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The V227A polymorphism at the PPARA locus is associated with serum lipid concentrations and modulates the association between dietary polyunsaturated fatty acid intake and serum high density lipoprotein concentrations in Chinese women

      Abstract

      Peroxisome proliferators activated receptor α (PPARα) regulates the transcription of several proteins involved in human lipoprotein metabolism. We screened the PPARA locus for polymorphisms in 20 unrelated subjects from each of three ethnic groups (Chinese, Malays and Asian Indians). Only the V227A polymorphism was observed. We genotyped 4248 subjects (2899 Chinese, 761 Malay and 588 Asian Indians) and found allele frequencies for the A227 allele of 0.04 in Chinese, 0.006 in Malays and 0.003 in Asian Indians. We examined the associations between this polymorphism and serum lipid concentrations in Chinese. In women, but not in men, the presence of the A227 allele was associated with lower serum concentrations of total cholesterol [5.38 mmol/l (95%CI: 5.22–5.54) versus 5.21 mmol/l (95%CI: 4.99–5.43), p = 0.047] and triglycerides [1.19 mmol/l (95%CI: 1.10–1.28) versus 1.09 mmol/l (95%CI: 0.98–1.21), p = 0.048]. We also found that the V227A polymorphism modulates the association between dietary polyunsaturated fatty acid intake and serum high density lipoprotein concentration (p-value for interaction = 0.049). Our findings implicate PPARα in the lipid lowering associated with diets high in PUFA and suggests that genetic variation at the PPARA locus may determine the lipid response to changes in PUFA intake.

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      References

        • Torra I.P.
        • Chinetti G.
        • Duval C.
        • Fruchart J.C.
        • Staels B.
        Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice.
        Curr Opin Lipidol. 2001; 12: 245-254
        • Evans D.
        • Aberle J.
        • Wendt D.
        • Wolf A.
        • Beisiegel U.
        • Mann W.A.
        A polymorphism, L162V, in the peroxisome proliferator-activated receptor alpha (PPARalpha) gene is associated with lower body mass index in patients with non-insulin-dependent diabetes mellitus.
        J Mol Med. 2001; 79: 198-204
        • Flavell D.M.
        • Jamshidi Y.
        • Hawe E.
        • et al.
        Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease.
        Circulation. 2002; 105: 1440-1445
        • Flavell D.M.
        • Pineda Torra I.
        • Jamshidi Y.
        • et al.
        Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects.
        Diabetologia. 2000; 43: 673-680
        • Lacquemant C.
        • Lepretre F.
        • Pineda Torra I.
        • et al.
        Mutation screening of the PPARalpha gene in type 2 diabetes associated with coronary heart disease.
        Diabetes Metab. 2000; 26: 393-401
        • Sapone A.
        • Peters J.M.
        • Sakai S.
        • et al.
        The human peroxisome proliferator-activated receptor alpha gene: identification and functional characterization of two natural allelic variants.
        Pharmacogenetics. 2000; 10: 321-333
        • Tai E.S.
        • Demissie S.
        • Cupples L.A.
        • et al.
        Association between the PPARA L162V polymorphism and plasma lipid levels: the Framingham Offspring Study.
        Arterioscler Thromb Vasc Biol. 2002; 22: 805-810
        • Vohl M.C.
        • Lepage P.
        • Gaudet D.
        • et al.
        Molecular scanning of the human PPARa gene: association of the L162v mutation with hyperapobetalipoproteinemia.
        J Lipid Res. 2000; 41: 945-952
        • Bosse Y.
        • Pascot A.
        • Dumont M.
        • et al.
        Influences of the PPAR alpha-L162V polymorphism on plasma HDL(2)-cholesterol response of abdominally obese men treated with gemfibrozil.
        Genet Med. 2002; 4: 311-315
        • Brisson D.
        • Ledoux K.
        • Bosse Y.
        • et al.
        Effect of apolipoprotein E, peroxisome proliferator-activated receptor alpha and lipoprotein lipase gene mutations on the ability of fenofibrate to improve lipid profiles and reach clinical guideline targets among hypertriglyceridemic patients.
        Pharmacogenetics. 2002; 12: 313-320
        • Price P.T.
        • Nelson C.M.
        • Clarke S.D.
        Omega-3 polyunsaturated fatty acid regulation of gene expression.
        Curr Opin Lipidol. 2000; 11: 3-7
        • Sessler A.M.
        • Ntambi J.M.
        Polyunsaturated fatty acid regulation of gene expression.
        J Nutr. 1998; 128: 923-926
        • Tai E.S.
        • Corella D.
        • Demissie S.
        • et al.
        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
        • Tai E.S.
        • Ordovas J.M.
        • Corella D.
        • et al.
        The TaqIB and -629C>A polymorphisms at the cholesteryl ester transfer protein locus: associations with lipid levels in a multiethnic population. The 1998 Singapore National Health Survey.
        Clin Genet. 2003; 63: 19-30
        • American College of Sports Medicine
        Position stand: the recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in health adults.
        Med Sci Sports Exerc. 1998; 30
        • Centers for Disease Control & Prevention
        Behavioural Risk Factor Surveillance System Questionnaire.
        Department of Health and Human Services, 1998
      1. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183–97.

