Genome-wide search for new genes controlling plasma lipid concentrations in mice and humans

Current Opinion in Lipidology

Volumn 16, Issue 2, 2005, Pages 127-137

  Wang, Xiaosong ^a   Paigen, Beverly ^a  

^a JACKSON LABORATORY   (United States)

Author keywords

Cholesterol; Genetics; HDL; LDL; Quantitative trait loci; Triglyceride

Indexed keywords

HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIPID; LOW DENSITY LIPOPROTEIN CHOLESTEROL; TRIACYLGLYCEROL;

ATHEROSCLEROSIS; BIOINFORMATICS; DRUG TARGETING; GENE; GENETICS; GENOME; GENOMICS; HUMAN; LIPID BLOOD LEVEL; MOUSE; NONHUMAN; PRIORITY JOURNAL; QUANTITATIVE TRAIT LOCUS; QUANTITATIVE TRAIT LOCUS MAPPING; REVIEW; SEQUENCE HOMOLOGY;

EID: 17144398839     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.mol.0000162317.09054.9d     Document Type: Review

References (60)

1. Brewer HB Jr, Santamarina-Fojo S, Shamburek RD. Genetic dyslipoproteinemias. In: Fuster V, Topol EJ, Nabel EG, editors. Atherothrombosis and coronary artery disease. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. pp. 55-83.
2. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003; 290:2292-2300. In a double-blind, randomized, placebo-controlled study, a recombinant apoA-I Milano/phospholipids complex administered intravenously for five doses produced significant regression of coronary atherosclerosis.
3. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004; 350:1505-1515. In humans with low HDL-C levels, CETP inhibition with torcetrapib markedly increases HDL-C levels. Additional clinical trials are needed to determine whether CETP inhibition reduces atherosclerosis in humans, and the dose effect in terms of treating atherosclerosis - partial inhibition increases HDL and may be protective but complete absence of CETP activity can create large, nonfunctional HDL that may be proatherogenic.
4. Clark RW, Sutfin TA, Ruggeri RB, et al. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol 2004; 24:490-497. Another study showing that CETP inhibitor torcetrapib is well tolerated, can increase HDL-C levels dose dependently, with simultaneous reduction of LDL-C levels.
5. Wang X, Paigen B. Genetics of variation in HDL cholesterol in humans and mice. Circ Res 2005; 96:27-42. An updated review of 37 mouse and 30 human QTLs for plasma HDL-C concentrations, human-mouse HDL-C QTL concordance and its implication in future studies.
6. Machleder D, Ivandic B, Welch C, et al. Complex genetic control of HDL levels in mice in response to an atherogenic diet: coordinate regulation of HDL levels and bile acid metabolism. J Clin Invest 1997; 99:1406-1419.
7. Dansky HM, Shu P, Donavan M, et al. A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse. Genetics 2002; 160:1599-1608.
8. Colinayo W, Qiao JH, Wang X, et al. Genetic loci for diet-induced atherosclerosis lesions and plasma lipids in mice. Mamm Genome 2003; 14:464-471.
9. Sehayek E, Duncan EM, Yu HJ, et al. Loci controlling plasma non-HDL and HDL cholesterol levels in a C57BL/6J × CASA/Rk intercross. J Lipid Res 2003; 44:1744-1750.
10. Gu L, Johnson MW, Lusis AJ. Quantitative trait locus analysis of plasma lipoprotein levels in an autoimmune mouse model: interactions between lipoprotein metabolism, autoimmune disease, and atherogenesis. Arterioscler Thramb Vasc Biol 1999; 19:442-453.
11. Ishimori N, Li R, Kelmenson PM, et al. Quantitative trait loci that determine plasma lipids and obesity in C57BL/6J and 129S1/SvlmJ inbred mice. J Lipid Res 2004; 45:1624-1632.
12. Lyons MA, Wittenburg H, Li R, et al. Quantitative trait loci that determine lipoprotein cholesterol levels in an intercross of 129S1/SvlmJ and CAST/Ei inbred mice. Physiol Genomics 2004; 17:60-68.
13. Lyons MA, Wittenburg H, Li R, et al. Quantitative trait loci that determine lipoprotein cholesterol levels in DBA/2J and CAST/Ei inbred mice. J Lipid Res 2003; 44:953-967.
14. Purcell-Huynh DA, Weinreb A, Castellani LW, et al. Genetic factors in lipoprotein metabolism: analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach. J Clin Invest 1995; 96:1845-1858.
15. Pitman WA, Korstanje R, Churchill GA, et al. Quantitative trait locus mapping of genes that regulate HDL cholesterol in SM/J and NZB/B1NJ inbred mice. Physiol Genomics 2002; 9:93-102.
16. Lyons MA, Korstanje R, Li R, et al. Genetic contributors to lipoprotein cholesterol levels in an intercross of 129S1/SvlmJ and RIIIS/J inbred mice. Physiol Genomics 2004; 17:114-121.
17. Suto J, Takahashi Y, Sekikawa K. Quantitative trait locus analysis of plasma cholesterol and triglycéride levels in C57BL/6J × RR F2 mice. Biochem Genet 2004; 42:347-363.
18. Anunciado RV, Nishimura M, Mori M, et al. Quantitative trait locus analysis of serum insulin, triglyceride, total cholesterol and phospholipid levels in the (SM/J × A/J)F2 mice. Exp Anim 2003; 52:37-42.
