DNA-Polymorphisms and Plasma Levels of Vascular Disease Risk Factors in Greenland Inuit

Summary

Greenland Inuit are a population with a low risk of cardiovascular disease. Recently, we stated that frequencies of potentially high risk alleles of the apolipoproteins, fibrinogen, factor V, glycoprotein IIIa and factor VII (FVII) genes have different allele frequencies in the Inuit when compared with Caucasian populations. We have extended this study and evaluated whether or not this was also true for the genetic polymorphisms of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), angiotensin-converting enzyme (ACE) and angiotensinogen in a group of 133 Greenland Inuit, aged 30-34 y. In addition, we compared the plasma levels of these factors and those of C-reactive protein (CRP) and D-Dimer in Inuit and in Danes, comparable for age and gender. Frequencies (f) were assessed of the alleles that are known as the potential high risk alleles in Caucasians.

In the Inuit, the f(insertion allele) of the t-PA intron8ins311 polymorphism was 0.37 (CI 0.32-0.43), the f(4G allele) of the PAI-1 promoter polymorphism was 0.88 (CI 0.83-0.91), the f(deletion allele) of the ACE intron16ins287 polymorphism was 0.40 (CI 0.33-0.47) and the f(M-allele) of the angiotensinogen M/T353 polymorphism was 0.30 (CI 0.25-0.38). As for fibrinogen and FVII polymorphisms, these frequencies are all significantly different from what is reported for Caucasian populations. In the Inuit, plasma levels of fibrinogen and D-Dimer were higher than in the Danes, the PAI-1 levels were lower and FVII, t-PA and CRP levels were comparable. The observed allele frequencies of the polymorphisms of t-PA, fibrinogen, FVII, ACE, angiotensinogen and the plasma levels of PAI-1 and D-Dimer were in accordance with the low CVD risk in the Inuit, considering the observed associations between these measures and CVD risk in Caucasian populations, but for other measures this was not the case (allele frequencies of the PAI-1 polymorphism, and plasma levels of fibrinogen, FVII and t-PA).

In conclusion there are clear differences in genetic background and plasma levels of risk factors in Greenland Inuit compared with Caucasian populations, and these differences were sometimes, but not always, in accordance with the observed low cardiovascular disease risk of the Inuit population.

• References

• 1 Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr 1980; 33: 2657-61.
• 2 Dyerberg J, Bang HO. A hypothesis on the development of acute myocardial infarction in Greenlanders. Scand J Clin Lab Invest 1982; 42: 7-13.
• 3 Bang HO, Dyerberg J, Nielsen AB. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet 1971; i: 1143-6.
• 4 de Knijff P, Johansen LG, Rosseneu M, Frants RR, Jespersen J, Havekes LM. Lipoprotein profile of a Greenland Inuit population. Arterioscler Thromb 1992; 12: 1371-9.
• 5 Hansen JPH, Hancke S, Møller-Petersen J. Atherosclerosis in native Greenlanders. An ultrasonographic investigation. Arctic Med Res 1990; 49: 151-6.
• 6 Ingeman-Nielsen MW. Arteriosclerosis in Greenlanders. Ugeskr Laeger 1990; 152: 2641-3.
• 7 Bjerregaard P, Mulvad G, Pedersen HS. Cardiovascular risk factors in Inuit of Greenland. Int J Epid 1997; 26: 1182-90.
• 8 Bjerregaard P, Young TK. The circumpolar Inuit, health of a population in transition. Munksgaard, Copenhagen 1998
• 9 Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1994; 118: 956-63.
• 10 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: Principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533-7.
• 11 Heinrich J, Balleisen L, Schulte H, Assmann G, Van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: Results from the PROCAM study in healthy men. Arterioscler Thromb 1994; 14: 54-9.
• 12 Assmann G, Cullen P, Heinrich J, Schulte H. Hemostatic variables in the prediction of coronary risk: results of the 8 year follow-up of healthy men in the Münster Heart Study (PROCAM). Isr J Med Sci 1996; 32: 364-70.
