Background: The small, dense LDL phenotype is associated with an increased cardiovascular disease risk. A genome-wide scan performed on the Quebec Family Study (QFS) revealed a quantitative trait locus for LDL peak particle diameter (LDL-PPD) on the 17q21 region. A positional candidate gene – the fatty acid synthase gene (FASN) – encodes a key enzyme in the biogenesis of membrane lipids. FASN may play a role in the regulation of feeding and may be a potential therapeutic target for obesity and insulin resistance. Methods: Analyses were performed on 592 subjects of the QFS. Dietary fat was estimated by a 3-day food record. LDL-PPD was measured by gradient gel electrophoresis on polyacrylamide gradient gels. Results: Five single nucleotide polymorphisms were genotyped in FASN gene. FASN rs4246444 was associated with LDL-PPD, but only when fat intake was taken into account (p = 0.001). High and low lipid consumers were defined using a cutoff of 35% of dietary fat intake. Carriers of the variant allele showed smaller LDL-PPD only when consuming a high amount of fat. This association remained significant after adjustments for age, sex, body mass index and plasma triglyceride levels. Conclusion: The results suggest that dietary fat intake may modify the effect of the FASN rs4246444 polymorphism on LDL-PPD.

Keywords:
FASN, Fatty acid synthase, Gene-diet interaction, Genome-wide linkage scan, LDL particle size, LDL-peak particle diameter
1.
Lamarche B, Lemieux I, Despres JP: The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects. Diabetes Metab 1999;25:199–211.
2.
St-Pierre AC, Cantin B, Dagenais GR, Mauriege P, Bernard PM, Despres JP, Lamarche B: Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study. Arterioscler Thromb Vasc Biol 2005;25:553–559.
3.
St-Pierre AC, Ruel IL, Cantin B, Dagenais GR, Bernard PM, Despres JP, Lamarche B: Comparison of various electrophoretic characteristics of LDL particles and their relationship to the risk of ischemic heart disease. Circulation 2001;104:2295–2299.
4.
Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM, Hennekens CH: A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996;276:882–888.
5.
Bosse Y, Vohl MC, Despres JP, Lamarche B, Rice T, Rao DC, Bouchard C, Perusse L: Heritability of LDL peak particle diameter in the Quebec Family Study. Genet Epidemiol 2003;25:375–381.
6.
Bosse Y, Perusse L, Despres JP, Lamarche B, Chagnon YC, Rice T, Rao DC, Bouchard C, Vohl MC: Evidence for a major quantitative trait locus on chromosome 17q21 affecting low-density lipoprotein peak particle diameter. Circulation 2003;107:2361–2368.
7.
Menendez JA, Vazquez-Martin A, Ortega FJ, Fernandez-Real JM: Fatty acid synthase: association with insulin resistance, type 2 diabetes, and cancer. Clin Chem 2009;55:425–438.
8.
Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP: Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 2000;288:2379–2381.
9.
Krauss RM, Dreon DM: Low-density-lipoprotein subclasses and response to a low-fat diet in healthy men. Am J Clin Nutr 1995;62:478S–487S.
10.
Krauss RM, Blanche PJ, Rawlings RS, Fernstrom HS, Williams PT: Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia. Am J Clin Nutr 2006;83:1025–1031.
11.
Bosse Y, Perusse L, Vohl MC: Genetics of LDL particle heterogeneity: from genetic epidemiology to DNA-based variations. J Lipid Res 2004;45:1008–1026.
12.
Krauss RM: Dietary and genetic effects on LDL heterogeneity. World Rev Nutr Diet 2001;89:12–22.
13.
Campos H, D’Agostino M, Ordovas JM: Gene-diet interactions and plasma lipoproteins: role of apolipoprotein E and habitual saturated fat intake. Genet Epidemiol 2001;20:117–128.
14.
Lai CQ, Corella D, Demissie S, Cupples LA, Adiconis X, Zhu Y, Parnell LD, Tucker KL, Ordovas JM: Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: the Framingham Heart Study. Circulation 2006;113:2062–2070.
15.
Herron KL, Lofgren IE, Adiconis X, Ordovas JM, Fernandez ML: Associations between plasma lipid parameters and APOC3 and APOA4 genotypes in a healthy population are independent of dietary cholesterol intake. Atherosclerosis 2006;184:113–120.
16.
Gomez P, Perez-Martinez P, Marin C, Camargo A, Yubero-Serrano EM, Garcia-Rios A, Rodriguez F, Delgado-Lista J, Perez-Jimenez F, Lopez-Miranda J: APOA1 and APOA4 gene polymorphisms influence the effects of dietary fat on LDL particle size and oxidation in healthy young adults. J Nutr 2010;140:773–778.
17.