19. Bretschger Seidelmann S, De Luca C, Leibel RL, et al. Quantitative trait locus mapping of genetic modifiers of metabolic syndrome and atherosclerosis in low-density lipoprotein receptor-deficient mice: identification of a locus for metabolic syndrome and increased atherosclerosis on chromosome 4. Arterioscler Thromb Vasc Biol 2005; 25:1-8.
20. Shike T, Hirose S, Kobayashi M, et al. Susceptibility and negative epistatic loci contributing to type 2 diabetes and related phenotypes in a KK/Ta mouse model. Diabetes 2001; 50:1943-1948.
21. Suto J, Sekikawa K. Quantitative trait locus analysis of plasma cholesterol and triglyceride levels in KK × RR F2 mice. Biochem Genet 2003; 41:325-341.
22. Suto J, Matsuura S, Yamanaka H, Sekikawa K. Quantitative trait loci that regulate plasma lipid concentration in hereditary obese KK and KK-Ay mice. Biochim Biophys Acta 1999; 1453:385-395.
23. Elbein SC, Hasstedt SJ. 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.
24. Reed DR, Nanthakumar E, North M, et al. 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.
25. Al-Kateb H, Bahring S, Hoffmann K, et al. Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia. Circ Res 2002; 90:951-958.
26. Bosse Y, Chagnon YC, Despres JP, et al. Genome-wide linkage scan reveals multiple susceptibility loci influencing lipid and lipoprotein levels in the Quebec Family Study. J Lipid Res 2004; 45:419-426.
27. Pollin TI, Hsueh WC, Steinle NI, et al. A genome-wide scan of serum lipid levels in the Old Order Amish. Atherosclerosis 2004; 173:89-96.
28. Coon H, Leppert MF, Eckfeldt JH, et al. Genome-wide linkage analysis of lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) Blood Pressure Study. Arterioscler Thromb Vasc Biol 2001; 21:1969-1976.
29. Coon H, Eckfeldt JH, Leppert MF, 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.
30. Sonnenberg GE, Krakower GR, Martin U, et al. Genetic determinants of obesity-related lipid traits. J Lipid Res 2004; 45:610-615.
31. Knoblauch H, Muller-Myhsok B, Busjahn A, et al. A cholesterol-lowering gene maps to chromosome 13q. Am J Hum Genet 2000; 66:157-166.
32. Broeckel U, Hengstenberg C, Mayer B, et al. A comprehensive linkage analysis for myocardial infarction and its related risk factors. Nat Genet 2002; 30:210-214.
33. Ober C, Abney M, McPeek MS. The genetic dissection of complex traits in a founder population. Am J Hum Genet 2001; 69:1068-1079.
34. Beekman M, Heijmans BT, Martin NG, et al. Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population. Eur J Hum Genet 2003; 11:845-850.
35. Imperatore G, Knowler WC, Pettitt DJ, 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.
36. Newman DL, Abney M, Dytch H, et al. 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.
37. Pajukanta P, Terwilliger JD, Perola M, 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.
38. Cantor RM, de Bruin T, Kono N, et al. Quantitative trait loci for apolipoprotein B, cholesterol, and triglycerides in familial combined hyperlipidemia pedigrees. Arterioscler Thromb Vasc Biol 2004; 24:1935-1941.
39. Arnett DK, Miller MB, Coon H, et al. Genome-wide linkage analysis replicates susceptibility locus for fasting plasma triglycerides: NHLBI Family Heart Study. Hum Genet 2004; 115:468-474.
40. Naoumova RP, Bonney SA, Eichenbaum-Voline S, et al. Confirmed locus on chromosome 11p and candidate loci on 6q and 8p for the triglyceride and cholesterol traits of combined hyperlipidemia. Arterioscler Thromb Vasc Biol 2003; 23:2070-2077.
41. Duggirala R, Blangero J, Almasy L, 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.
42. Shearman AM, Ordovas JM, Cupples LA, 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.
43. Klos KL, Kardia SL, Ferrell RE, et al. 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. Arterioscler Thromb Vasc Biol 2001; 21:971-978.
44. Austin MA, Edwards KL, Monks SA, et al. Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia. J Lipid Res 2003; 44:2161-2168.
45. Stoll M, Kwitek-Black AE, Cowley AW Jr, et al. New target regions for human hypertension via comparative genomics. Genome Res 2000; 10:473-482.
46. Sugiyama F, Churchill GA, Higgins DC, et al. Concordance of murine quantitative trait loci for salt-induced hypertension with rat and human loci. Genomics 2001; 71:70-77.
47. Korstanje R, DiPetrillo K. Unraveling the genetics of chronic kidney disease using animal models. Am J Physiol Renal Physiol 2004; 287: F347-F352.
48. Bosse Y, Chagnon YC, Despres JP, et al. Compendium of genome-wide scans of lipid-related phenotypes: adding a new genome-wide search of apolipoprotein levels. J Lipid Res 2004; 45:2174-2184. The authors summarized genome scan studies of lipid-related phenotypes in humans as of April 2003. They caution that the false-positive rate is likely high, and some of the replications may be by chance.
