Abstract
20 min readA genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels. Linkage analyses were conducted for four quantitative lipoprotein/lipid traits, i.e., total cholesterol, triglyceride, HDL-cholesterol (HDL-C), and LDL-C concentrations, in 930 subjects enrolled in the Québec Family Study. A maximum of 534 pairs of siblings from 292 nuclear families were available. Linkage was tested using both allele-sharing and variance-component linkage methods. The strongest evidence of linkage was found on chromosome 12q14.1 at marker D12S334 for HDL-C, with a logarithm of the odds (LOD) score of 4.06. Chromosomal regions harboring quantitative trait loci (QTLs) for LDL-C included 1q43 (LOD = 2.50), 11q23.2 (LOD = 3.22), 15q26.1 (LOD = 3.11), and 19q13.32 (LOD = 3.59). In the case of triglycerides, three markers located on 2p14, 11p13, and 11q24.1 provided suggestive evidence of linkage (LOD > 1.75). Tests for total cholesterol levels yielded significant evidence of linkage at 15q26.1 and 18q22.3 with the allele-sharing linkage method, but the results were nonsignificant with the variance-component method.In conclusion, this genome scan provides evidence for several QTLs influencing lipid and lipoprotein levels. Promising candidate genes were located in the vicinity of the genomic regions showing evidence of linkage. A genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels. Linkage analyses were conducted for four quantitative lipoprotein/lipid traits, i.e., total cholesterol, triglyceride, HDL-cholesterol (HDL-C), and LDL-C concentrations, in 930 subjects enrolled in the Québec Family Study. A maximum of 534 pairs of siblings from 292 nuclear families were available. Linkage was tested using both allele-sharing and variance-component linkage methods. The strongest evidence of linkage was found on chromosome 12q14.1 at marker D12S334 for HDL-C, with a logarithm of the odds (LOD) score of 4.06. Chromosomal regions harboring quantitative trait loci (QTLs) for LDL-C included 1q43 (LOD = 2.50), 11q23.2 (LOD = 3.22), 15q26.1 (LOD = 3.11), and 19q13.32 (LOD = 3.59). In the case of triglycerides, three markers located on 2p14, 11p13, and 11q24.1 provided suggestive evidence of linkage (LOD > 1.75). Tests for total cholesterol levels yielded significant evidence of linkage at 15q26.1 and 18q22.3 with the allele-sharing linkage method, but the results were nonsignificant with the variance-component method. In conclusion, this genome scan provides evidence for several QTLs influencing lipid and lipoprotein levels. Promising candidate genes were located in the vicinity of the genomic regions showing evidence of linkage. Studies investigating the genetics of blood lipids and lipoproteins have clearly established that genetic factors contribute to these phenotypes (1Mitchell B.D. Kammerer C.M. Blangero J. Mahaney M.C. Rainwater D.L. Dyke B. Hixson J.E. Henkel R.D. Sharp R.M. Comuzzie A.G. VandeBerg J.L. Stern M.P. MacCluer J.W. Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study.Circulation. 1996; 94: 2159-2170Crossref PubMed Scopus (322) Google Scholar, 2Rice T. Vogler G.P. Perry T.S. Laskarzewski P.M. Rao D.C. Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Iowa Lipid Research Clinics family study.Hum. Hered. 1991; 41: 107-121Crossref PubMed Scopus (41) Google Scholar). Until recently, the molecular bases of blood lipids have been mainly investigated using a candidate gene approach. Although genes accountable for several monogenic dyslipidemias have been identified (3Hegele R.A. Monogenic dyslipidemias: window on determinants of plasma lipoprotein metabolism.Am. J. Hum. Genet. 2001; 69: 1161-1177Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar), those underlying the variation in the population at large remain to be found. These results have motivated several investigators to use the genome-scan approach to identify chromosomal regions harboring genes controlling lipoprotein/lipid levels. Such an approach has the ability to find quantitative trait loci (QTLs) without being dependent on an understanding of the physiology governing the traits. Genome scans can generate useful leads and hypotheses whose usefulness is greatly enhanced when the findings are replicated in independent samples (4Province M.A. Sequential methods of analysis for genome scans.Adv. Genet. 