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Analysis of the effect of multiple genetic variants of cardiovascular disease risk on insulin concentration variability in healthy adults of the STANISLAS cohort

The role of FGB −455 G/A polymorphism

      Abstract

      Introduction

      Given the hypothesis of a common soil for atherosclerosis, type 2 diabetes and metabolic syndrome, we tested the contribution of gene polymorphisms involved in cardiovascular diseases on fasting insulin concentration (FIC).

      Methods

      The polymorphisms were investigated by a multiplex assay in 308 apparently healthy French middle-aged men and women, taken from the STANISLAS cohort. FIC was measured by a microparticular enzymatic immunoassay.

      Results

      After a series of regression analyses involving 34 polymorphisms, FGB455G/A was the only polymorphism that remained significantly associated with FIC when adjusting the analyses for multiple testing. Stepwise models showed that FGB polymorphism accounted for 4.39% of FIC variability in men. Additionally, interactions between FGB and with environmental factors (alcohol and smoking in men, and BMI in women) were found.

      Discussion

      To our knowledge, this is the first study reporting an influence of FGB polymorphism on FIC in a healthy population. Our results concord with the already shown link between fibrinogen concentration and FIC, and support the hypothesis of a relationship between fibrinogen and endothelium in FIC homeostasis whose alteration may induce several metabolic disorders. The contribution of this gene, although modest, is consistent with the polygenic nature of insulin levels.