49. Darvasi A. Experimental strategies for the genetic dissection of complex traits in animal models. Nat Genet 1998; 18:19-24.
50. Kelmenson P, Petkov P, Wang X, et al. A Torrid zone on mouse chromosome 1 containing a cluster of recombinational hotspots. Genetics (in press).
51. Li R, Lyons MA, Wittenburg H, et al. Combining data from multiple inbred line crosses improves the power and resolution of QTL mapping. Genetics 2005; 16 January [Epub ahead of print]. QTL intervals found in F2 crosses are usually large (more than 20 cM). These authors found that combining multiple crosses that identify QTLs at the same chromosome location can significantly narrow a QTL. This new method will help to narrow a QTL by using existing data rather than making new crosses.
52. DiPetrillo K, Tsaih SW, Sheehan S, et al. Genetic analysis of blood pressure in C3H/HeJ and SWR/J mice. Physiol Genomics 2004; 17:215-220.
53. Yalcin B, Fullerton J, Miller S, et al. Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice. Proc Natl Acad Sci USA 2004; 101:9734-9739. Previous studies found that the mouse genome is a mosaic of haplotype blocks that are about 1-2 Mb in length. This article showed that the 'block concept may be too simple, and it is unsafe to assume that a high-fidelity haplotype block exists between markers that share the same strain distribution pattern. We therefore should be cautious in applying the 'haplotype block' concept in in-silico QTL analysis.
54. Wang X, Korstanje R, Higgins D, Paigen B. Haplotype analysis in multiple crosses to identify a QTL gene. Genome Res 2004; 14:1767-1772. The authors demonstrated that SNP analysis in multiple mouse crosses can be used to test and help prove a candidate gene.
55. Pletcher MT, McClurg P, Batalov S, et al. Use of a dense single nucleotide polymorphism map for in silico mapping in the mouse. PLoS Biol 2004; 2:e93. The improved in-silico QTL analysis identified genes for not only a Mendelian trait, but also complex traits such as plasma HDL-C levels and gallstone formation. This method has the potential to narrow a QTL to a region less than 1 Mb in size.
56. Morabia A, Cayanis E, Costanza MC, et al. Association of extreme blood lipid profile phenotypic variation with 11 reverse cholesterol transport genes and 10 nongenetic cardiovascular disease risk factors. Hum Mol Genet 2003; 12:2733-2743. The authors performed a logistic regression analysis of cases (with high LDL-C and low HDL-C levels) and controls (with low LDL-C and high HDL-C levels). They showed that a subset of nine genetic variants in seven genes, coupled with five environmental risk factors, produce a model for plasma lipid regulation.
57. Knoblauch H, Bauerfeind A, Toliat MR, et al. Haplotypes and SNPs in 13 lipides relevant genes explain most of the genetic variance in high-density lipoprotein and low-density lipoprotein cholesterol. Hum Mol Genet 2004; 13:993-1004. A total of 230 haplotypes in 13 genes together explain most of the genetic variance of plasma HDL-C and LDL-C levels. Genetic variances in LIPC and CETP are important contributors to plasma HDL-C variance, and genetic variances in APOE and CETP together contribute to most of the variance of LDL-C levels in the population studied.
58. Frikke-Schmidt R, Nordestgaard BG, Jensen GB, Tybjaerg-Hansen A. Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population. J Clin Invest 2004; 114:1343-1353. The authors demonstrated that, in the general population, at least 10% of individuals with low HDL-C are heterozygous for mutations in ABCA1, and that both mutations and SNPs in ABCA1 contribute to HDL-C levels. This study supports the theory that complex traits are caused by common variants, each contributing a small to moderate phenotypic effect, and extreme phenotypes in the general population may be due to rare mutations.
59. Cohen JC, Kiss RS, Pertsemlidis A, et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 2004; 305:869-872. Nonsynonymous sequence variants in ABCA1 are significantly more common in tow HDL-C than in high HDL-C individuals. Meanwhile, rare alleles of ABCA1 unique in low HDL-C individuals contribute significantly to low plasma HDL-C levels in the general population. This strategy to analyze the relationships between rare alleles and low or high levels of a trait to find out whether these rare alleles contribute to population variance may also be used for other traits.
60. Wang X, Ria M, Kelmenson PM, et al. Positional identification of OX40 ligand as a gene that influences atherosclerosis susceptibility. Nat Genet (in press).