Genetic variation in estrogen receptor, C-reactive protein and fibrinogen does not predict the plasma levels of inflammation markers after longterm hormone replacement therapy

Summary

Markers of inflammation, such as C-reactive protein (CRP) and fibrinogen, are associated with the risk of atherothrombosis. Plasma levels of these markers of inflammation are affected by hormone replacement therapy (HRT) and modulated by smoking. We studied whether genetic variation in the estrogen receptor- 1 (ESR1), CRP and fibrinogen-β genes influences the plasma levels of inflammation markers after HRT. Plasma CRP and fibrinogen were measured after five years follow-up in healthy postmenopausal women (per-protocol group) who were randomised to hormone therapy (n=187) or no treatment (n=249). The effect of HRT, smoking and genetic variations in ESR1 (PvuII and XbaI), CRP (1444C/T) and fibrinogen-β ( FGB, –455G/A) were determined. The plasma concentration of CRP was higher in the HRT group than in the control group (2.03 mg/l and 1.41 mg/l, respectively; p < 0.001), while the concentration of fibrinogen was lower in the HRT group than in the control group (3.02 g/l and 3.20 g/l, respectively; p < 0.001), indicating that it is unlikely that inflammation is the common underlying pathway. There was a significant interaction between smoking and HRT on the ibrinogen (p=0.02), but not on the CRP concentration (n.s.). Genetic polymorphisms in ESR1, CRP and fibrinogen were not associated with an effect of HRT on the CRP and fibrinogen plasma levels, and no significant interaction with smoking was observed. In conclusion, higher plasma levels of CRP and lower plasma levels of fibrinogen were observed in women using HRT; however, genetic polymorphisms in ESR1, CRP and FGB were not associated with these effects of HRT.

Keywords

Genetic variation - estrogen - hormone replacement therapy - fibrinogen - C-reactive protein

