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A genome-wide scan of serum lipid levels in the Old Order Amish

      Abstract

      Elevated serum low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) and decreased high density lipoprotein cholesterol (HDL-C) levels are established risk factors for cardiovascular disease (CVD). To identify quantitative trait loci influencing lipid levels, we conducted genome-wide linkage analyses of total serum cholesterol (TSC), HDL-C, ln-transformed TG (LNTG) and LDL-C levels in 612 individuals from 28 families of the Amish Family Diabetes Study (AFDS). Subjects were genotyped for 373 microsatellite markers covering all 22 autosomes and the X chromosome at an average density of 9.7 centimorgans. All lipid traits exhibited moderate estimated heritability (h2±S.E.): TSC, 0.63±0.11; HDL-C, 0.54±0.08; LNTG, 0.37±0.08; LDL-C, 0.62±0.10. The highest logarithm of the odds (LOD) score observed was 2.47 (P=0.0003), at 3p25 for LDL-C. LOD scores exceeding 2.0 (P<0.001) were also observed at 2p23 (LOD=2.17) and 19p13 (LOD=2.23) for LDL-C, and at 11q23 (LOD=2.03) for LNTG. Three additional regions exhibited LOD scores greater than 1.5, corresponding to a P-value of <0.005. Many of the regions suggestively linked in this genome-wide scan contain genes encoding proteins with established roles in lipid metabolism, including apolipoproteins, peroxisome proliferater-activated receptor-γ and the LDL receptor.

      Abbreviations:

      TSC (total serum cholesterol), HDL-C (high density lipoprotein cholesterol), TG (triglyceride), LNTG (ln-transformed triglyceride), LDL-C (low density lipoprotein cholesterol), LOD (logarithm of the odds)

      Keywords

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      References

      1. National Heart, Lung and Blood Institute (NHLBI). Morbidity and mortality: 2002 chartbook on cardiovascular, lung, and blood diseases. Bethesda, MD: US Department of Health and Human Services, Public Health Service (PHS), National Institutes of Health (NIH); 2002.

      2. Executive summary of the third report of the national cholesterol education program (NCEP). expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285(19):2486–97.

      3. Gotto AM, Pownall HJ. Manual of lipid disorders: reducing the risk for coronary heart disease. 2nd ed. Baltimore, MD: Lippincott Williams and Wilkins; 2002. p. 207–45.