2001; 42: 499-514Crossref PubMed Google Scholar). To date, the results of full genome scans for lipoprotein/lipid traits have produced a number of significant findings. For total cholesterol, the results from the Pima Indian community have provided evidence of linkage on chromosome 19p (5Imperatore G. Knowler W.C. Pettitt D.J. Kobes S. Fuller J.H. Bennett P.H. Hanson R.L. A locus influencing total serum cholesterol on chromosome 19p: results from an autosomal genomic scan of serum lipid concentrations in Pima Indians.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2651-2656Crossref PubMed Scopus (64) Google Scholar). The 1q region was also suggested to contain a locus influencing cholesterol level in obese families (6Reed D.R. Nanthakumar E. North M. Bell C. Price R.A. A genome-wide scan suggests a locus on chromosome 1q21-q23 contributes to normal variation in plasma cholesterol concentration.J. Mol. Med. 2001; 79: 262-269Crossref PubMed Scopus (30) Google Scholar). A cholesterol-lowering gene was mapped as well on 13q from an extended Israeli family and replicated by the same investigators with a healthy white twin cohort (7Knoblauch H. Muller-Myhsok B. Busjahn A. Ben Avi L. Bahring S. Baron H. Heath S.C. Uhlmann R. Faulhaber H.D. Shpitzen S. Aydin A. Reshef A. Rosenthal M. Eliav O. Muhl A. Lowe A. Schurr D. Harats D. Jeschke E. Friedlander Y. Schuster H. Luft F.C. Leitersdorf E. A cholesterol-lowering gene maps to chromosome 13q.Am. J. Hum. Genet. 2000; 66: 157-166Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Loci controlling LDL-cholesterol (LDL-C) were reported on 19q in the Hutterites community (8Ober C. Abney M. McPeek M.S. The genetic dissection of complex traits in a founder population.Am. J. Hum. Genet. 2001; 69: 1068-1079Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar) and on 11p in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (9Coon H. Eckfeldt J.H. Leppert M.F. Myers R.H. Arnett D.K. Heiss G. Province M.A. Hunt S.C. A genome-wide screen reveals evidence for a locus on chromosome 11 influencing variation in LDL cholesterol in the NHLBI Family Heart Study.Hum. Genet. 2002; 111: 263-269Crossref PubMed Scopus (25) Google Scholar). For HDL-C, several major loci were mapped, including 5q in the NHLBI Family Heart Study (10Peacock J.M. Arnett D.K. Atwood L.D. Myers R.H. Coon H. Rich S.S. Province M.A. Heiss G. Genome scan for quantitative trait loci linked to high-density lipoprotein cholesterol: the NHLBI Family Heart Study.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1823-1828Crossref PubMed Scopus (56) Google Scholar), 8q in Finnish families (11Soro A. Pajukanta P. Lilja H.E. Ylitalo K. Hiekkalinna T. Perola M. Cantor R.M. Viikari J.S. Taskinen M.R. Peltonen L. Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1–24.2, and 20q13.11 in Finnish families.Am. J. Hum. Genet. 2002; 70: 1333-1340Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar), 9p in Mexican Americans (12Arya R. Duggirala R. Almasy L. Rainwater D.L. Mahaney M.C. Cole S. Dyer T.D. Williams K. Leach R.J. Hixson J.E. MacCluer J.W. O'Connell P. Stern M.P. Blangero J. Linkage of high-density lipoprotein-cholesterol concentrations to a locus on chromosome 9p in Mexican Americans.Nat. Genet. 2002; 30: 102-105Crossref PubMed Scopus (86) Google Scholar), and 6q in the Framingham Study (13Cupples L.A. Ordovas J.M. Rao V.S. Harmon M.D. Wilson P.W.F. Schaefer E.J. Myers R.H. Evidence of a gene at 6q for high density lipoprotein cholesterol: the Framingham Study (Abstract).Am. J. Hum. Genet. 1998; 63: 16Google Scholar). However, the most promising location for an HDL-C locus is on 16q22-q23, from linkages in both Mexican Americans (14Mahaney M.C. Almasy L. Rainwater D.L. VandeBerg J.L. Cole S.A. Hixson J.E. Blangero J. MacCluer J.W. A quantitative trait locus on chromosome 16q influences variation in plasma HDL-C levels in Mexican Americans.