• 13 Ridker PM, Hennekens CH, Cerskus A, Stampfer MJ. Plasma concentration of cross-linked fibrin degradation product (D-Dimer) and the risk of futuremyocardial infarction among apparently healthy men. Circulation 1994; 90: 2236-40.
• 14 Gram J, Jespersen J. A simplified estimation of tissue plasminogen activator (t-PA) inhibition in human plasma. Fibrinolysis 1987; 1: 33-7.
• 15 Hamsten A, de Faire U, Waldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
• 16 Green F, Kelleher C, Wilkes H, Temple A, Mease T, Humphries S. A common genetic polymorphism associates with lower coagulation factor VII levels in healthy individuals. Arterioscler Thrombos 1991; 11: 540-6.
• 17 Lane A, Cruickshank JK, Mitchell J, Henderson A, Humphries S, Green FR. Genetic and environmental determinants of factor VII coagulant activity in ethnic groups at differing risk of coronary heart disease. Atherosclerosis 1992; 94: 43-50.
• 18 Lane A, Green F, Scarabin PY, Nicaud V, Bara L, Humphries S, Evans A, Luc G, Cambou JP, Arveiler D, Cambien F. Factor VII Arg/Gln353 polymorphism determines factor VII coagulant activity in patients with myocardial infarction (MI) and control subjects in Belfast and in France but is not a strong indicator of MI risk in the ECTIM study. Atherosclerosis 1996; 119: 119-27.
• 19 Dawson S, Wiman B, Hamsten A, Green F, Humphries S, Henney A. The two allele sequencies of a common polymorphism in the promoter of plasminogen activator inhibitor-1 gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-45.
• 20 van der Bom JG, de Knijff P, Haverkate F, Bots M, Meijer P, de Jong PTVM, Hofman A, Kluft C, Grobbee DE. Tissue plasminogen activator and risk of myocardial infarction. The Rotterdam Study. Circulation 1997; 95: 2623-7.
• 21 Eriksson P, Kallin B, van’t Hooft FM, Båvenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-5.
• 22 Cambien F, Porer O, Lecerf L, Evans A, Cambou J, Arveiler D, Luc G, Bard J, Bara L, Ricard S, Tiret L, Amouyel P, Alhenc-Gelas F, Soubrier F. Deletion polymorphism in the gene for angiotensin converting enzyme is a potent risk factor for myocardial infarction. Nature 1992; 359: 641-4.
• 23 Samani NJ, Thompson JR, O’Toole L, Channer K, Woods KL. A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. Circulation 1996; 94: 708-12.
• 24 Ishigami T, Umemura S, Iwamoto T, Tamura K, Hibi K, Yamaguchi S, Nyuui N, Kimura K, Miyazaki N, Ishii M. Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis. Circulation 1995; 91: 951-4.
• 25 Klausen IC, Gerdes LU, Schmidt EB, Dyerberg J, Faergeman O. Differences in apolipoprotein(a) polymorphisms in West Greenland Eskimos and Caucasian Danes. Hum Genet 1992; 89: 384-8.
• 26 Harvald B. Genetic epidemiology of Greenland. Clin Genet 1989; 36: 364-7.
• 27 de Maat MPM, de Knijff P, Green FR, Thomas AE, Jespersen J, Kluft C. Gender-related association between β-fibrinogen genotype and plasma fibrinogen levels and linkage disequilibrium at the fibrinogen locus in Greenland Inuit. Arterioscler Thromb Vasc Biol 1995; 15: 856-60.
• 28 De Maat MPM, Kluft C, Jespersen J, Gram J. World distribution of factor V Leiden mutation. Letter. Lancet 1996; 347: 58
• 29 De Maat MPM, Green F, de Knijff P, Jespersen J, Kluft C. Factor VII polymorphisms in populations with different risk of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997; 17: 1918-23.
