Download PDF
Thromb Haemost 2012; 107(03): 458-467
DOI: 10.1160/TH11-07-0497
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Replication and characterisation of genetic variants in the fibrinogen gene cluster with plasma fibrinogen levels and haematological traits in the Third National Health and Nutrition Examination Survey

Janina M. Jeff
1   Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA
,
Kristin Brown-Gentry
1   Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA
,
Dana C. Crawford
1   Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA
2   Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville Tennessee, USA
› Author Affiliations Financial support: This study was supported by grant N01-HV-48195 from the National Heart, Lung, and Blood Institute (NHLBI) at the National Institute of Health (NIH) of the United States of America.
Further Information

Publication History

Received: 19 July 2011

Accepted after major revision: 05 January 2011

Publication Date:
22 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Previous genetic association studies of the fibrinogen gene cluster have identified associations with plasma fibrinogen levels. These studies are typically limited to plasma fibrinogen measured among European-descent populations. We sought to replicate previous well-known associations with fibrinogen variants and plasma fibrinogen. We then sought to identify and characterise novel associations with fibrinogen variants with plasma fibrinogen and several haematological traits in three racial/ethnic populations. We genotyped 25 single nucleotide polymorphisms (SNPs) in the fibrinogen gene cluster in 2,631 non-Hispanic whites, 2,108 non-Hispanic blacks, and 2,073 Mexican-Americans from the Third National Health and Nutrition Examination Survey (NHANES). We performed single SNP tests of association for plasma fibrinogen, mean platelet volume, platelet distribution width, platelet count, white blood cell count, and serum triglycerides. Five previously identified associations with plasma fibrinogen replicated in our study in non-Hispanic whites and blacks. We identified two novel associations between genetic variants and decreased plasma fibrinogen: rs2227395 (p=0.0007; non-Hispanic whites) and rs2070022 (p=0.001; Mexican-Americans). Several fibrinogen SNPs were also associated with haema-tological traits: rs6050 with decreased platelet distribution width in non-Hispanic whites; rs6050 and rs2066879 with decreased and increased platelet distribution width, respectively, in non-Hispanic whites; rs2227409 with increased mean platelet volume, rs2070017 with decreased platelet count, and rs6063 with increased platelet distribution width in non-Hispanic blacks; and rs4220 and rs2227395 with decreased white blood cell count, rs2227409 with increased platelet distribution width, rs2066860 and rs1800792 with increased and decreased triclyceride levels, respectively, and rs1800792 with decreased platelet counts in Mexican-Americans. We successfully replicated and identified novel associations with fibrinogen variants and plasma fibrinogen. These data confirm the importance of the fibrinogen gene cluster for plasma fibrinogen levels as well as suggest this gene cluster may have pleiotropic effects on haematological traits.

Keywords

Fibrinogen - pleiotropy - replication

 