      Keywords

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      References

        • Stern M.P.
        Diabetes and cardiovascular disease. The “common soil” hypothesis.
        Diabetes. 1995; 44: 369-374
        • Undlien D.E.
        • Berg J.P.
        Common variants in the regulatory region of the insulin gene are associated with fasting plasma insulin levels in juvenile obesity.
        Eur J Endocrinol. 2001; 144: 457-459
        • Urhammer S.A.
        • Fridberg M.
        • Hansen T.
        • et al.
        A prevalent amino acid polymorphism at codon 98 in the hepatocyte nuclear factor-1alpha gene is associated with reduced serum C-peptide and insulin responses to an oral glucose challenge.
        Diabetes. 1997; 46: 912-916
        • Duggirala R.
        • Stern M.P.
        • Mitchell B.D.
        • et al.
        Quantitative variation in obesity-related traits and insulin precursors linked to the OB gene region on human chromosome 7.
        Am J Hum Genet. 1996; 59: 694-703
        • Mitchell B.D.
        • Cole S.A.
        • Hsueh W.C.
        • et al.
        Linkage of serum insulin concentrations to chromosome 3p in Mexican Americans.
        Diabetes. 2000; 49: 513-516
        • Feng Y.
        • Niu T.
        • Xu X.
        • et al.
        Insertion/deletion polymorphism of the ACE gene is associated with type 2 diabetes.
        Diabetes. 2002; 51: 1986-1988
        • Cong N.D.
        • Hamaguchi K.
        • Saikawa T.
        • Hara M.
        • Sakata T.
        The I/D polymorphism of angiotensin-converting enzyme gene but not the angiotensinogen gene is associated with insulin response to oral glucose in Japanese.
        Proc Soc Exp Biol Med. 1999; 220: 46-51
        • Russo G.T.
        • Meigs J.B.
        • Cupples L.A.
        • et al.
        Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study.
        Atherosclerosis. 2001; 158: 173-181
        • Perez-Jimenez F.
        • Lopez-Miranda J.
        • Gomez P.
        • et al.
        The SstI polymorphism of the apo C-III gene is associated with insulin sensitivity in young men.
        Diabetologia. 2002; 45: 1196-1200
        • van’t Hooft F.M.
        • von Bahr S.J.
        • Silveira A.
        • et al.
        Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration.
        Arterioscler Thromb Vasc Biol. 1999; 19: 3063-3070
        • Thomas A.E.
        • Green F.R.
        • Lamlum H.
        • Humphries S.E.
        The association of combined alpha and beta fibrinogen genotype on plasma fibrinogen levels in smokers and non-smokers.
        J Med Genet. 1995; 32: 585-589
        • Carter A.M.
        • Mansfield M.W.
        • Stickland M.H.
        • Grant P.J.
        Beta-fibrinogen gene -455 G/A polymorphism and fibrinogen levels. Risk factors for coronary artery disease in subjects with NIDDM.
        Diab Care. 1996; 19: 1265-1268
        • Kessler C.
        • Spitzer C.
        • Stauske D.
        • et al.
        The apolipoprotein E and beta-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease.
        Arterioscler Thromb Vasc Biol. 1997; 17: 2880-2884
        • Humphries S.E.
        • Ye S.
        • Talmud P.
        • et al.
        European Atherosclerosis Research Study: genotype at the fibrinogen locus (G-455-A beta-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Evidence for gender–genotype–environment interaction.
        Arterioscler Thromb Vasc Biol. 1995; 15: 96-104
        • de Maat M.P.
        • Kastelein J.J.
        • Jukema J.W.
        • et al.
        -455G/A polymorphism of the beta-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. REGRESS group.
        Arterioscler Thromb Vasc Biol. 1998; 18: 265-271
        • Imperatore G.
        • Riccardi G.
        • Iovine C.
        • Rivellese A.A.
        • Vaccaro O.
        Plasma fibrinogen: a new factor of the metabolic syndrome. A population-based study.
        Diab Care. 1998; 21: 649-654
        • Siest G.
        • Visvikis S.
        • Herbeth B.
        • et al.
        Objectives, design and recruitment of a familial and longitudinal cohort for studying gene–environment interactions in the field of cardiovascular risk: the Stanislas cohort.
        Clin Chem Lab Med. 1998; 36: 35-42
        • Mansour-Chemaly M.
        • Haddy N.
        • Siest G.
        • Visvikis S.
        Family studies: their role in the evaluation of genetic cardiovascular risk factors.
        Clin Chem Lab Med. 2002; 40: 1085-1096
        • Matthews D.R.
        • Hosker J.P.
        • Rudenski A.S.
        • et al.
        Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • Ponthieux A.
        • Herbeth B.
        • Droesch S.
        • et al.
        Biological determinants of serum ICAM-1, E-selectin, P-selectin and L-selectin levels in healthy subjects: the Stanislas study.
        Atherosclerosis. 2004; 172: 299-308
        • Miller S.A.
        • Dykes D.D.
        • Polesky H.F.
        A simple salting out procedure for extracting DNA from human nucleated cells.
        Nucleic Acids Res. 1988; 16: 1215
        • Cheng S.
        • Pallaud C.
        • Grow M.A.
        • et al.
        A multilocus genotyping assay for cardiovascular disease.
        Clin Chem Lab Med. 1998; 36: 561-566
        • Hoppe C.
        • Klitz W.
        • Cheng S.
        • et al.
        • CSSCD Investigators
        Gene interactions and stroke risk in children with sickle cell anemia.
        Blood. 2004; 103: 2391-2396
        • Altshuler D.
        • Hirschhorn J.N.
        • Klannemark M.
        • et al.
        The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.
        Nat Genet. 2000; 26: 76-80
        • Luan J.
        • Browne P.O.
        • Harding A.H.
        • et al.
        Evidence for gene-nutrient interaction at the PPARgamma locus.
        Diabetes. 2001; 50: 686-689
        • Mancini F.P.
        • Vaccaro O.
        • Sabatino L.
        • et al.
        Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes.
        Diabetes. 1999; 48: 1466-1468
        • Meirhaeghe A.
        • Fajas L.
        • Helbecque N.
        Impact of the Peroxisome Proliferator Activated Receptor gamma2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus.
        Int J Obes Relat Metab Disord. 2000; 24: 195-199
        • Kamath S.
        • Lip G.Y.
        Fibrinogen: biochemistry, epidemiology and determinants.
        QJM. 2003; 96: 711-729
        • Dunn E.J.
        • Ariens R.A.
        Fibrinogen and fibrin clot structure in diabetes.
        Herz. 2004; 29: 470-479
        • Green F.
        • Hamsten A.
        • Blomback M.
        • Humphries S.
        The role of β-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infection and healthy controls from Sweden.
        Thromb Haemost. 1993; 70: 915-920
        • Behague I.
        • Poirier O.
        • Nicaud V.
        • et al.
        Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins sur l’Infarctus du Myocarde.
        Circulation. 1996; 93: 440-449
        • Scarabin P.Y.
        • Bara L.
        • Ricard S.
        • et al.
        Genetic variation at the β-fibrinogen locus in relation to fibrinogen concentrations and risk of myocardial infarction: the ECTIM study.
        Arterioscler Thromb. 1993; 13: 886-891
        • Smith G.D.
        • Harbord R.
        • Milton J.
        • Ebrahim S.
        • Sterne J.A.
        Does elevated plasma fibrinogen increase the risk of coronary heart disease? Evidence from a meta-analysis of genetic association studies.
        Arterioscler Thromb Vasc Biol. 2005; 25: 2228-2233
        • Reinhart W.H.
        Fibrinogen—marker or mediator of vascular disease?.
        Vasc Med. 2003; 8: 211-216
        • Pallaud C.
        • Sass C.
        • Zannad F.
        • Siest G.
        • Visvikis S.
        APOC3, CETP, fibrinogen, and MTHFR are genetic determinants of carotid intima-media thickness in healthy men (the Stanislas cohort).
        Clin Genet. 2001; 59: 316-324
        • Hsueh W.A.
        • Lyon C.J.
        • Quinones M.J.
        Insulin resistance and the endothelium.
        Am J Med. 2004; 117: 109-117
        • Rabe T.
        • Runnebaum B.
        Update on oral contraception.
        Eur J Obstet Gynecol Reprod Biol. 1993; 49: 10-12