum Genet. 1988;80:287–292.[Medline] [Order article via Infotrieve]
  47. Fullerton SM, Clark AG, Weiss KM, Nickerson DA, Taylor SL, Stengård JH, Viekko S, Vartiainen E, Perola M, Boerwinkle E, et al. Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am J Hum Genet. 2000;67:881–900.[Medline] [Order article via Infotrieve]
  48. Sham PC, Cherny SS, Purcell S, Hewitt JK. Power of linkage versus association analysis of quantitative traits, by use of variance-components models, for sibship data. Am J Hum Genet. 2000;66:1616–1630.[Medline] [Order article via Infotrieve]
  49. Xhignesse M, Lussier-Cacan S, Sing CF, Kessling AM, Davignon J. Influences of common variants of apolipoprotein E on measures of lipid metabolism in a sample selected for health. Arterioscler Thromb. 1991;11:1100–1110.[Abstract/Free Full Text]
  50. Gueguen R, Visvikis S, Steinmetz J, Siest G, Boerwinkle E. An analysis of genotype effect and their interactions by using the apolipoprotein E polymorphism and longitudinal data. Am J Hum Genet. 1989;45:793–802.[Medline] [Order article via Infotrieve]
  51. Fumeron F, Rigaud D, Bertiere MC, Bardon S, Dely C, Apfelbaum M. Association of apolipoprotein epsilon 4 allele with hypertriglyceridemia in obesity. Clin Genet.1988;34:258–264.
  52. Reilly SL, Ferrell RE, Kottke BA, Sing CF. The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, Minnesota, II: regression relationships with concomitants. Am J Hum Genet. 1992;51:1311–1324.[Medline] [Order article via Infotrieve]
  53. Reilly SL, Ferrell RE, Sing CF. The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, MN, III: correlations and covariances. Am J Hum Genet. 1994;55:1001–1018.[Medline] [Order article via Infotrieve]
  54. Nakamuta M, Taniguchi S, Ishida BY, Kobayashi K, Chan L. Phenotype interaction of apobec-1 and CETP, LDLR, and apoE gene expression in mice: role of apoB mRNA editing in lipoprotein phenotype expression. Arterioscler Thromb Vasc Biol. 1998;18:747–755.[Abstract/Free Full Text]
  55. Rogaeva E, Premkumar S, Song Y, Sorbi S, Brindle N, Paterson A, Duara R, Levesque G, Yu G, Nishimura M, et al. Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. JAMA. 1998;280:614–618.[Abstract/Free Full Text]
  56. Scott WK, Grubber JM, Conneally PM, Small GW, Hulette CM, Rosenberg CK, Saunders AM, Roses AD, Haines JL, Pericak-Vance MA. Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet. 2000;66:922–932.[Medline] [Order article via Infotrieve]
  57. Wu WS, Holmans P, Wavrant-DeVrieze F, Shears S, Kehoe P, Crook R, Booth J, Williams N, Perez-Tur J, Roehl K, et al. Genetic studies on chromosome 12 in late-onset Alzheimer disease. JAMA. 1998;280:619–622.[Abstract/Free Full Text]
  58. Castro G, Nihoul LP, Dengremont C, deGeitere C, Delfly B, Tailleux A, Fievet C, Duverger N, Denefle P, Fruchart J-C, et al. Cholesterol efflux, lecithin-cholesterol acyltransferase activity and pre-ß particle formation by serum from human apolipoprotein A-I and apolipoprotein A-I/apolipoprotein A-II transgenic mice consistent with the latter being less effective for reverse cholesterol transport. Biochemistry. 1997;36:2243–2249.[Medline] [Order article via Infotrieve]
  59. Cool DR, Normant E, Shen F, Chen H-C, Pannell L, Zhang Y, Loh YP. Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe (fat) mice. Cell. 1997;88:73–83.[Medline] [Order article via Infotrieve]
  60. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19:155–157.[Medline] [Order article via Infotrieve]
  61. Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter EH. Hyperproinsulinemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat Genet. 1995;10:135–142.[Medline] [Order article via Infotrieve]
  62. Fowkes FGR, Connor JM, Smith FB, Wood J, Donnan PT, Lowe GDO. Fibrinogen genotype and risk of peripheral atherosclerosis. Lancet. 1992;339:693–696.[Medline] [Order article via Infotrieve]
  63. Murdock DK, Murdock AK, Murdock RW, Olson KJ, Frane AM, Kersten ME, Joyce DM, Gantner SF. Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J. 1999;138:151–155.[Medline] [Order article via Infotrieve]
  64. Raspe E, Madsen L, Lefebvre AM, Leitersdorf I, Gelman L, Peinado-Onsurbe J, Dallongeville J, Fruchart JC, Berge R, Staels B. Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPARalpha activation. J Lipid Res. 1999;40:2099–2110.[Abstract/Free Full Text]
  65. Boerwinkle E, Sing CF. Bias of the contribution of single-locus effects to the variance of a quantitative trait. Am J Hum Genet. 1986;39:137–144.[Medline] [Order article via Infotrieve]
  66. Prenger VL, Beaty TH, Kwiterovich PO. Genetic determination of HDL-C and apo-A1 plasma levels in a family study of cardiac catheterization patients. Am J Hum Genet. 1992;51:1047–1057.[Medline] [Order article via Infotrieve]
  67. Juo SH, Beaty TH, Xu J, Prenger VL, Coresh J, Kwiterovich PO. Segregation analysis of two-locus models regulating apolipoprotein-A1 levels. Genet Epidemiol. 1998;15:73–86.[Medline] [Order article via Infotrieve]
  68. Amos CI, Elston RC, Srinivasan SR, Wilson AF, Cresanta JL, Ward LJ, Berenson GS. Linkage and segregation analysis of apolipoproteins-A-1 and B, and lipoprotein cholesterol levels in a large pedigree with excess coronary heart disease: the Bogalusa Heart Study. Genet Epidemiol. 1987;4:115–128.[Medline] [Order article via Infotrieve]
  69. Hasstedt SJ, Alberts JJ, Cheung MC, Jorde LB, Wilson DE, Edwards CQ, Cannon WN, Ash KO, Williams RR. The inheritance of high density lipoprotein cholesterol and apolipoprotein A-I and A-II. Atherosclerosis. 1984;51:21–29.[Medline] [Order article via Infotrieve]
  70. Krieger M. Charting the fate of the "good cholesterol": identification and characterization of the high density lipoprotein receptor SR-BI. Annu Rev Biochem. 1999;68:523–558.[Medline] [Order article via Infotrieve]
  71. Kozarsky KF, Donahee MH, Rigotti A, Iqbal SN, Edelman ER, Krieger M. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature. 1997;387:414–417.[Medline] [Order article via Infotrieve]
  72. Sharp D, Blinderman L, Combs KA, Kienzle B, Ricci B, Wager-Smith K, Gil CM, Turck CW, Bouma M-E, Rader DJ, et al. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature. 1993;365:65–69. [Medline] [Order article via Infotrieve]



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