• 30 de Maat MPM, Bladbjerg EM, Johansen LG, Bentzen J, Jespersen J. PlA1/A2 polymorphism of platelet glycoprotein IIIa and risk of cardiovascular disease. Lancet 1997; 349: 1099
• 31 Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promoter region of the β fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost 1991; 65: 487-90.
• 32 Thomas A, Lamlum H, Humphries S, Green F. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A^-455 (HaeIII), C/T^-148 (HindIII/AluI), T/G⁺¹⁶⁸⁹ (AvaII), and BclI (β-fibrinogen) and TaqI (α-fibrinogen), and their detection by PCR. Human Mutation 1994; 3: 79-81.
• 33 Marchetti G, Gemmati D, Patracchini P, Pinotti M, Bernardi F. PCR detection of a repeat polymorphism within the F7 gene. Nucleic Acids Research 1991; 19: 4570
• 34 Ludwig M, Wohn KD, Schleuning WD, Olek K. Allelic dimorphisms in the human tissue-type plasminogen activator (t-PA) gene as a result of an Alu insertion/deletion event. Hum Genet 1992; 88: 388-92.
• 35 Mansfield MW, Stikland MH, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes. Thromb Haemost 1995; 74: 1032-4.
• 36 Katsuya T, Koike G, Yee TW, Sharpe N, Jackson R, Norton R, Horiuchi M, Pratt RE, Dzau VJ, MacMahon S. Association of angiotensinogen gene T235 variant with increased risk of coronary heart disease. Lancet 1995; 345: 1600-3.
• 37 Jespersen J, Sidelmann J. A study of the conditions and accuracy of the thrombin time assay of plasma fibrinogen. Acta Haematol 1982; 67: 2-7.
• 38 Declerck PJ, Moreau H, Jespersen J, Gram J, Kluft C. Multicentre evaluation of commercially available methods for the immunological determination of plasminogen activator inhibitor-1 (PAI-1). Thromb Haemost 1993; 70: 858-63.
• 39 Rånby M, Bergsdorf N, Nilsson T, Mellbring G, Winblad B, Bucht G. Age dependence of tissue plasminogen activator concentrations in plasma, as studied by an improved enzyme-linked immunosorbent assay. Clin Chem 1986; 32: 2160-5.
• 40 Buttery JE, Stuart S. Assessment and optimization of kinetic methods for angiotensin-converting enzyme in plasma. Clin Chem 1993; 39: 312-6.
• 41 Chakravarti A, Buetow KH, Antonarakis SE, Waber PG, Boehm CD, Kazazian HH. Nonuniform recombination within the human β-globin gene cluster. Am J Hum Genet 1984; 36: 1239-58.
• 42 Saha N, Liu Y, Heng CK, Hong S, Low PS, Tay JSH. Association of factor VII genotype with plasma factor VII activity and antigen levels in healthy Indian adults and interaction with triglycerides. Arterioscler Thromb 1994; 14: 1923-7.
• 43 Fujisawa T, Ikegami H, Shen GQ, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Rakugi H, Higaki J, Ohishi M, Fujii K, Fukuda M, Ogihara T. Angiotensin I-converting enzyme gene polymorphism is associated with myocardial infarction, but not with retinopathy or nephropha-thy, in NIDDM. Diabetes Care 1995; 18: 983-5.
• 44 Nakai K, Itoh C, Miura Y, Hotta K, Musha T, Itoh T, Miyakawa T, Iwasaki R, Hiramori K. Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentration and increased risk for CAD in the Japanese. Circulation 1994; 90: 2199-202.
• 45 Das I. Raised C-reactive protein levels in serum from smokers. Clin Chim Acta 1985; 153: 9-13.
• 46 de Maat MPM, Pietersma A, Kofflard M, Sluiter W, Kluft C. Association of plasma fibrinogen levels with coronary artery disease, smoking and inflammatory markers. Atherosclerosis 1996; 121: 185-91.
