The Pro12Ala substitution in the peroxisome proliferator activated receptor gamma 2 is associated with an insulin-sensitive phenotype in families with familial combined hyperlipidemia and in nondiabetic elderly subjects with dyslipidemia


      Dyslipidemias and insulin resistance often present simultaneously, as in familial combined hyperlipidemia (FCHL), and therefore may have a common genetic background. In our previous study the Pro12Ala substitution of peroxisome proliferator receptor γ 2 (PPARγ2) associated with insulin sensitivity, low body mass index (BMI) and high-density lipoprotein (HDL) cholesterol levels. In this study, we investigated the role of this substitution in dyslipidemias. Therefore, 228 nondiabetic members of FCHL families and 866 nondiabetic elderly subjects with (n=217) and without dyslipidemia (n=649) were genotyped. The allele frequencies of the Pro12Ala substitution did not differ between elderly subjects with or without dyslipidemia or 27 probands with FCHL. However, this substitution was associated with low fasting insulin levels both in FCHL family members (P=0.036 adjusted for gender and age) and elderly subjects with dyslipidemia (P=0.050) but not in elderly subjects without dyslipidemia (P=0.080). In addition, the Ala12 allele of PPARγ2 was associated with low BMI (P=0.034) and low total triglycerides (P=0.027), and increased HDL-cholesterol (P<0.001) in elderly subjects with dyslipidemia (n=299) but not among any other study groups. We conclude that the Ala12 isoform of PPARγ2 ameliorates the insulin resistance and unfavorable lipid and lipoprotein profiles in FCHL and hyperlipidemic elderly subjects.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Laakso M
        • Sarlund H
        • Mykkänen L
        Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance.
        Arteriosclerosis. 1990; 10: 223-231
        • Taskinen M
        Insulin resistance and lipoprotein metabolism.
        Curr. Opin. Lipidol. 1995; 6: 153-160
        • Karhapää P
        • Voutilainen E
        • Malkki M
        • Laakso M
        Obese men with type IIB hyperlipidemia are insulin resistant.
        Arterioscler. Thromb. 1993; 13: 1469-1475
        • Goldstein J
        • Schrott H
        • Hazzard W
        • Bierman E
        • Motulsky A
        Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia.
        J. Clin. Invest. 1973; 52: 1544-1568
        • Nikkilä E
        • Aro A
        A family study of lipids and lipoproteins in coronary heart disease.
        Lancet. 1973; 1: 954-958
        • Aitman T
        • Godsland I
        • Farren B
        • Crook D
        • Wong J
        • Scott J
        Defects in insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 748-754
        • Bredie S
        • Cees J
        • Smits P
        • Stalenhoef A
        Nonobese patients with familial combined hyperlipidemia are insulin resistant compared with their nonaffected relatives.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1465-1471
        • Ascaso J
        • Merchante A
        • Lorente R.I
        • Real J
        • Martinez-Valls J
        • Carmena R
        A study of insulin resistance using the minimal model in nondiabetic familial combined hyperlipidemic patients.
        Metabolism. 1998; 47: 508-513
        • Karjalainen L
        • Pihlajamäki J
        • Karhapää P
        • Laakso M
        Impaired insulin-stimulated glucose oxidation and free fatty acid suppression in patients with familial combined hyperlipidemia-a precursor defect for dyslipidemias.
        Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1548-1553
        • Arner P
        Is familial combined hyperlipidaemia a genetic disorder of adipose tissue.
        Curr. Opin. Lipidol. 1997; 8: 89-94
        • de Graaf J
        • Stalenhoef A
        Defects of lipoprotein metabolism in familial combined hyperlipidemia.
        Curr. Opin. Lipidol. 1998; 9: 189-196
        • Schoonjans K
        • Martin G
        • Staels B
        • Auwerx J
        Peroxisome proliferator-activated receptors, orphans with ligands and functions.
        Curr. Opin. Lipidol. 1997; 8: 159-166
        • Spiegelman B
        PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.