  • References

  • 1 Pennington J, Garner SF, Sutherland J. et al. Residual subset population analysis in WBC-reduced blood components using real-time PCR quantitation of specific mRNA. Transfusion 2001; 41: 1591-1600.
    CrossrefPubMedGoogle Scholar
  • 2 Evans DM, Frazer IH, Martin NG. Genetic and environmental causes of variation in basal levels of blood cells. Twin Res 1999; 2: 250-257.
    CrossrefPubMedGoogle Scholar
  • 3 Meade TW, Mellows S, Brozovic M. et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533-537.
    PubMedGoogle Scholar
  • 4 Tosetto A, Prati P, Baracchini C. et al. Association of plasma fibrinogen, C-reactive protein and G-455>A polymorphism with early atherosclerosis in the VITA Project cohort. Thromb Haemost 2011; 105: 329-335.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Boos CJ, Lip GY. Platelet activation and cardiovascular outcomes in acute coronary syndromes. J Thromb Haemost 2006; 4: 2542-2543.
    CrossrefPubMedGoogle Scholar
  • 6 Danesh J, Lewington S. Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies. J Cardiovasc Risk 1998; 5: 229-232.
    PubMedGoogle Scholar
  • 7 Ensrud K, Grimm Jr RH. The white blood cell count and risk for coronary heart disease. Am Heart J 1992; 124: 207-213.
    CrossrefPubMedGoogle Scholar
  • 8 Kannel WB, Wolf PA, Castelli WP. et al. Fibrinogen and risk of cardiovascular disease. The Framingham Study. J Am Med Assoc 1987; 258: 1183-1186.
    CrossrefPubMedGoogle Scholar
  • 9 Collet JP, Soria J, Mirshahi M. et al. Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibri-nolysis related to an abnormal clot structure. Blood 1993; 82: 2462-2469.
    PubMedGoogle Scholar
  • 10 Voetsch B, Loscalzo J. Genetic Determinants of Arterial Thrombosis. Arterioscler Thromb Vasc Biol 2003; 24: 216-229.
    PubMedGoogle Scholar
  • 11 Siegerink B, Rosendaal FR, Algra A. Genetic variation in fibrinogen; its relationship to fibrinogen levels and the risk of myocardial infarction and ischemic stroke. J Thromb Haemost 2009; 7: 385-390.
    CrossrefPubMedGoogle Scholar
  • 12 Boekholdt SM, Bijsterveld NR, Moons AH. et al. Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review. Circulation 2001; 104: 3063-3068.
    CrossrefPubMedGoogle Scholar
  • 13 Folsom AR, Aleksic N, Ahn C. et al. Beta-fibrinogen gene –455G/A polymorphism and coronary heart disease incidence: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 2001; 11: 166-170.
    CrossrefPubMedGoogle Scholar
  • 14 Koch W, Hoppmann P, Biele J. et al. Fibrinogen genes and myocardial infarction: a haplotype analysis. Arterioscler Thromb Vasc Biol 2008; 28: 758-763.
    CrossrefPubMedGoogle Scholar
  • 15 Hamsten A, Iselius L, de Faire U. et al. Genetic and cultural inheritance of plasma fibrinogen concentration. Lancet 1987; 2: 988-991.
    PubMedGoogle Scholar
  • 16 Meisinger C, Prokisch H, Gieger C. et al. A genome-wide association study identifies three loci associated with mean platelet volume. Am J Hum Genet 2009; 84: 66-71.
    CrossrefPubMedGoogle Scholar
  • 17 Soranzo N, Spector TD, Mangino M. et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 2009; 41: 1182-1190.
    CrossrefPubMedGoogle Scholar
  • 18 Margaglione M, Grandone E. Population genetics of venous thromboembolism. A narrative review. Thromb Haemost 2011; 105: 221-231.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Rosendaal FR, Doggen CJ, Zivelin A. et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-708.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Grody WW, Griffin JH, Taylor AK. et al. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med 2001; 3: 139-148.
    CrossrefPubMedGoogle Scholar
  • 21 Grody WW. Molecular genetic risk screening. Annu Rev Med 2003; 54: 473-490.
    CrossrefPubMedGoogle Scholar
  • 22 McGlennen RC, Key NS. Clinical and laboratory management of the prothrom-bin G20210A mutation. Arch Pathol Lab Med 2002; 126: 1319-1325.
    PubMedGoogle Scholar
  • 23 Crawford DC, Sanders CL, Qin X. et al. Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey. Circulation 2006; 114: 2458-2465.
    CrossrefPubMedGoogle Scholar
  • 24 Chang MH, Lindegren ML, Butler MA. et al. Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991–1994. Am J Epidemiol 2009; 169: 54-66.
    PubMedGoogle Scholar
  • 25 Steinberg KK, Sanderlin KC, Ou CY. et al. DNA banking in epidemiologic studies. Epidemiol Rev 1997; 19: 156-162.
    CrossrefPubMedGoogle Scholar
  • 26 Centers for Disease Control and Prevention Third National Health and Nutrition Examination Survey, 1988–94, Plan and Operations Procedures Manual.
    PubMed
  • 27 Centers for Disease Control and Prevention Plan and Operation of the Third National Health and Nutrition Examination Survey, 1988–94. Bethesda: MD;
  • 28 Gunter EW, Lewis BG, Koncikowski S. Laboratory Procedures Used for the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994. 1996
    PubMedGoogle Scholar
  • 29 Daum P, Estergreen J, Wener M. Laboratory Procedure Manual: Rate of Clot Formation on the STA-Compact. 2000
    PubMedGoogle Scholar
  • 30 Carlson CS, Eberle MA, Rieder MJ. et al. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 2004; 74: 106-120.
    CrossrefPubMedGoogle Scholar
  • 31 Crawford DC, Akey DT, Nickerson DA. The patterns of natural variation in human genes. Annu Rev Genomics Hum Genet 2005; 6: 287-312.
    CrossrefPubMedGoogle Scholar
  • 32 Grady BJ, Torstenson E, Dudek SM. et al. