Polymorphisms of the HDL Receptor Gene Associated with HDL Cholesterol Levels in Diabetic Kindred from Three PopulationsMcCarthy J.J.a · Lewitzky S.b · Reeves C.b · Permutt A.c · Glaser B.d · Groop L.C.e · Lehner T.f · Meyer J.M.b
aSan Diego State University, San Diego, Calif., bMillennium Pharmaceuticals, Inc., Cambridge, Mass., cDivision of Metabolism, Endocrinology and Diabetes, Washington University Medical School, St.Louis,Mo.,USA; dEndocrinology and Metabolism Service, Internal Medicine Department, Hebrew University, Hadassah Medical Center, Jerusalem, Israel; eDepartment of Endocrinology, Wallenberg Laboratory, Malmö University Hospital, University of Lund, Malmö, Sweden; fRockefeller University, New York, N.Y., USA
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Objective: We examined polymorphisms in the HDL receptor, SR-BI, for association with plasma HDL cholesterol levels. Methods: Study subjects, including 847 women and 725 men, were from families originally ascertained for type 2 diabetes from Finland, Sweden and Israel. Four common polymorphisms were examined in linear regression analysis: an exon 1 missense (EX1), exon 8 silent (EX8), intron 5 (IVS5) and intron 10 (IVS10) variants. Results: Genotype combinations for the three polymorphisms in linkage disequilibrium (IVS5, EX8 and IVS10) were found to be associated with HDL-C among women from the Israeli (p = 0.01) and Swedish (p = 0.06) populations. In Finnish women, the association was only apparent after taking into account effect modification by triglyceride levels (p = 0.04). One specific pattern of genotypes, denoted by presence of the IVS5_T and EX8_C alleles, and absence of the IVS10_G allele, was consistently associated with the lowest mean levels of HDL-C in women from all three populations. These same associations were not found in men. Conclusions: Polymorphic variation of the SR-BI gene may influence HDL-C levels and act in a sex-dependent manner.
© 2003 S. Karger AG, Basel
- Jeppesen J, Hein HO, Suadicani P, Gyntelberg F: Relation of high TG-low HDL cholesterol and LDL cholesterol to the incidence of ischemic heart disease. An 8-year follow-up in the Copenhagen Male Study. Arterioscler Thromb Vasc Biol 1997;17:1114–1120.
- Groop L, Forsblom C, Lehtovirta M, Tuomi T, Karanko S, Nissen M, Ehrnstrom BO, Forsen B, Isomaa B, Snickars B, Taskinen MR: Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes 1996;45:1585–1593.
- Shaw JT, Purdie DM, Neil HA, Levy JC, Turner RC: The relative risks of hyperglycaemia, obesity and dyslipidaemia in the relatives of patients with Type II diabetes mellitus. Diabetologia 1999;42:24–27.
- Knudsen P, Eriksson J, Lahdenpera S, Kahri J, Groop L, Taskinen MR: Changes of lipolytic enzymes cluster with insulin resistance syndrome. Botnia Study Group. Diabetologia 1995;38:344–350.
Ginsberg HN: Diabetic dyslipidemia: Basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels. Diabetes 1996;45(suppl 3):S27–30.
- Ginsberg HN: Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis. Diabetes Care 1991;14:839–855.
- Semenkovich CF, Heinecke JW: The mystery of diabetes and atherosclerosis: Time for a new plot. Diabetes 1997;46:327–334.
- Perusse L, Rice T, Despres JP, Bergeron J, Province MA, Gagnon J, Leon AS, Rao DC, Skinner JS, Wilmore JH, Bouchard C: Familial resemblance of plasma lipids, lipoproteins and postheparin lipoprotein and hepatic lipases in the HERITAGE Family Study. Arterioscler Thromb Vasc Biol 1997;17:3263–3269.
- Rice T, Vogler GP, Perry TS, Laskarzewski PM, Rao DC: 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;41:107–121.
- Austin MA, King MC, Bawol RD, Hulley SB, Friedman GD: Risk factors for coronary heart disease in adult female twins. Genetic heritability and shared environmental influences. Am J Epidemiol 1987;125:308–318.
- Breslow JL: Genetics of lipoprotein abnormalities associated with coronary artery disease susceptibility. Annu Rev Genet 2000;34:233–254.
- Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M: Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996;271:518–520.
- Rigotti A, Trigatti BL, Penman M, Rayburn H, Herz J, Krieger M: A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc Natl Acad Sci USA 1997;94:12610–12615.
- Varban ML, Rinninger F, Wang N, Fairchild-Huntress V, Dunmore JH, Fang Q, Gosselin ML, Dixon KL, Deeds JD, Acton SL, Tall AR, Huszar D: Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol. Proc Natl Acad Sci USA 1998;95:4619–4624.
- Acton S, Osgood D, Donoghue M, Corella D, Pocovi M, Cenarro A, Mozas P, Keilty J, Squazzo S, Woolf EA, Ordovas JM: Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population. Arterioscler Thromb Vasc Biol 1999;19:1734–1743.
- Permutt MA, Wasson JC, Suarez BK, Lin J, Thomas J, Meyer J, Lewitzky S, Rennich JS, Parker A, DuPrat L, Maruti S, Chayen S, Glaser B: A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population. Diabetes 2001;50:681–685.
- Parker A, Meyer J, Lewitzky S, Rennich JS, Chan G, Thomas JD, Orho-Melander M, Lehtovirta M, Forsblom C, Hyrkko A, Carlsson M, Lindgren C, Groop LC: A gene conferring susceptibility to type 2 diabetes in conjunction with obesity is located on chromosome 18p11. Diabetes 2001;50:675–680.
Livak KJ: Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 1999;14:143–149.
Lewontin R: The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 1964;49:49–67.
- Excoffier L, Slatkin M: Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995;12:921–927.
- Fluiter K, van der Westhuijzen DR, van Berkel TJ: In vivo regulation of scavenger receptor BI and the selective uptake of high density lipoprotein cholesteryl esters in rat liver parenchymal and Kupffer cells. J Biol Chem 1998;273:8434–8438.
- Landschulz KT, Pathak RK, Rigotti A, Krieger M, Hobbs HH: Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat. J Clin Invest 1996;98:984–995.
- 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.
- Tai ES, Adiconis X, Ordovas JM, Carmena-Ramon R, Real J, Corella D, Ascaso J, Carmena R: Polymorphisms at the SRBI locus are associated with lipoprotein levels in subjects with heterozygous familial hypercholesterolemia. Clin Genet 2003;63:53–58.
McCarthy J, Reeves C, Lehner T, Moliterno D, Newby L, Rogers W, Topol E: Association of genetic variants in the HDL receptor, SR-BI, with abnormal lipids in women with coronary artery disease. J Med Genet 2003;40:453–458.
- Ehm MG, Karnoub MC, Sakul H, Gottschalk K, Holt DC, Weber JL, Vaske D, Briley D, Briley L, Kopf J, McMillen P, Nguyen Q, Reisman M, Lai EH, Joslyn G, Shepherd NS, Bell C, Wagner MJ, Burns DK: Genomewide search for type 2 diabetes susceptibility genes in four American populations. Am J Hum Genet 2000;66:1871–1881.
- Shaw JT, Lovelock PK, Kesting JB, Cardinal J, Duffy D, Wainwright B, Cameron DP: Novel susceptibility gene for late-onset NIDDM is localized to human chromosome 12q. Diabetes 1998;47:1793–1796.
- Bowden DW, Sale M, Howard TD, Qadri A, Spray BJ, Rothschild CB, Akots G, Rich SS, Freedman BI: Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy. Diabetes 1997;46:882–886.
- Lindgren CM, Mahtani MM, Widen E, McCarthy MI, Daly MJ, Kirby A, Reeve MP, Kruglyak L, Parker A, Meyer J, Almgren P, Lehto M, Kanninen T, Tuomi T, Groop LC, Lander ES: Genomewide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia study. Am J Hum Genet 2002;70:509–516.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.