The risk of cardiovascular diseases (CVDs) is modulated by gene–diet interactions. The objective of this study was to examine whether gene–diet interactions affect peak particle diameters (PPD) of low-density lipoprotein (LDL). Methods: The study included 674 participants. A food frequency questionnaire was administered to obtain dietary information. LDL-PPD was determined by non-denaturing 2–16% polyacrylamide gradient gel electrophoresis. Peroxisome proliferator-activated receptor (PPAR) gene polymorphisms PPAR α L162V (rs1800206), PPAR γ P12A (rs1801282) and PPAR δ –87T→C (rs2016520) were determined by PCR-RFLP. Results: Among carriers of thePPAR α L162V polymorphism, gene–diet interaction effects on LDL-PPD were observed with saturated fat (p = 0.0005) and total dietary fat (p = 0.006). Among PPAR α V162 carriers, subjects with higher saturated fat intakes had smaller LDL-PPD than those with lower intakes (254.23 ± 2.74 vs. 256.21 ± 2.61 Å, respectively, p = 0.007). Among subjects homozygous for the PPAR α L162 allele, those with higher saturated fat intakes had larger LDL-PPD than those with lower saturated fat intakes (255.86 ± 2.66 vs. 255.05 ± 2.65 Å, respectively, p = 0.01). Gene–diet interactions were also found for PPAR γ P12A polymorphism with saturated fat intake (p = 0.04) and for PPAR δ –87T→C with the polyunsaturated/saturated fat ratio (p = 0.0013). Conclusions: These results stress that dietary factors should be included in studies determining the effect of different polymorphisms on CVD risk factors.

1.
Lindgren FT, Jensen LC, Wills RD, Freeman NK: Flotation rates, molecular weights and hydrated densities of the low-density lipoproteins. Lipids 1969;4:337–344.
2.
Berneis K, Rizzo M: LDL size: does it matter? Swiss Med Wkly 2004;134:720–724.
3.
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) final report. Circulation 2002;106:3143–3421.
4.
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.
5.
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.
6.
Siri-Tarino PW, Sun Q, Hu FB, Krauss RM: Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr 2010;91:502–509.
7.
de Graaf J, Swinkels DW, Demacker PN, de Haan AF, Stalenhoef AF: Differences in the low density lipoprotein subfraction profile between oral contraceptive users and controls. J Clin Endocrinol Metab 1993;76:197–202.
8.
Kratz M, Gülbahçe E, von Eckardstein A, Cullen P, Cignarella A, Assmann G, Wahrburg U: Dietary mono- and polyunsaturated fatty acids similarly affect LDL size in healthy men and women. J Nutr 2002;132:715–718.
9.
Mori TA, Burke V, Puddey IB, Watts GF, O’Neal DN, Best JD, Beilin LJ: Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am J Clin Nutr 2000;71:1085–1094.
10.
Wooten JS, Biggerstaff KD, Ben-Ezra V: Responses of LDL and HDL particle size and distribution to omega–3 fatty acid supplementation and aerobic exercise. J Appl Physiol 2009;107:794–800.
11.
Austin MA: Genetic epidemiology of low-density lipoprotein subclass phenotypes. Ann Med 1992;24:477–481.
12.
Bavirti S, Ghanaat F, Tayek JA: Peroxisome proliferator-activated receptor-gamma agonist increases both low-density lipoprotein cholesterol particle size and small high-density lipoprotein cholesterol in patients with type 2 diabetes independent of diabetic control. Endocr Pract 2003;9:487–493.
13.
Schoonjans K, Staels B, Auwerx J: The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996;1302:93–109.
14.
Duval C, Muller M, Kersten S: PPARα and dyslipidemia. Biochim Biophys Acta 2007;1771:961–971.
15.
Vohl MC, Lepage P, Gaudet D, Brewer CG, Betard C, Perron P, Houde G, Cellier C, Faith JM, et al: Molecular scanning of the human PPARα gene: association of the L162V mutation with hyperapobetalipoproteinemia. J Lipid Res 2000;41:945–952.
16.
Robitaille J, Brouillette C, Houde A, Lemieux S, Perusse L, Tchernof A, Gaudet D, Vohl MC: Association between the PPARα-L162V polymorphism and components of the metabolic syndrome. J Hum Genet 2004;49:482–489.
17.
Tai ES, Corella D, Demissie S, Cupples LA, Coltell O, Schaefer EJ, Tucker KL, Ordovas JM: Polyunsaturated fatty acids interact with the PPARA-L162V polymorphism to affect plasma triglyceride and apolipoprotein C-III concentrations in the Framingham Heart Study. J Nutr 2005;135:397–403.
18.
Volcik KA, Nettleton JA, Ballantyne CM, Boerwinkle E: Peroxisome proliferator-activated receptor [alpha] genetic variation interacts with n-6 and long-chain n-3 fatty acid intake to affect total cholesterol and LDL-cholesterol concentrations in the Atherosclerosis Risk in Communities Study. Am J Clin Nutr 2008;87:1926–1931.
19.
Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM: mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 1994;8:1224–1234.
20.
Robitaille J, Despres JP, Perusse L, Vohl MC: The PPAR-gamma P12A polymorphism modulates the relationship between dietary fat intake and components of the metabolic syndrome: results from the Québec Family Study. Clin Genet 2003;63:109–116.
21.
Anderson AL, Harris TB, Houston DK, Tylavsky FA, Lee JS, Sellmeyer DE, Sahyoun NR: Relationships of dietary patterns with body composition in older adults differ by gender and PPAR-γ Pro12Ala genotype. Eur J Nutr 2010;49:385–394.
22.