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 339-345Crossref PubMed Scopus (41) Google Scholar) and combined Dutch and Finnish families (15Pajukanta P. Allayee H. Krass K.L. Kuraishy A. Soro A. Lilja H.E. Mar R. Taskinen M.R. Nuotio I. Laakso M. Rotter J.I. De Bruin T.W. Cantor R.M. Lusis A.J. Peltonen L. Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.Am. J. Hum. Genet. 2003; 72: 903-917Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Data from the Finnish families have also suggested a low HDL-C locus within this region (11Soro A. Pajukanta P. Lilja H.E. Ylitalo K. Hiekkalinna T. Perola M. Cantor R.M. Viikari J.S. Taskinen M.R. Peltonen L. Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1–24.2, and 20q13.11 in Finnish families.Am. J. Hum. Genet. 2002; 70: 1333-1340Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Finally, a putative locus for familial low HDL-C has also been identified near the apolipoprotein A-I (apoA-I)/apoC-III/apoA-IV gene cluster on 11q23 (16Kort E.N. Ballinger D.G. Ding W. Hunt S.C. Bowen B.R. Abkevich V. Bulka K. Campbell B. Capener C. Gutin A. Harshman K. McDermott M. Thorne T. Wang H. Wardell B. Wong J. Hopkins P.N. Skolnick M. Samuels M. Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23.Am. J. Hum. Genet. 2000; 66: 1845-1856Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). The search for loci influencing triglyceride levels has been similarly fruitful. Genome-wide evidence of linkage has been reported on 2q in Hutterites (17Newman D.L. Abney M. Dytch H. Parry R. McPeek M.S. Ober C. Major loci influencing serum triglyceride levels on 2q14 and 9p21 localized by homozygosity-by-descent mapping in a large Hutterite pedigree.Hum. Mol. Genet. 2003; 12: 137-144Crossref PubMed Scopus (46) Google Scholar), 10p in Finnish families (18Pajukanta P. Terwilliger J.D. Perola M. Hiekkalinna T. Nuotio I. Ellonen P. Parkkonen M. Hartiala J. Ylitalo K. Pihlajamaki J. Porkka K. Laakso M. Viikari J. Ehnholm C. Taskinen M.R. Peltonen L. 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: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar), 15q in a second set of Mexican Americans ascertained for type 2 diabetes (19Duggirala R. Blangero J. Almasy L. Dyer T.D. Williams K.L. Leach R.J. O'Connell P. Stern M.P. A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans.Am. J. Hum. Genet. 2000; 66: 1237-1245Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar), and 19q in white Utah families (20Elbein S.C. Hasstedt S.J. Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q.Diabetes. 2002; 51: 528-535Crossref PubMed Scopus (75) Google Scholar). Based on these observations, it is clear that lipid and lipoprotein traits are influenced by several loci. However, additional genome scans are required to strengthen previous observations and identify the most promising regions underlying the genetic components of these phenotypes. Thus, the purpose of this study was to identify the genomic regions influencing total cholesterol, LDL-C, HDL-C, and triglyceride levels in a cohort of French-Canadian families. The Québec Family Study (QFS) is an ongoing investigation of French-Canadian families studying the genetics of obesity and its comorbidities (21Bouchard C. Genetic epidemiology, association, and sib-pair linkage: results from the Québec Family Study.in: Bray G.A. Ryan D.H. Molecular and Genetic Aspects of Obesity. Louisiana State University Press, Baton Rouge, LA1996: 470-481Google Scholar). There are four phases in the QFS, and the forth phase is currently in progress. The first phase includes the data collection that took place from 1979 to 1981 on families randomly ascertained. In phase 2, a sample of families from phase 1 were remeasured and additional families, ascertained through obese proband, were recruited and incorporated into the cohort. In the third phase, members of the phase 2 cohort were remeasured and the children of the adult offspring were recruited when they reached 10 years of age. DNA analyses are available for subjects in phase 2 and later. In the current study, the subjects were participants from phase 