• 47 Haverkate F, Thompson SG, Pyke SDM, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet 1997; 349: 462-6.
• 48 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-9.
• 49 Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An Insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343-6.
• 50 Cambien F, Costerousse O, Tiret L, Poirier O, Lecerf L, Gonzales MF, Evans A, Arveiler D, Cambou JP, Luc G, Rakotovao R, Ducimetiere P, Soubrier F, Alhenc-Gelas F. Plasma level and gene polymorphism of angiotensin-converting enzyme in relation to myocardial infarction. Circulation 1994; 90: 669-76.
• 51 Green FR, Hamsten A, Blombäck M, Humphries S. The role of β-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden. Thromb Haemost 1993; 70: 915-20.
• 52 Humphries SE, Cook M, Dubowitz M, Stirling Y, Meade TW. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet 1987; 1: 1452-5.
• 53 Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G, Cambou J, Scarabin P, Bara L, Green F, Cambien F. β fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. Circulation 1996; 93: 440-9.
• 54 Iacoviello L, De Knijff P, Amore C, D’Orazio A, Kluft D, Donati MB. DNA polymorphisms of factor VII gene in an Italian sample of patients with myocardial infarction. Thromb Haemost 1995; 73: 949 (abs 195).
• 55 Humphries S, Temple A, Lane A, Green F, Cooper J, Miller G. Low plasma levels of factor VIIc and antigen are more strongly associated with the 10 base pair promoter (-323) insertion than the glutamine 353 variant. Thromb Haemost 1996; 75: 567-72.
• 56 Bernardi F, Marchetti G, Pinotti M, Arcieri P, Baroncini C, Papacchini M, Zepponi E, Ursicino N, Chiarotti F, Mariani G. Factor VII gene polymorphisms contribute about one third of the factor VII level variation in plasma. Arterioscler Thromb Vasc Biol 1996; 16: 72-6.
• 57 Moor E, Silveira A, van’t Hooft F, Suontaka AM, Eriksson P, Blombäck M, Hamsten A. Coagulation factor VII mass and activity in young men with myocardial infarction at a young age. Arterioscler Thromb Vasc Biol 1995; 15: 655-64.
• 58 Meilahn E, Ferrell R, Kiss J, Temple A, Green F, Humphries S, Kuller L. Genetic determination of coagulation factor VIIc levels among healthy middle-aged women. Thromb Haemost 1995; 73: 623-5.
• 59 Benham FJ, Spurr N, Povey S, Brinton BT, Goodfellow PN, Solomon E, Harris JR T. Assignment of tissue-type plasminogen activator to chromosome 8 in man and identification of a common restriction length polymorphism within the gene. Mol Biol Med 1984; 2: 251-9.
• 60 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Miletich JP. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor (PAI-1) gene in a large cohort of US men. Circulation 1997; 95: 59-62.
• 61 Panahloo A, Andrès C, Mohamed-Ali V, Gould MM, Talmud P, Humphries SE, Yudkin JS. The insertion allele of the ACE gene I/D polymorphism. A candidate gene for insulin resistance?. Circulation 1995; 92: 3390-3.
• 62 Wang XL, McCredie RM, Wilcken DEL. Genotype distribution of angiotensin-converting enzyme polymorphism in Australian healthy and coronary populations and relevance to myocardial infarction and coronary artery disease. Arterioscler Thromb Vasc Biol 1996; 16: 115-9.
• 63 Sertic J, Hebrang D, Janus D, Salzer B, Niksir M, Cvorisec D, Stavljenic-Rukavina A. Association between deletion polymorphism of the angiotensin-converting enzyme gene and cerebral atherosclerosis. Eur J Clin Chem Clin Biochem 1996; 34: 301-4.
• 64 Caulfield M, Lavender P, Farrall M, Munroe P, Lawson M, Turner P, Clark AJL. Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med 1994; 330: 1629-33.