        • Hegele R.A.
        Monogenic dyslipidemias: window on determinants of plasma lipoprotein metabolism.
        Am. J. Hum Genet. 2001; 69: 1161-1177
        • Pajukanta P.
        • Nuotio I.
        • Terwilliger J.D.
        • Porkka K.V.
        • Ylitalo K.
        • Pihlajamaki J.
        • et al.
        Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.
        Nat. Genet. 1998; 18: 369-373
        • Coon H.
        • Myers R.H.
        • Borecki I.B.
        • Arnett D.K.
        • Hunt S.C.
        • Province M.A.
        • et al.
        Replication of linkage of familial combined hyperlipidemia to chromosome 1q with additional heterogeneous effect of apolipoprotein A-I/C-III/A-IV locus. The NHLBI Family Heart Study.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2275-2280
        • Aouizerat B.E.
        • Allayee H.
        • Cantor R.M.
        • Davis R.C.
        • Lanning C.D.
        • Wen P.Z.
        • et al.
        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
        • Imperatore G.
        • Knowler W.C.
        • Pettitt D.J.
        • Kobes S.
        • Fuller J.H.
        • Bennett P.H.
        • et al.
        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: 2651-2656
        • Coon H.
        • Eckfeldt J.H.
        • Leppert M.F.
        • Myers R.H.
        • Arnett D.K.
        • Heiss G.
        • et al.
        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: 263-269
        • Soro A.
        • Pajukanta P.
        • Lilja H.E.
        • Ylitalo K.
        • Hiekkalinna T.
        • Perola M.
        • et al.
        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: 1333-1340
        • Mahaney M.C.
        • Almasy L.
        • Rainwater D.L.
        • VandeBerg J.L.
        • Cole S.A.
        • Hixson J.E.
        • et al.
        A quantitative trait locus on chromosome 16q influences variation in plasma HDL-C levels in Mexican Americans.
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: 339-345
        • Pajukanta P.
        • Allayee H.
        • Krass K.L.
        • Kuraishy A.
        • Soro A.
        • Lilja H.E.
        • et al.
        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: 903-917
        • Almasy L.
        • Hixson J.E.
        • Rainwater D.L.
        • Cole S.
        • Williams J.T.
        • Mahaney M.C.
        • et al.
        Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism.
        Am. J. Hum. Genet. 1999; 64: 1686-1693
        • Arya R.
        • Duggirala R.
        • Almasy L.
        • Rainwater D.L.
        • Mahaney M.C.
        • Cole S.
        • et al.
        Linkage of high-density lipoprotein-cholesterol concentrations to a locus on chromosome 9p in Mexican Americans.
        Nat. Genet. 2002; 30: 102-105
        • Duggirala R.
        • Blangero J.
        • Almasy L.
        • Dyer T.D.
        • Williams K.L.
        • Leach R.J.
        • et al.
        A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans.
        Am. J. Hum Genet. 2000; 66: 1237-1245
        • Shearman A.M.
        • Ordovas J.M.
        • Cupples L.A.
        • Schaefer E.J.
        • Harmon M.D.
        • Shao Y.
        • et al.
        Evidence for a gene influencing the TG/HDL-C ratio on chromosome 7q32.3-qter: a genome-wide scan in the Framingham study.
        Hum Mol. Genet. 2000; 9: 1315-1320
        • Pajukanta P.
        • Terwilliger J.D.
        • Perola M.
        • Hiekkalinna T.
        • Nuotio I.
        • Ellonen P.
        • 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
        • Elbein 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: 528-535
        • Newman 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: 137-144
        • Agarwala R.
        • Biesecker L.G.
        • Hopkins K.A.
        • Francomano C.A.
        • Schaffer A.A.
        Software for constructing and verifying pedigrees within large genealogies and an application to the Old Order Amish of Lancaster County.
        Genome Res. 1998; 8: 211-221
        • Cross H.E.
        Population studies and the Old Order Amish.
        Nature. 1976; 262: 17-20
        • Hsueh W.C.
        • Mitchell B.D.
        • Aburomia R.
        • Pollin T.
        • Sakul H.
        • Gelder E.M.
        • et al.
        Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.
        Diabetes Care. 2000; 23: 595-601
        • Hsueh W.C.
        • St Jean P.L.
        • Mitchell B.D.
        • Pollin T.I.
        • Knowler W.C.
        • Ehm M.G.
        • et al.
        Genomewide and fine- mapping linkage studies of type 2 diabetes and glucose traits in the Old Order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21–q24.
        Diabetes. 2003; 52: 550-557
        • Almasy L.
        • Blangero J.
        Multipoint quantitative-trait linkage analysis in general pedigrees.
        Am. J. Hum Genet. 1998; 62: 1198-1211
        • Fernandez J.R.
        • Etzel C.
        • Beasley T.M.
        • Shete S.
        • Amos C.I.
        • Allison D.B.
        Improving the power of sib pair quantitative trait loci detection by phenotype winsorization.
        Hum Hered. 2002; 53: 59-67
        • Hsueh W.C.
        • Mitchell B.D.
        • Schneider J.L.
        • St Jean P.L.
        • Pollin T.I.
        • Ehm M.G.
        • et al.
        Genomewide scan of obesity in the Old Order Amish.
        J. Clin. Endocrinol. Metab. 2001; 86: 1199-1205
      4. Snitker S, Hsueh WC, Mitchell BD, Pollin TI, Steinle N, Jalali SA, et al. The Old Order Amish lifestyle may be protective against aspects of the metabolic syndrome. Obes Res 2000;8(Suppl 1):40S.