2 and phase 3 to maximize the number of subjects available for transversal analysis. Serum lipid and lipoprotein concentrations were available for 930 members of 292 nuclear families. This sample represents a half-and-half mixture of random sampling and ascertainment through obese probands. The characteristics of the subjects in the four sex-by-generation groups (fathers, mothers, sons, and daughters) are reported in Table 1. All subjects were free of familial lipid disorders requiring lipid-lowering drugs. The Institutional Review Board of Laval University approved all procedures, and all subjects gave written informed consent.TABLE 1Characteristics of genomic-scan participants by gender and generation groupsFathers (n = 194)Mothers (n = 261)Sons (n = 213)Daughters (n = 262)Age (years)55.5 ± 10.154.8 ± 12.526.7 ± 9.727.9 ± 10.6BMI (kg/m2)28.4 ± 5.828.7 ± 8.026.4 ± 7.226.8 ± 8.8Cholesterol (mmol/l)5.42 ± 0.855.44 ± 1.084.47 ± 0.914.48 ± 0.80LDL-C (mmol/l)3.49 ± 0.783.35 ± 0.952.77 ± 0.782.64 ± 0.70HDL-C (mmol/l)1.07 ± 0.271.37 ± 0.351.11 ± 0.251.28 ± 0.30Triglyceride (mmol/l)1.96 ± 1.121.62 ± 0.811.31 ± 0.691.23 ± 0.56Values are means ± SD. BMI, body mass index; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol. Open table in a new tab Values are means ± SD. BMI, body mass index; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol. Blood samples were collected in the morning from an antecubital vein after a 12 h overnight fast. The plasma was separated immediately after blood collection by centrifugation at 3,000 rpm for 10 min for the measurement of plasma lipoprotein/lipid levels. Cholesterol (22Allain C.C. Poon L.S. Chan C.S. Richmond W. Fu P.C. Enzymatic determination of total serum cholesterol.Clin. Chem. 1974; 20: 470-475Crossref PubMed Scopus (7371) Google Scholar) and triglyceride (23Fossati P. Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide.Clin. Chem. 1982; 28: 2077-2080Crossref PubMed Scopus (2104) Google Scholar) concentrations were determined enzymatically using a Technicon RA-500 automated analyzer (Bayer, Tarrytown, NY). HDL fraction was obtained after precipitation of LDL in the infranatant (>1.006 g/ml) with heparin and MnCl2 (24Burstein M. Samaille J. Sur un dosage rapide du cholestérol lié aux B-lipoprotéines du sérum.Clin. Chim. Acta. 1960; 5: 609Crossref PubMed Scopus (548) Google Scholar). The cholesterol content of the infranatant fraction was measured before and after the precipitation step for the measurement of HDL-C and for the calculation of LDL-C. Body mass index (BMI) was determined by weight (kg)/height (m2). A total of 443 markers spanning the 22 autosomal chromosomes with an average intermarker distance of 7.2 centimorgans (cM) were genotyped as described previously (25Chagnon Y.C. Borecki I.B. Perusse L. Roy S. Lacaille M. Chagnon M. Ho-Kim M.A. Rice T. Province M.A. Rao D.C. Bouchard C. Genome-wide search for genes related to the fat-free body mass in the Quebec Family Study.Metabolism. 2000; 49: 203-207Abstract Full Text PDF PubMed Scopus (104) Google Scholar). These markers included 337 microsatellite markers (dinucleotide, trinucleotide, and tetranucleotide repeats) and 106 polymorphisms in 65 candidate genes. The results were stored in a local dBase IV database, GENEMARK, which inspects results for Mendelian inheritance incompatibilities within nuclear families and extended pedigrees. The OMIM gene map (http://www.ncbi.nlm.nih.gov/htbin-post/Omim/getmap) and the bioinformatic site from the University of California, Santa Cruz (http://genome.ucsc.edu/) were used to identify candidate genes. The triglyceride and cholesterol variables were log10 transformed to normalize their distribution before adjustment for covariates. Lipid and lipoprotein traits were adjusted for the effects of age, including squared and cubic terms to allow for nonlinearity, as well as for gender and BMI. The adjustments were performed using a stepwise multiple regression procedure retaining only significant terms (P < 0.05). Separate regression models were used for each of six age-by-sex (<30, 30–50, and ≥50 years in male and