        Diabetes. 1998; 47: 507-514
        • Zhu Y
        • Qi C
        • Korenberg J.R
        • Chen X.N
        • Noya D
        • Rao M.S
        • et al.
        Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms.
        Proc. Natl. Acad. Sci. 1995; 92: 7921-7925
        • Fajas L
        • Auboeuf D
        • Raspe E
        • Schoonjans K
        • Lefebvre A.M
        • Saladin R
        • et al.
        The organization, promoter analysis, and expression of the human PPARgamma gene.
        J. Biol. Chem. 1997; 272: 18779-18789
        • Fajas L
        • Fruchart J
        • Auwerx J
        PPARg3 mRNA: a distinct PPARg mRNA subtype transcribed from an independent promoter.
        FEBS. Lett. 1998; 438: 55-60
        • Kliewer S
        • Lenhard J
        • Willson T
        • Patel I
        • Morris D
        • Lehman J
        Cell 83 — a prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor g and promotes adipocyte differentiation.
        Cell. 1995; 83: 813-819
        • Forman B.M
        • Tontonoz P
        • Chen J
        • Brun R.P
        • Spiegelman B.M
        • Evans R.M
        15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma.
        Cell. 1995; 83: 803-812
        • Lehmann J.M
        • Moore L.B
        • Smith Oliver T.A
        • Wilkison W.O
        • Willson T.M
        • Kliewer S.A
        An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).
        J. Biol. Chem. 1995; 270: 12953-12966
        • Berger J
        • Bailey P
        • Biswas C
        • Cullinan C
        • Doebber T
        • Hayes N
        • et al.
        Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-g: binding and activation correlate with antidiabetic actions in db/db mice.
        Endocrinology. 1996; 137: 4189-4195
        • Hu E
        • Kim J
        • Sarraf P
        • Spiegelman B
        Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma.
        Science. 1996; 274: 2100-2103
        • Zhang B
        • Berger J
        • Zhou G
        • Elbrecht A
        • Biswas S
        • White-Carrington S
        • et al.
        Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor gamma.
        J. Biol. Chem. 1996; 271: 31771-31774
        • Adams M
        • Reginato M
        • Shao D
        • Lazar M
        • Chatterjee V
        Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site.
        J. Biol. Chem. 1997; 272: 5128-5132
        • Camp H
        • Tafuri S
        Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase.
        J. Biol. Chem. 1997; 272: 10811-10816
        • Werman A
        • Hollenberg A
        • Solanes G
        • Bjorbaek C
        • Vidal Puig A.J
        • Flier J.S
        Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin.
        J. Biol. Chem. 1997; 272: 20230-20235
        • Deeb S
        • Fajas L
        • Nemoto M
        • Pihlajamäki J
        • Mykkänen L
        • Kuusisto J
        • et al.
        A Pro12Ala substitution in the human peroxisome proliferator activated receptor gamma 2 is associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.
        Nature Genet. 1998; 20: 284-287
        • Ristow M
        • Muller-Wieland D
        • Pfeiffer A
        • Krone W
        • Kahn C
        Obesity associated with a mutation in a genetic regulator of adipocyte differentiation.
        NEJM. 1998; 339: 953-959
        • Meirhaeghe A
        • Fajas L
        • Helbecque N
        • Cottel D
        • Lebel P
        • Dallongeville J
        • et al.
        A genetic polymorphism of the peroxisome profilerator-activated receptor gamma gene influences plasma leptin levels in obese humans.
        Hum. Mol. Genet. 1997; 7: 435-440
        • De la Chapelle A
        Disease gene mapping in isolated human populations the example of Finland.
        J. Med. Genet. 1993; 30: 857-865
        • Kittles R
        • Perola M
        • Peltonen L
        • Bergen A
        • Aragon R
        • Virkkunen M
        • et al.
        Dual origins of Finns revealed by Y chromosome haplotype variation.
        Am. J. Hum. Genet. 1998; 62: 1171-1179
        • Voutilainen E
        Serum lipids and lipoproteins in male survivors of acute myocardial infarction and their first-degree relatives: a case-control study. Kuopio University Publications, Kuopio, Finland1992
        • Koivisto U
        • Hämäläinen L
        • Taskinen M
        • Kettunen K
        • Kontula K
        Prevalence of familial hypercholesterolemia among young north Karelian patients with coronary heart disease: a study based on diagnosis by polymerase chain reaction.