        • Chawla A.
        • Barak Y.
        • Nagy L.
        • Liao D.
        • Tontonoz P.
        • Evans R.M.
        PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation.
        Nat. Med. 2001; 7: 48-52
        • Kersten S.
        • Desvergne B.
        • Wahli W.
        Roles of PPARs in health and disease.
        Nature. 2000; 405: 421-424
        • Hui D.Y.
        • Howles P.N.
        Carboxyl ester lipase: structure–function relationship and physiological role in lipoprotein metabolism and atherosclerosis.
        J. Lipid Res. 2002; 43: 2017-2030
        • Soria L.F.
        • Ludwig E.H.
        • Clarke H.R.
        • Vega G.L.
        • Grundy S.M.
        • McCarthy B.J.
        Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.
        Proc. Natl. Acad. Sci. U.S.A. 1989; 86: 587-591
        • Tybjaerg-Hansen A.
        • Steffensen R.
        • Meinertz H.
        • Schnohr P.
        • Nordestgaard B.G.
        Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease.
        N. Engl. J. Med. 1998; 338: 1577-1584
        • Reue K.
        • Xu P.
        • Wang X.P.
        • Slavin B.G.
        Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene.
        J. Lipid Res. 2000; 41: 1067-1076
        • Berge K.E.
        • Tian H.
        • Graf G.A.
        • Yu L.
        • Grishin N.V.
        • Schultz J.
        • et al.
        Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.
        Science. 2000; 290: 1771-1775
        • Lee M.H.
        • Lu K.
        • Patel S.B.
        Genetic basis of sitosterolemia.
        Curr Opin Lipidol. 2001; 12: 141-149
        • Lu K.
        • Lee M.H.
        • Hazard S.
        • Brooks-Wilson A.
        • Hidaka H.
        • Kojima H.
        • et al.
        Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.
        Am. J. Hum Genet. 2001; 69: 278-290
        • Patel S.B.
        • Salen G.
        • Hidaka H.
        • Kwiterovich P.O.
        • Stalenhoef A.F.
        • Miettinen T.A.
        • et al.
        Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21.
        J. Clin. Invest. 1998; 102: 1041-1044
        • Miettinen T.A.
        Phytosterolaemia, xanthomatosis and premature atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis.
        Eur. J. Clin. Invest. 1980; 10: 27-35
        • Nguyen L.B.
        • Shefer S.
        • Salen G.
        • Ness G.C.
        • Tint G.S.
        • Zaki F.G.
        • et al.
        A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis.
        J. Clin. Invest. 1990; 86: 923-931
        • Hobbs H.H.
        • Russell D.W.
        • Brown M.S.
        • Goldstein J.L.
        The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.
        Annu. Rev. Genet. 1990; 24: 133-170
        • Reed 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: 262-269
        • Yamakawa-Kobayashi K.
        • Yanagi H.
        • Fukayama H.
        • Hirano C.
        • Shimakura Y.
        • Yamamoto N.
        • et al.
        Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey.
        Hum. Mol. Genet. 1999; 8: 331-336
        • Pennacchio L.A.
        • Olivier M.
        • Hubacek J.A.
        • Krauss R.M.
        • Rubin E.M.
        • Cohen J.C.
        Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride leve ls.
        Hum. Mol. Genet. 2002; 11: 3031-3038
        • Pennacchio L.A.
        • Olivier M.
        • Hubacek J.A.
        • Cohen J.C.
        • Cox D.R.
        • Fruchart J.C.
        • et al.
        An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.
        Science. 2001; 294: 169-173
        • Talmud P.J.
        • Hawe E.
        • Martin S.
        • Olivier M.
        • Miller G.J.
        • Rubin E.M.
        • et al.
        Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides.
        Hum. Mol. Genet. 2002; 11: 3039-3046
        • Groenendijk M.
        • Cantor R.M.
        • de Bruin T.W.
        • Dallinga-Thie G.M.
        The apoAI-CIII-AIV gene cluster.
        Atherosclerosis. 2001; 157: 1-11
        • Jong M.C.
        • Hofker M.H.
        • Havekes L.M.
        Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484
        • Meirhaeghe A.
        • Helbecque N.
        • Cottel D.
        • Arveiler D.
        • Ruidavets J.B.
        • Haas B.
        • et al.
        Impact of sulfonylurea receptor 1 genetic variability on non-insulin-dependent diabetes mellitus prevalence and treatment: a population study.
        Am. J. Med. Genet. 2001; 101: 4-8
        • Benovic J.L.
        • Onorato J.J.
        • Arriza J.L.
        • Stone W.C.
        • Lohse M.
        • Jenkins N.A.
        • et al.
        Cloning, expression, and chromosomal localization of beta-adrenergic receptor kinase 2. A new member of the receptor kinase family.
        J. Biol. Chem. 1991; 266: 14939-14946
        • Calabrese G.
        • Sallese M.
        • Stornaiuolo A.
        • Stuppia L.
        • Palka G.
        • De Blasi A.
        Chromosome mapping of the human arrestin (SAG), beta-arrestin 2 (ARRB2), and beta-adrenergic receptor kinase 2 (ADRBK2) genes.
        Genomics. 1994; 23: 286-288
        • Villa P.
        • Aznar J.
        • Vaya A.
        • Espana F.
        • Ferrando F.
        • Mira Y.
        • et al.
        Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis.
        Thromb. Haemost. 1999; 82: 1011-1014
        • Peacock J.M.
        • Arnett D.K.
        • Atwood L.D.
        • Myers R.H.
        • Coon H.
        • Rich S.S.
        • et al.
        Genome scan for quantitative trait loci linked to high-density lipoprotein cholesterol: The NHLBI Family Heart Study.
        Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1823-1828
        • Broeckel U.
        • Hengstenberg C.
        • Mayer B.
        • Holmer S.
        • Martin L.J.
        • Comuzzie A.G.
        • et al.
        A comprehensive linkage analysis for myocardial infarction and its related risk factors.
        Nat. Genet. 2002; 30: 210-214
        • Aouizerat B.E.
        • Allayee H.
        • Cantor R.M.
        • Davis R.C.
        • Lanning C.D.
        • Wen P.Z.
        • et al.
        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