female) groups. Regression parameters were estimated after exclusion of outliers (±3 SD), and residuals were computed for all subjects. Residual scores were then standardized to a mean of 0 and an SD of 1 before genetic analyses. Subjects whose values were greater than 4 SD from the mean and were separated by more than 1 SD from the nearest internal score were excluded from the analysis because they were considered to be sparse outliers (four subjects for total cholesterol, one for triglyceride, two for LDL-C, and three for HDL-C). Adjustments of the phenotypes were performed using SAS (version 8.02). We conducted quantitative trait linkage analyses using two different methods. We used the new Haseman-Elston regression-based method (26Elston R.C. Buxbaum S. Jacobs K.B. Olson J.M. Haseman and Elston revisited.Genet. Epidemiol. 2000; 19: 1-17Crossref PubMed Scopus (235) Google Scholar), which models the trait covariance between sibpairs, instead of the squared sibpair trait difference used in the original method. It regresses the mean-corrected sibpair product on the number of alleles shared identical by descent (IBD). Singlepoint and multipoint estimates of alleles shared IBD were generated using GENIBD software, and linkage was tested using SIBPAL2 software from the S.A.G.E. 4.0 statistical package (27S.A.G.E. Statistical Analysis for Genetic Epidemiology. Release 4.0. Department of Epidemiology and Biostatistics, Rammelkamp Center for Education and Research, Metro Health Campus, Case Western Reserve University, Cleveland, OH1999Google Scholar). The maximum number of sibpairs was 534. In the alternative method, the phenotypic covariance among members of a family is assumed to result from the additive effects of linkage attributable to a QTL, a residual familial component attributable to polygenes, and an individual-specific random environmental component. Hypothesis testing was performed by the likelihood ratio test, which tests the null hypothesis that the additive genetic variance attributable to the QTL (σq) equals zero (σq = 0) by comparing the likelihood of this restricted model with that of a model in which σq is estimated (σq ≠ 0). The difference in minus twice the log likelihoods is approximately distributed as a 50:50 mixture of a χ2 and a point-mass distribution at zero. The logarithm of the odds (LOD) score was computed as χ2/(2 loge 10). These analyses were performed using the quantitative transmission disequilibrium test computer program (28Abecasis G.R. Cardon L.R. Cookson W.O. A general test of association for quantitative traits in nuclear families.Am. J. Hum. Genet. 2000; 66: 279-292Abstract Full Text Full Text PDF PubMed Scopus (965) Google Scholar). We used a LOD score of ≥3.00 (P ≤ 0.0001) to indicate adequate evidence of linkage and a LOD threshold of ≥1.75 (P ≤ 0.0023) as suggestive (29Rao D.C. Province M.A. The future of path analysis, segregation analysis, and combined models for genetic dissection of complex traits.Hum. Hered. 2000; 50: 34-42Crossref PubMed Scopus (58) Google Scholar). Before the genome-scan analysis, total cholesterol, triglyceride, LDL-C, and HDL-C levels were adjusted in a stepwise manner for the effects of age, age2, age3, gender, and BMI. These covariates accounted for 0–15.3%, 5.7–30.2%, 0–10.6%, and 6.6–32.2% of the total phenotypic variation in total cholesterol, triglyceride, LDL-C, and HDL-C, respectively, depending on the age-by-sex groups (see Methods). An overview of the variance component-based linkage results for the LDL-C, HDL-C, and triglyceride phenotypes is given in Fig. 1. Numerous peaks with LOD scores greater than 1.75 are observed for LDL-C, including on chromosomes 1q43, 3q23, 11q13-q24, 13q32, 15q26, 18q21, and 19q13. The highest peak among them is located on chromosome 19q13, with a LOD score of 3.59 for a marker within the gene coding apoE. The peak on chromosome 11q was quite broad and encompassed a 1-LOD support interval (1 LOD unit reduction from the peak) of ∼40 cM. In contrast, only one chromosomal region reaches the significance level of linkage for HDL-C. However, this peak located on