Abstract
The frequent coincidence of hypertension and dyslipidemia suggests that related genetic factors might underlie these common risk factors for cardiovascular disease. To investigate whether quantitative trait loci (QTLs) regulating lipid levels map to chromosomes known to contain genes regulating blood pressure, we used a genome scanning approach to map QTLs influencing cholesterol and phospholipid phenotypes in a large set of recombinant inbred strains and in congenic strains derived from the spontaneously hypertensive rat and normotensive Brown-Norway (BN.Lx) rat fed normal and high cholesterol diets. QTLs regulating lipid phenotypes were mapped by scanning the genome with 534 genetic markers. A significant relationship (P < 0.00006) was found between basal HDL2 cholesterol levels and the D19Mit2 marker on chromosome 19. Analysis of congenic strains of spontaneously hypertensive rat indicated that QTLs regulating postdietary lipid phenotypes exist also on chromosomes 8 and 20. Previous studies in the recombinant inbred and congenic strains have demonstrated the presence of blood pressure regulatory genes in corresponding segments of chromosomes 8, 19, and 20. These findings provide support for the hypothesis that blood pressure and certain lipid subfractions can be modulated by linked genes or perhaps even the same genes.
Full Text
The Full Text of this article is available as a PDF (172.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Azoulay M., Henry I., Tata F., Weil D., Grzeschik K. H., Chaves M. E., McIntyre N., Williamson R., Humphries S. E., Junien C. The structural gene for lecithin:cholesterol acyl transferase (LCAT) maps to 16q22. Ann Hum Genet. 1987 May;51(Pt 2):129–136. doi: 10.1111/j.1469-1809.1987.tb01054.x. [DOI] [PubMed] [Google Scholar]
- Belknap J. K. Empirical estimates of Bonferroni corrections for use in chromosome mapping studies with the BXD recombinant inbred strains. Behav Genet. 1992 Nov;22(6):677–684. doi: 10.1007/BF01066638. [DOI] [PubMed] [Google Scholar]
- Bottger A., den Bieman M., Lankhorst A. E., van Lith H. A., van Zutphen L. F. Strain-specific response to hypercholesterolaemic diets in the rat. Lab Anim. 1996 Apr;30(2):149–157. doi: 10.1258/002367796780865736. [DOI] [PubMed] [Google Scholar]
- Brault D., Noé L., Etienne J., Hamelin J., Raisonnier A., Souli A., Chuat J. C., Dugail I., Quignard-Boulangé A., Lavau M. Sequence of rat lipoprotein lipase-encoding cDNA. Gene. 1992 Nov 16;121(2):237–246. doi: 10.1016/0378-1119(92)90127-b. [DOI] [PubMed] [Google Scholar]
- Chajek-Shaul T., Hayek T., Walsh A., Breslow J. L. Expression of the human apolipoprotein A-I gene in transgenic mice alters high density lipoprotein (HDL) particle size distribution and diminishes selective uptake of HDL cholesteryl esters. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6731–6735. doi: 10.1073/pnas.88.15.6731. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen J. C., Wang Z., Grundy S. M., Stoesz M. R., Guerra R. Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels. J Clin Invest. 1994 Dec;94(6):2377–2384. doi: 10.1172/JCI117603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dall'Aglio E., Tosini P., Ferrari P., Zavaroni I., Passeri M., Reaven G. M. Abnormalities of insulin and lipid metabolism in Milan hypertensive rats. Am J Hypertens. 1991 Sep;4(9):773–775. doi: 10.1093/ajh/4.9.773. [DOI] [PubMed] [Google Scholar]
- Darvasi A., Soller M. Advanced intercross lines, an experimental population for fine genetic mapping. Genetics. 1995 Nov;141(3):1199–1207. doi: 10.1093/genetics/141.3.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Erlanson-Albertsson C. Pancreatic colipase. Structural and physiological aspects. Biochim Biophys Acta. 1992 Apr 8;1125(1):1–7. doi: 10.1016/0005-2760(92)90147-n. [DOI] [PubMed] [Google Scholar]
- Homanics G. E., de Silva H. V., Osada J., Zhang S. H., Wong H., Borensztajn J., Maeda N. Mild dyslipidemia in mice following targeted inactivation of the hepatic lipase gene. J Biol Chem. 1995 Feb 17;270(7):2974–2980. doi: 10.1074/jbc.270.7.2974. [DOI] [PubMed] [Google Scholar]
- Jacob H. J., Brown D. M., Bunker R. K., Daly M. J., Dzau V. J., Goodman A., Koike G., Kren V., Kurtz T., Lernmark A. A genetic linkage map of the laboratory rat, Rattus norvegicus. Nat Genet. 1995 Jan;9(1):63–69. doi: 10.1038/ng0195-63. [DOI] [PubMed] [Google Scholar]
- Kirchgessner T. G., LeBoeuf R. C., Langner C. A., Zollman S., Chang C. H., Taylor B. A., Schotz M. C., Gordon J. I., Lusis A. J. Genetic and developmental regulation of the lipoprotein lipase gene: loci both distal and proximal to the lipoprotein lipase structural gene control enzyme expression. J Biol Chem. 1989 Jan 25;264(3):1473–1482. [PubMed] [Google Scholar]
- Kren V. Genetics of the polydactyly-luxate syndrome in the Norway rat, Rattus norvegicus. Acta Univ Carol Med Monogr. 1975;(68):1–103. [PubMed] [Google Scholar]
- Kren V., Krenová D., Pravenec M., Zdobinská M. Chromosome 8 congenic strains: tools for genetic analysis of limb malformation, plasma triglycerides, and blood pressure in the rat. Folia Biol (Praha) 1995;41(6):284–293. [PubMed] [Google Scholar]
- Manly K. F. A Macintosh program for storage and analysis of experimental genetic mapping data. Mamm Genome. 1993;4(6):303–313. doi: 10.1007/BF00357089. [DOI] [PubMed] [Google Scholar]
- Mathern P., Goldmuntz E. A., Du Y., Zha H., Cash J. M., Crofford L. J., Wilder R. L., Remmers E. F. Nine polymorphic markers characterized by polymerase chain reaction techniques form two linkage groups on rat chromosome 8. Cytogenet Cell Genet. 1994;66(4):283–286. doi: 10.1159/000133713. [DOI] [PubMed] [Google Scholar]
- McLean J., Wion K., Drayna D., Fielding C., Lawn R. Human lecithin-cholesterol acyltransferase gene: complete gene sequence and sites of expression. Nucleic Acids Res. 1986 Dec 9;14(23):9397–9406. doi: 10.1093/nar/14.23.9397. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mehlum A., Staels B., Duverger N., Tailleux A., Castro G., Fievet C., Luc G., Fruchart J. C., Olivecrona G., Skretting G. Tissue-specific expression of the human gene for lecithin: cholesterol acyltransferase in transgenic mice alters blood lipids, lipoproteins and lipases towards a less atherogenic profile. Eur J Biochem. 1995 Jun 1;230(2):567–575. doi: 10.1111/j.1432-1033.1995.tb20597.x. [DOI] [PubMed] [Google Scholar]
- Meroni G., Malgaretti N., Magnaghi P., Taramelli R. Nucleotide sequence of the cDNA for lecithin-cholesterol acyl transferase (LCAT) from the rat. Nucleic Acids Res. 1990 Sep 11;18(17):5308–5308. doi: 10.1093/nar/18.17.5308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Neumann P. E. Inference in linkage analysis of multifactorial traits using recombinant inbred strains of mice. Behav Genet. 1992 Nov;22(6):665–676. doi: 10.1007/BF01066637. [DOI] [PubMed] [Google Scholar]
- Pravenec M., Gauguier D., Schott J. J., Buard J., Kren V., Bila V., Szpirer C., Szpirer J., Wang J. M., Huang H. Mapping of quantitative trait loci for blood pressure and cardiac mass in the rat by genome scanning of recombinant inbred strains. J Clin Invest. 1995 Oct;96(4):1973–1978. doi: 10.1172/JCI118244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pravenec M., Gauguier D., Schott J. J., Buard J., Kren V., Bílá V., Szpirer C., Szpirer J., Wang J. M., Huang H. A genetic linkage map of the rat derived from recombinant inbred strains. Mamm Genome. 1996 Feb;7(2):117–127. doi: 10.1007/s003359900031. [DOI] [PubMed] [Google Scholar]
- Pravenec M., Klír P., Kren V., Zicha J., Kunes J. An analysis of spontaneous hypertension in spontaneously hypertensive rats by means of new recombinant inbred strains. J Hypertens. 1989 Mar;7(3):217–221. [PubMed] [Google Scholar]
- Pulcini T., Terru P., Sparrow J. T., Pownall H. J., Ponsin G. Plasma factors affecting the in vitro conversion of high-density lipoproteins labeled with a non-transferable marker. Biochim Biophys Acta. 1995 Jan 3;1254(1):13–21. doi: 10.1016/0005-2760(94)00156-s. [DOI] [PubMed] [Google Scholar]
- Purcell-Huynh D. A., Weinreb A., Castellani L. W., Mehrabian M., Doolittle M. H., Lusis A. J. 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 Oct;96(4):1845–1858. doi: 10.1172/JCI118230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reaven G. M., Chang H. Relationship between blood pressure, plasma insulin and triglyceride concentration, and insulin action in spontaneous hypertensive and Wistar-Kyoto rats. Am J Hypertens. 1991 Jan;4(1 Pt 1):34–38. doi: 10.1093/ajh/4.1.34. [DOI] [PubMed] [Google Scholar]
- Reaven G. M., Chen Y. D. Role of insulin in regulation of lipoprotein metabolism in diabetes. Diabetes Metab Rev. 1988 Nov;4(7):639–652. doi: 10.1002/dmr.5610040703. [DOI] [PubMed] [Google Scholar]