        J. Lipid Res. 1993; 34: 269-277
        • Mykkänen L
        • Laakso M
        • Uusitupa M
        • Pyörälä K
        Prevalence of diabetes and impaired glucose tolerance in elderly subjects and their association with obesity and family history of diabetes.
        Diabetes Care. 1990; 11: 1099-1105
        • Mykkanen L
        • Kuusisto J
        • Pyorala K
        • Laakso M
        Cardiovascular disease risk factors as predictors of type 2 (non-insulin-dependent) diabetes mellitus in elderly subjects.
        Diabetologia. 1993; 36: 553-559
      1. Diabetes mellitus: report of a WHO study group. Geneva, Switzerland: World Health Organization, 1985.

        • Penttilä I
        • Voutilainen E
        • Laitinen P
        • Juutilainen P
        Comparison of different analytical and precipitation methods for the direct estimation of serum high density lipoprotein cholesterol.
        Scand. J. Clin. Lab. Invest. 1984; 41: 353-360
        • Kretz K
        • Carson G
        • O’Brien J
        Direct sequencing from low-melt agarose with sequenase.
        Nucleic Acid Res. 1989; 17: 58-64
        • George V
        • Elston R
        Testing the association between quantitative traits and polymorphic markers in pedigrees.
        Genet. Epidemiol. 1987; 4: 193-201
        • Reaven G
        Role of insulin resistance in human disease.
        Diabetes. 1988; 37: 1595-1607
        • Kwiterovich P
        Genetics and molecular biology of familial combined hyperlipidemia.
        Curr. Opin. Lipidol. 1993; 4: 133-143
        • Nevin D
        • Brunzell J
        • Deeb S
        The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity.
        Arterioscler. Thromb. 1994; 14: 869-873
        • Wojciechowski A.P
        • Farrall M
        • Cullen P
        • Wilson T.M
        • Bayliss J.D
        • Farren B
        • et al.
        Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23-q24.
        Nature. 1991; 349: 161-164
        • Dallinga Thie G.M
        • Bu X.D
        • van Linde Sibenius Trip M
        • Rotter J.I
        • Lusis A.J
        • de Bruin T.W
        Apolipoprotein A-I/C-III/A-IV gene cluster in familial combined hyperlipidemia: effects on LDL-cholesterol and apolipoproteins B and C-III.
        J. Lipid Res. 1996; 37: 136-147
        • Wijsman E.M
        • Brunzell J.D
        • Jarvik G.P
        • Austin M.A
        • Motulsky A.G
        • Deeb S.S
        Evidence against linkage of familial combined hyperlipidemia to the apolipoprotein AI–CIII–AIV gene complex.
        Arterioscler. Thromb. Vasc. Biol. 1998; 18: 215-226
        • Tahvanainen E
        • Pajukanta P
        • Porkka K
        • Nieminen S
        • Ikävalko L
        • Nuotio I
        • et al.
        Haplotypes of the apoA-I/C-III/A-IV gene cluster and familial combined hyperlipidemia.
        Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1810-1817
        • Pajukanta P
        • Nuotio I
        • Terwilliger J
        • Porkka K
        • Ylitalo K
        • Pihlajamäki J
        • et al.
        Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.
        Nature Genet. 1998; 18: 369-373
        • Sniderman A
        • Cianflone K
        Substrate delivery as a determinant of hepatic apoB secretion.
        Arterioscler. Thromb. 1993; 13: 629-636
        • Randle P
        • Hales C
        • Garland P
        • Newsholme E
        The glucose fatty acid cycle and its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.
        Lancet. 1963; 1: 785-789
        • Beamer B
        • Yen C
        • Andersen R
        • Muller D
        • Elahi D
        • Cheskin L
        • et al.
        Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two caucasian populations.
        Diabetes. 1998; 47: 1806-1808