chromosome 12q14 provided the highest LOD score observed in the study (LOD = 4.06). In the case of triglycerides, four genomic regions exceeded the 1.75 LOD score threshold: 2p14, 5q14, 11p13, and 11q24. Although interesting, these peaks did not reach the magnitude of those observed for LDL-C and HDL-C. Remarkably, the two peaks for triglycerides on chromosome 11 did not overlap with the large one observed for LDL-C. Linkage was also tested using singlepoint and multipoint allele-sharing methods. All chromosomal regions with a variance-component LOD score of ≥1.75 or an allele-sharing P value of ≤0.0023 are reported in Table 2 for the four lipid traits. Six, 17, 9, and 13 markers showed suggestive evidence of linkage with at least one of the methods used for total cholesterol, LDL-C, HDL-C, and triglycerides, respectively. Among all of these markers, only seven of them provided suggestive evidence of linkage (LOD ≥ 1.75 or P ≤ 0.0023) with both the allele-sharing and the variance-components linkage methods. These markers are highlighted in Table 2 and correspond to chromosome regions 1q43, 15q26.1, and 19q13.32 for LDL-C, 12q14.1 for HDL-C, and 2p14, 11p13, and 11q24.1 for triglycerides. All singlepoint and multipoint results around these chromosomal regions are provided in the supplemental table. Although some markers provided fairly good evidence of linkage with total cholesterol, results were inconsistent across linkage methods (Table 2). Positional candidate genes in the seven regions identified as most promising in addition to the large 11q region for LDL-C are summarized in Table 3.TABLE 2Summary of P values of <0.0023 from the allele-sharing method (singlepoint and multipoint) or LOD scores of >1.75 from the variance-component methodPhenotypeChromosomeDistanceMarkeraMarkers showing suggestive evidence of linkage (P ≤ 0.0023 or LOD score ≥ 1.75) with the three linkage methods used are shown in boldface.PLOD ScoreSinglepointMultipointcMCholesterol1239.8D1S5470.0002080.0004371.212241.2D2S29680.0429400.0304382.041590.8D15S6520.0000770.0362950.731620.9D16S4030.0019930.0188060.961871.9ATA82B020.0000590.0021771.15204.5D20S4820.0018040.0398830.46LDL-C1230.4D1S34620.0263310.0055011.791239.8D1S5470.0000080.0000782.503145.1D3S17640.0285760.0125462.791179.8D11S9110.3272520.0046522.571182.3D11S20020.0129920.0014072.8111107.8D11S20000.0404860.0010692.5511115.7DRD20.0090480.0012133.2211118.5UCP30.3256120.0223302.061397.0D13S7930.0077660.0152801.851590.8D15S6520.0003150.0002883.111862.0D18S380.0515640.0057642.041862.5MC4R0.1504900.0050142.241871.9ATA82B020.0015170.0173651.011957.5D19S1780.0126000.0006173.241958.6APOE0.0000050.0002413.591962.8GYS10.1948590.0015682.93204.5D20S4820.0000130.0006901.64HDL-C2171.7D2S17760.0010520.0056080.351253.4D12S3980.0421140.0043481.931261.0D12S3340.0022040.0007464.061268.5D12S3750.0021960.0014070.88167.4D16S2870.0002510.3133830.211812.3D18S5420.0619550.0007171.191813.3MC5R0.1214240.0020610.942045.9D20S1970.0154070.0015051.012047.0D20S1760.6279250.0004660.81Triglyceride1111.2D1S28600.0005860.0011531.391117.7ATP1A10.2479560.0020421.051229.3AGT0.0008930.0086740.82267.8D2S4410.0000090.0013462.324149.6UCP0.0000430.1899940.33573.5D5S15010.0362990.0041202.23573.9CART0.0000680.0150521.677151.6NOS0.0008480.0723590.21820.0LPL0.0012730.0326910.55888.3D8S11190.0011590.1263620.311131.3ATA34E080.0224950.0003301.691134.9D11S13920.0001050.0000092.1111125.6D11S44640.0012040.0018901.93P values of ≤0.0001 and logarithm of the odds (LOD) scores of ≥3.00 are shown in boldface.a Markers showing suggestive evidence of linkage (P ≤ 0.0023 or LOD score ≥ 1.75) with the three linkage methods used are shown in boldface. Open table in a new tab TABLE 3Positional candidate genes within chromosomal regions showing suggestive evidence of linkage with the three linkage methodsPhenotypesChromosome RegionMarkerLOD ScoreCandidate Genes (Distance from the Marker in MbaDistances separating the marker and the candidate genes are taken from the bioinformatic site of the University of California, Santa Cruz (http://genome.ucsc.edu/). Negative or positive values indicate that the