        • Deurenberg-Yap M.
        • Li T.
        • Tan W.L.
        • van Staveren W.A.
        • Chew S.K.
        • Deurenberg P.
        Can dietary factors explain differences in serum cholesterol profiles among different ethnic groups (Chinese, Malays and Indians) in Singapore?.
        Asia Pac J Clin Nutr. 2001; 10: 39-45
        • Hara M.
        • Wang X.
        • Paz V.P.
        • et al.
        Identification of three missense mutations in the peroxisome proliferator-activated receptor alpha gene in Japanese subjects with maturity-onset diabetes of the young.
        J Hum Genet. 2001; 46: 285-288
        • Yamakawa-Kobayashi K.
        • Ishiguro H.
        • Arinami T.
        • Miyazaki R.
        • Hamaguchi H.
        A Val227Ala polymorphism in the peroxisome proliferator activated receptor alpha (PPARalpha) gene is associated with variations in serum lipid levels.
        J Med Genet. 2002; 39: 189-191
        • Cobb M.M.
        • Risch N.
        Low-density lipoprotein cholesterol responsiveness to diet in normolipidemic subjects.
        Metabolism. 1993; 42: 7-13
        • Cobb M.M.
        • Teitlebaum H.
        Determinants of plasma cholesterol responsiveness to diet.
        Br J Nutr. 1994; 71: 271-282
        • Jacobs D.R.
        • Anderson J.T.
        • Hannan P.
        • Keys A.
        • Blackburn H.
        Variability in individual serum cholesterol response to change in diet.
        Arteriosclerosis. 1983; 3: 349-356
        • Katan M.B.
        • Beynen A.C.
        • de Vries J.H.
        • Nobels A.
        Existence of consistent hypo- and hyperresponders to dietary cholesterol in man.
        Am J Epidemiol. 1986; 123: 221-234
        • O’ Hanesian M.A.
        • Rosner B.
        • Bishop L.M.
        • Sacks F.M.
        Effects of inherent responsiveness to diet and day-to-day diet variation on plasma lipoprotein concentrations.
        Am J Clin Nutr. 1996; 64: 53-59
        • Mahaney M.C.
        • Blangero J.
        • Rainwater D.L.
        • et al.
        Pleiotropy and genotype by diet interaction in a baboon model for atherosclerosis: a multivariate quantitative genetic analysis of HDL subfractions in two dietary environments.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1134-1141
        • Rainwater D.L.
        • Kammerer C.M.
        • Hixson J.E.
        • et al.
        Two major loci control variation in beta-lipoprotein cholesterol and response to dietary fat and cholesterol in baboons.
        Arterioscler Thromb Vasc Biol. 1998; 18: 1061-1068
        • Rainwater D.L.
        • Kammerer C.M.
        • VandeBerg J.L.
        Evidence that multiple genes influence baseline concentrations and diet response of Lp(a) in baboons.
        Arterioscler Thromb Vasc Biol. 1999; 19: 2696-2700
        • Ordovas J.M.
        Gene–diet interaction and plasma lipid responses to dietary intervention.
        Biochem Soc Trans. 2002; 30: 68-73
        • Lichtenstein A.H.
        • Ausman L.M.
        • Jalbert S.M.
        • Schaefer E.J.
        Effects of different forms of dietary hydrogenated fats on serum lipoprotein cholesterol levels.
        N Engl J Med. 1999; 340: 1933-1940
        • Jalouli M.
        • Carlsson L.
        • Ameen C.
        • et al.
        Sex difference in hepatic peroxisome proliferator-activated receptor alpha expression: influence of pituitary and gonadal hormones.
        Endocrinology. 2003; 144: 101-109
        • Campbell S.E.
        • Mehan K.A.
        • Tunstall R.J.
        • Febbraio M.A.
        • Cameron-Smith D.
        17beta-estradiol upregulates the expression of peroxisome proliferator-activated receptor alpha and lipid oxidative genes in skeletal muscle.
        J Mol Endocrinol. 2003; 31: 37-45
        • Costet P.
        • Legendre C.
        • More J.
        • Edgar A.
        • Galtier P.
        • Pineau T.
        Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis.
        J Biol Chem. 1998; 273: 29577-29585
        • Djouadi F.
        • Weinheimer C.J.
        • Saffitz J.E.
        • et al.
        A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha-deficient mice.
        J Clin Invest. 1998; 102: 1083-1091
        • Yoon M.
        • Jeong S.
        • Nicol C.J.
        • et al.
        Fenofibrate regulates obesity and lipid metabolism with sexual dimorphism.
        Exp Mol Med. 2002; 34: 481-488
        • Puckey L.H.
        • Knight B.L.
        Interaction of oestrogen and peroxisome proliferator-activated receptors with apolipoprotein(a) gene enhancers.
        Biochem J. 2002; 366: 157-163
      2. The BIP study group, Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;102:21–7.

        • Robins S.J.
        • Rubins H.B.
        • Faas F.H.
        • et al.
        Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT).
        Diabetes Care. 2003; 26: 1513-1517
        • Tenkanen L.
        • Manttari M.
        • Manninen V.
        Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil. Experience from the Helsinki Heart Study.
        Circulation. 1995; 92: 1779-1785