Brown S, Ordovas JM, Campos H: Interaction between the APOC3 gene promoter polymorphisms, saturated fat intake and plasma lipoproteins. Atherosclerosis 2003;170:307–313.
18.
Moreno JA, Perez-Jimenez F, Marin C, Gomez P, Perez-Martinez P, Moreno R, Bellido C, Fuentes F, Lopez-Miranda J: The effect of dietary fat on LDL size is influenced by apolipoprotein E genotype in healthy subjects. J Nutr 2004;134:2517–2522.
19.
Bouchard C: Genetic epidemiology, association, and sib-pair linkage: results from the Quebec Family Study; in Bray GA, Ryan DH (eds): Molecular and Genetic Aspects of Obesity. Baton Rouge, Louisiana University Press, 1996, pp 470–481.
20.
Allain CC, Poon LS, Chan CS, Richmond W, Fu PC: Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470–475.
21.
Fossati P, Prencipe L: Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982;28:2077–2080.
22.
Laurell CB: Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Anal Biochem 1966;15:45–52.
23.
Tchernof A, Lamarche B, Prud’Homme D, Nadeau A, Moorjani S, Labrie F, Lupien PJ, Despres JP: The dense LDL phenotype. Association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in men. Diabetes Care 1996;19:629–637.
24.
Tremblay A, Leblanc C, Bouchard C: The reproducibility of a three-day dietary record. Nutr Res 1983;3:819–830.
25.
Verdier P, Beare-Rogers JL: The Canadian Nutrient File. J Can Diet Assoc 1984;45:52–55.
26.
Bonfield JK, Smith K, Staden R: A new DNA sequence assembly program. Nucleic Acids Res 1995;23:4992–4999.
27.
Livak KJ: Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 1999;14:143–149.
28.
Dolley G, Berthier MT, Lamarche B, Despres JP, Bouchard C, Perusse L, Vohl MC: Influences of the phosphatidylcholine transfer protein gene variants on the LDL peak particle size. Atherosclerosis 2007;195:297–302.
29.
Dolley G, Lamarche B, Despres JP, Bouchard C, Perusse L, Vohl MC: Phosphoinositide cycle gene polymorphisms affect the plasma lipid profile in the Quebec Family Study. Mol Genet Metab 2009;97:149–154.
30.
Berndt J, Kovacs P, Ruschke K, Kloting N, Fasshauer M, Schon MR, Korner A, Stumvoll M, Bluher M: Fatty acid synthase gene expression in human adipose tissue: association with obesity and type 2 diabetes. Diabetologia 2007;50:1472–1480.
31.
Davis RA: Cell and molecular biology of the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver. Biochim Biophys Acta 1999;1440:1–31.
32.
Maiyoh GK, Kuh JE, Casaschi A, Theriault AG: Cruciferous indole-3-carbinol inhibits apolipoprotein B secretion in HepG2 cells. J Nutr 2007;137:2185–2189.
33.
Peter A, Cegan A, Wagner S, Lehmann R, Stefan N, Konigsrainer A, Konigsrainer I, Haring HU, Schleicher E: Hepatic lipid composition and stearoyl-coenzyme A desaturase 1 mRNA expression can be estimated from plasma VLDL fatty acid ratios. Clin Chem 2009;55:2113–2120.
34.
McNamara JR, Jenner JL, Li Z, Wilson PW, Schaefer EJ: Change in LDL particle size is associated with change in plasma triglyceride concentration. Arterioscler Thromb 1992;12:1284–1290.
35.
Tan CE, Foster L, Caslake MJ, Bedford D, Watson TD, McConnell M, Packard CJ, Shepherd J: Relations between plasma lipids and postheparin plasma lipases and VLDL and LDL subfraction patterns in normolipemic men and women. Arterioscler Thromb Vasc Biol 1995;15:1839–1848.
36.
Schleinitz D, Klöting N, Körner A, Berndt J, Reichenbächer M, Tönjes A, Ruschke K, Böttcher Y, Dietrich K, Enigk B, Filz M, Schön MR, Jenkner J, Kiess W, Stumvoll M, Blüher M, Kovacs P: Effect of genetic variation in the human fatty acid synthase gene (FASN) on obesity and fat depot-specific mRNA expression. Obesity (Silver Spring) 2010;18:1218–1225.
37.
Goff DC Jr, D’Agostino RB Jr, Haffner SM, Otvos JD: Insulin resistance and adiposity influence lipoprotein size and subclass concentrations. Results from the Insulin Resistance Atherosclerosis Study. Metabolism 2005;54:264–270.
38.
Xu J, Nakamura MT, Cho HP, Clarke SD: Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem 1999;274:23577–23583.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: 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.
You do not currently have access to this content.