• References

• 1 Salomaa V, Rasi V, Pekkanen J. et al. Association of hormone replacement therapy with hemostatic and other cardiovascular risk factors. The FINRISK Hemostasis Study. Arterioscler Thromb Vasc Biol 1995; 15: 1549-1555.
• 2 The Writing Group for the PEPI Trial Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Am Med Assoc 1995; 273: 199-208.
• 3 Barrett-Connor E, Laakso M. Ischemic heart disease risk in postmenopausal women. Effects of estrogen use on glucose and insulin levels. Arteriosclerosis 1990; 10: 531-534.
• 4 Madsen JS, Kristensen SR, Klitgaard NA. et al. Effect of long-term hormone replacement therapy on plasma homocysteine in postmenopausal women: a randomized controlled study. Am J Obstet Gynecol 2002; 187: 33-39.
• 5 Scarabin PY, Alhenc-Gelas M, Plu-Bureau G. et al. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997; 17: 3071-3078.
• 6 Koh KK, Mincemoyer R, Bui MN. et al. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997; 336: 683-690.
• 7 Vehkavaara S, Hakala-Ala-Pietila T, Virkamaki A. et al. Differential effects of oral and transdermal estrogen replacement therapy on endothelial function in postmenopausal women. Circulation 2000; 102: 2687-2693.
• 8 Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998; 19: 55-72.
• 9 Hulley S, Grady D, Bush T. et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc 1998; 280: 605-613.
• 10 Rossouw JE, Anderson GL, Prentice RL. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2002; 288: 321-333.
• 11 Grady D, Herrington D, Bittner V. et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). J Am Med Assoc 2002; 288: 49-57.
• 12 Cushman M, Meilahn EN, Psaty BM. et al. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999; 19: 893-899.
• 13 Vehkavaara S, Silveira A, Hakala-Ala-Pietila T. et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001; 85: 619-625.
• 14 Teede HJ, McGrath BP, Smolich JJ. et al. Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Arterioscler Thromb Vasc Biol 2000; 20: 1404-1409.
• 15 Walsh BW. The effects of estrogen and selective estrogen receptor modulators on cardiovascular risk factors. Ann NY Acad Sci 2001; 949: 163-167.
• 16 Acs N, Vajo Z, Miklos Z. et al. The effects of postmenopausal hormone replacement therapy on hemostatic variables: a meta-analysis of 46 studies. Gynecol Endocrinol 2002; 16: 335-346.
• 17 Herrington DM. Role of estrogen receptor-alpha in pharmacogenetics of estrogen action. Curr Opin Lipidol 2003; 14: 145-150.
• 18 Herrington DM, Howard TD, Hawkins GA. et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002; 346: 967-974.
• 19 Herrington DM, Howard TD, Brosnihan KB. et al. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 2002; 105: 1879-1882.
• 20 Brull DJ, Serrano N, Zito F. et al. Human CRP gene polymorphism influences CRP levels: Implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol 2003; 23: 2063-2069.
• 21 D'Aiuto F, Casas JP, Shah T. et al. C-reactive protein (+1444C>T) polymorphism influences CRP response following a moderate inflammatory stimulus. Atherosclerosis 2005; 179: 413-417.
• 22 Thomas AE, Green FR, Kelleher CH. et al. Variation in the promoter region of the beta fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost 1991; 65: 487-490.
• 23 Mueck AO, Seeger H. Smoking, estradiol metabolism and hormone replacement therapy. Arzneimittelforschung 2003; 53: 1-11.
• 24 Mosekilde L, Hermann AP, Beck-Nielsen H. et al. The Danish Osteoporosis Prevention Study (DOPS): project design and inclusion of 2000 normal perimenopausal women. Maturitas 1999; 31: 207-219.
• 25 Von Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-246.
• 26 Ioannidis JP, Ralston SH, Bennett ST. et al. Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. J Am Med Assoc 2004; 292: 2105-2114.
• 27 Brull DJ, Dhamrait S, Moulding R. et al. The effect of fibrinogen genotype on fibrinogen levels after strenuous physical exercise. Thromb Haemost 2002; 87: 37-41.
• 28 Verschuur M, de Jong M, Felida L. et al. A hepatocyte nuclear factor-3 site in the fibrinogen beta promoter is important for interleukin 6-induced expression, and its activity is influenced by the adjacent –148C/T polymorphism. J Biol Chem 2005; 280: 16763-16771.
• 29 Kobayashi N, Fujino T, Shirogane T. et al. Estrogen receptor alpha polymorphism as a genetic marker for bone loss, vertebral fractures and susceptibility to estrogen. Maturitas 2002; 41: 193-201.
• 30 Thomas A, Lamlum H, Humphries S. et al. 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 (beta-fibrinogen) and TaqI (alpha-fibrinogen), and their detection by PCR. Hum.Mutat 1994; 3: 79-81.
• 31 Bladbjerg EM, Gram J, Jespersen J. et al. Internal quality control of PCR-based genotyping methods in research studies and patient diagnostics. Thromb Haemost 2002; 87: 812-816.
• 32 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978-989.
• 33 Tanck MW, Klerkx AH, Jukema JW. et al. Estimation of multilocus haplotype effects using weighted penalised log-likelihood: analysis of five sequence variations at the cholesteryl ester transfer protein gene locus. Ann Hum Genet 2003; 67: 175-184.
• 34 Lowe GD. Hormone replacement therapy: prothrombotic vs. protective effects. Pathophysiol Haemost Thromb 2002; 32: 329-332.
• 35 Yilmazer M, Fenkci V, Fenkci S. et al. Hormone replacement therapy, C-reactive protein, and fibrinogen in healthy postmenopausal women. Maturitas 2003; 46: 245-253.
• 36 Schuit SC, Oei HH, Witteman JC. et al. Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction. J Am Med Assoc 2004; 291: 2969-2977.
• 37 Jeng MH, Shupnik MA, Bender TP. et al. Estrogen receptor expression and function in long-term estrogen- deprived human breast cancer cells. Endocrinology 1998; 139: 4164-4174.
• 38 Green FR. Fibrinogen polymorphisms and atherothrombotic disease. Ann NY Acad Sci 2001; 936: 549-559.
• 39 de Maat MP, Trion A. C-reactive protein as a risk factor versus risk marker. Curr Opin Lipidol 2004; 15: 651-657.
• 40 Puder JJ, Blum CA, Mueller B. et al. Menstrual cycle symptoms are associated with changes in lowgrade inflammation. Eur J Clin Invest 2006; 36: 58-64.
• 41 Blum CA, Muller B, Huber P. et al. Low-grade inflammation and estimates of insulin resistance during the menstrual cycle in lean and overweight women. J Clin Endocrinol Metab 2005; 90: 3230-3235.
• 42 Dreon DM, Slavin JL, Phinney SD. Oral contraceptive use and increased plasma concentration of C-reactive protein. Life Sci 2003; 73: 1245-1252.
• 43 Wunder DM, Yared M, Bersinger NA. et al. Serum leptin and C-reactive protein levels in the physiological spontaneous menstrual cycle in reproductive age women. Eur J Endocrinol 2006; 155: 137-142.