gene is located downstream or upstream from the marker, respectively.)LDL-C 1q43D1S5472.50ABCB10 (−11.7), GGPS1 (−6.2) 11q14.1D11S20022.81LRP5 (−11.6), CPT1A (−11.2), UCP2 (−6.3), UCP3 (−6.2) 11q23.2DRD23.22ACAT1/SOAT1 (−5.5), APOA1 (3.4), APOC3 (3.4), APOA4 (3.4), APOA5 (3.3) 15q26.1D15S6523.11CYP11A (−18.3) 19q13.32APOE3.59LRP3 (−11.7), LIPE (−2.5), APOC4 (0), APOE (0), APOC1(0), APOC2 (0)HDL-C 12q14.1D12S3344.06SOAT2 (−7.3), APOF (−4.4), LRP1 (−3.5), CYP27B1 (−3.2)Triglyceride 2p14D2S4412.32FABP1 (19.6) 11p13D11S13922.11ABCC8 (−17.6), LRP4 (12.6) 11q24.1D11S44641.93ACAT1 (−15.4), APOA1 (−6.6), APOC3 (−6.6), APOA4 (−6.6), APOA5 (−6.6), ACAD8 (11)ABC, ATP binding cassette; ACAD8, acyl-CoA dehydrogenase family, member 8; APO, apolipoprotein; CPT1A, carnitine palmitoyltransferase 1A; CYP, cytochrome P450; FABP1, fatty acid binding protein 1; GGPS1, geranylgeranyl diphosphate synthase 1; LIPE, hormone-sensitive lipase; LRP, low density lipoprotein receptor-related protein; SOAT, sterol O-acyltransferase; UCP, uncoupling protein.a Distances separating the marker and the candidate genes are taken from the bioinformatic site of the University of California, Santa Cruz (http://genome.ucsc.edu/). Negative or positive values indicate that the gene is located downstream or upstream from the marker, respectively. Open table in a new tab P values of ≤0.0001 and logarithm of the odds (LOD) scores of ≥3.00 are shown in boldface. ABC, ATP binding cassette; ACAD8, acyl-CoA dehydrogenase family, member 8; APO, apolipoprotein; CPT1A, carnitine palmitoyltransferase 1A; CYP, cytochrome P450; FABP1, fatty acid binding protein 1; GGPS1, geranylgeranyl diphosphate synthase 1; LIPE, hormone-sensitive lipase; LRP, low density lipoprotein receptor-related protein; SOAT, sterol O-acyltransferase; UCP, uncoupling protein. The present study confirms the existence of multiple loci influencing blood lipids and lipoproteins. Based on this genome-wide scan, evidence of linkage was found on chromosome regions 1q43, 11q13-q24, 15q26.1, and 19q13.32 for LDL-C, 12q14.1 for HDL-C, and 2p14, 11p13, and 11q24.1 for triglycerides. Some of these regions have been previously linked to lipid-related phenotypes, whereas others represent new findings. In genome-wide linkage studies, independent replication of positive findings is important to distinguish between true and false positives (4Province M.A. Sequential methods of analysis for genome scans.Adv. Genet. 2001; 42: 499-514Crossref PubMed Google Scholar). For complex traits, determining whether a given study has replicated an initial study's findings is difficult. It has been demonstrated that the location estimate may be many centimorgans away from the true locus (30Roberts S.B. MacLean C.J. Neale M.C. Eaves L.J. Kendler K.S. Replication of linkage studies of complex traits: an examination of variation in location estimates.Am. J. Hum. Genet. 1999; 65: 876-884Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). Given this variation in position, it is difficult to distinguish between random variation around a single locus and the presence of multiple genetic signals. Despite these limitations, we present in Table 4 the positive findings reported by previous genome scans on lipid-related phenotypes that are located around (and potentially replicated) the chromosomal regions identified in the current study.TABLE 4Possible replication of the current chromosomal regions identified with those from previous genome scans on lipid-related phenotypesChromosomeLocationaThe physical distance is the location of the marker(s) that defines the peak or is closest to the signal and is obtained from the genome browser of the University of California, Santa Cruz (http://genome.ucsc.edu).StudyPhenotypesLOD ScoreMb1q239.8This reportLDL-C2.52p68.4This reportTriglyceride2.373.1Finnish families (11)HDL-C2.175.5–88Northeastern Indian (41)Triglyceride/HDL ratio1.985.1San Antonio FHS (39)Unesterified HDL2a-C2.31130.2Rochester FHS (36)Cholesterol1.836.2This reportTriglyceride2.146.3National Heart, Lung, and Blood Ins
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