Adamo KB, Dent R, Langefeld CD, Cox M, Williams K, Carrick KM, Stuart JS, Sundseth SS, Harper ME, et al: Peroxisome proliferator-activated receptor gamma 2 and acyl-CoA synthetase 5 polymorphisms influence diet response. Obesity (Silver Spring) 2007;15:1068–1075.
23.
Memisoglu A, Hu FB, Hankinson SE, Manson JE, De Vivo I, Willett WC, Hunter DJ: Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. Hum Mol Genet 2003;12:2923–2929.
24.
Luan J, Browne PO, Harding AH, Halsall DJ, O’Rahilly S, Chatterjee VK, Wareham NJ: Evidence for gene-nutrient interaction at the PPARγ locus. Diabetes 2001;50:686–689.
25.
Franks PW, Jablonski KA, Delahanty L, Hanson RL, Kahn SE, Altshuler D, Knowler WC, Florez JC: The Pro12Ala variant at the peroxisome proliferator-activated receptor gamma gene and change in obesity-related traits in the Diabetes Prevention Program. Diabetologia 2007;50:2451–2460.
26.
Vaccaro O, Lapice E, Monticelli A, Giacchetti M, Castaldo I, Galasso R, Pinelli M, Donnarumma G, Rivellese AA, et al: Pro12Ala polymorphism of the PPARγ2 locus modulates the relationship between energy intake and body weight in type 2 diabetic patients. Diabetes Care 2007;30:1156–1161.
27.
Wagner KD, Wagner N: Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) acts as regulator of metabolism linked to multiple cellular functions. Pharmacol Ther 2010;125:423–435.
28.
Robitaille J, Gaudet D, Perusse L, Vohl MC: Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta –87T>C polymorphism and dietary fat in French-Canadians. Int J Obes (Lond) 2007;31:411–417.
29.
Skogsberg J, Kannisto K, Cassel TN, Hamsten A, Eriksson P, Ehrenborg E: Evidence that peroxisome proliferator-activated receptor delta influences cholesterol metabolism in men. Arterioscler Thromb Vasc Biol 2003;23:637–643.
30.
Gouni-Berthold I, Giannakidou E, Faust M, Berthold HK, Krone W: The peroxisome proliferator-activated receptor delta +294T/C polymorphism in relation to lipoprotein metabolism in patients with diabetes mellitus type 2 and in non-diabetic controls. Atherosclerosis 2005;183:336–341.
31.
Paradis AM, Pérusse L, Godin G, Vohl MC: Validity of a self-reported measure of familial history of obesity. Nutr J 2008;7:27.
32.
Goulet J, Nadeau G, Lapointe A, Lamarche B, Lemieux S: Validity and reproducibility of an interviewer-administered food frequency questionnaire for healthy French-Canadian men and women. Nutr J 2004;3:13.
33.
Albers JJ, Warnick GR, Wiebe D, King P, Steiner P, Smith L, Breckenridge C, Chow A, Kuba K, et al: Multi-laboratory comparison of three heparin-Mn2+ precipitation procedures for estimating cholesterol in high-density lipoprotein. Clin Chem 1978;24:853–856.
34.
Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502.
35.
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.
36.
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.
37.
Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J, Shuldiner AR: Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun 1997;241:270–274.
38.
Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, et al: The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000;26:76–80.
39.
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.
40.
Varady KA, Bhutani S, Klempel MC, Lamarche B: Improvements in LDL particle size and distribution by short-term alternate day modified fasting in obese adults. Br J Nutr 2011;105:580–583.
41.
Kim DS, Kim YK, Kim DS, Chae HJ, Park TS, Cho YI, Jeong SK: Low-density lipoprotein particle size in hepatic steatosis and metabolic syndrome. Diabetol Metab Syndr 2010;2:18.
42.
Berneis KK, Krauss RM: Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 2002;43:1363–1379.
43.
Austin MA, King MC, Vranizan KM, Krauss RM: Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 1990;82:495–506.
44.
Dreon DM, Fernstrom HA, Campos H, Blanche P, Williams PT, Krauss RM: Change in dietary saturated fat intake is correlated with change in mass of large low-density-lipoprotein particles in men. Am J Clin Nutr 1998;67:828–836.
45.
Hihi AK, Michalik L, Wahli W: PPARs: transcriptional effectors of fatty acids and their derivatives. Cell Mol Life Sci 2002;59:790–798.
46.
Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, et al: Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 1999;3:397–403.
47.
Rudkowska I, Garenc C, Couture P, Vohl MC: Omega-3 fatty acids regulate gene expression levels differently in subjects carrying the PPARα L162V polymorphism. Genes Nutr 2009;4:199–205.
48.
Kersten S: Peroxisome proliferator activated receptors and lipoprotein metabolism. PPAR Res 2008;2008:132960.
49.
Wang H, Eckel RH: Lipoprotein lipase: from gene to obesity. Am J Physiol Endocrinol Metab 2009;297:E271–E288.
50.
Jansen H, Hop W, van Tol A, Bruschke AV, Birkenhäger JC: Hepatic lipase and lipoprotein lipase are not major determinants of the low density lipoprotein subclass pattern in human subjects with coronary heart disease. Atherosclerosis 1994;107:45–54.
51.
Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J: A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998;20:284–287.
52.
Wang N: PPAR-δ in vascular pathophysiology. PPAR Res 2008;2008:164163.
53.
Burch LR, Donnelly LA, Doney AS, Brady J, Tommasi AM, Whitley AL, Goddard C, Morris AD, Hansen MK, Palmer CN: Peroxisome proliferator-activated receptor-delta genotype influences metabolic phenotype and may influence lipid response to statin therapy in humans: a genetics of diabetes audit and research Tayside study. J Clin Endocrinol Metab 2010;95:1830–1837.
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