- Reaven G. M., Mondon C. E., Chen Y. D., Breslow J. L. Hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene are neither insulin resistant nor hyperinsulinemic. J Lipid Res. 1994 May;35(5):820–824. [PubMed] [Google Scholar]
- Reaven G. M. Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995 Jul;75(3):473–486. doi: 10.1152/physrev.1995.75.3.473. [DOI] [PubMed] [Google Scholar]
- Reaven G. M., Twersky J., Chang H. Abnormalities of carbohydrate and lipid metabolism in Dahl rats. Hypertension. 1991 Nov;18(5):630–635. doi: 10.1161/01.hyp.18.5.630. [DOI] [PubMed] [Google Scholar]
- Remmers E. F., Du Y., Zha H., Goldmuntz E. A., Wilder R. L. Ten polymorphic DNA loci, including five in the rat MHC (RT1) region, form a single linkage group on rat chromosome 20. Immunogenetics. 1995;41(5):316–319. doi: 10.1007/BF00172157. [DOI] [PubMed] [Google Scholar]
- Scherer G., Bausch E., Gaa A., von Deimling O. Gene mapping on mouse chromosome 8 by interspecific crosses: new data on a linkage group conserved on human chromosome 16q. Genomics. 1989 Aug;5(2):275–282. doi: 10.1016/0888-7543(89)90058-x. [DOI] [PubMed] [Google Scholar]
- Serikawa T., Kuramoto T., Hilbert P., Mori M., Yamada J., Dubay C. J., Lindpainter K., Ganten D., Guénet J. L., Lathrop G. M. Rat gene mapping using PCR-analyzed microsatellites. Genetics. 1992 Jul;131(3):701–721. doi: 10.1093/genetics/131.3.701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Terpstra A. H., Woodward C. J., Sanchez-Muniz F. J. Improved techniques for the separation of serum lipoproteins by density gradient ultracentrifugation: visualization by prestaining and rapid separation of serum lipoproteins from small volumes of serum. Anal Biochem. 1981 Feb;111(1):149–157. doi: 10.1016/0003-2697(81)90243-8. [DOI] [PubMed] [Google Scholar]
- Thorburn A. W., Storlien L. H., Jenkins A. B., Khouri S., Kraegen E. W. Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats. Am J Clin Nutr. 1989 Jun;49(6):1155–1163. doi: 10.1093/ajcn/49.6.1155. [DOI] [PubMed] [Google Scholar]
- Vincent M., Boussaïri E. H., Cartier R., Lo M., Sassolas A., Cerutti C., Barrès C., Gustin M. P., Cuisinaud G., Samani N. J. High blood pressure and metabolic disorders are associated in the Lyon hypertensive rat. J Hypertens. 1993 Nov;11(11):1179–1185. [PubMed] [Google Scholar]
- Vrána A., Kazdová L., Dobesová Z., Kunes J., Kren V., Bílá V., Stolba P., Klimes I. Triglyceridemia, glucoregulation, and blood pressure in various rat strains. Effects of dietary carbohydrates. Ann N Y Acad Sci. 1993 Jun 14;683:57–68. doi: 10.1111/j.1749-6632.1993.tb35692.x. [DOI] [PubMed] [Google Scholar]
- Warden C. H., Davis R. C., Yoon M. Y., Hui D. Y., Svenson K., Xia Y. R., Diep A., He K. Y., Lusis A. J. Chromosomal localization of lipolytic enzymes in the mouse: pancreatic lipase, colipase, hormone-sensitive lipase, hepatic lipase, and carboxyl ester lipase. J Lipid Res. 1993 Aug;34(8):1451–1455. [PubMed] [Google Scholar]
- Warden C. H., Langner C. A., Gordon J. I., Taylor B. A., McLean J. W., Lusis A. J. Tissue-specific expression, developmental regulation, and chromosomal mapping of the lecithin: cholesterol acyltransferase gene. Evidence for expression in brain and testes as well as liver. J Biol Chem. 1989 Dec 25;264(36):21573–21581. [PubMed] [Google Scholar]
- Williams R. R., Hunt S. C., Hopkins P. N., Stults B. M., Wu L. L., Hasstedt S. J., Barlow G. K., Stephenson S. H., Lalouel J. M., Kuida H. Familial dyslipidemic hypertension. Evidence from 58 Utah families for a syndrome present in approximately 12% of patients with essential hypertension. JAMA. 1988 Jun 24;259(24):3579–3586. doi: 10.1001/jama.259.24.3579. [DOI] [PubMed] [Google Scholar]
- Williams R. R., Hunt S. C., Hopkins P. N., Wu L. L., Lalouel J. M. Evidence for single gene contributions to hypertension and lipid disturbances: definition, genetics, and clinical significance. Clin Genet. 1994 Jul;46(1 Spec No):80–87. doi: 10.1111/j.1399-0004.1994.tb04207.x. [DOI] [PubMed] [Google Scholar]
- Zavaroni I., Mazza S., Dall'Aglio E., Gasparini P., Passeri M., Reaven G. M. Prevalence of hyperinsulinaemia in patients with high blood pressure. J Intern Med. 1992 Mar;231(3):235–240. doi: 10.1111/j.1365-2796.1992.tb00529.x. [DOI] [PubMed] [Google Scholar]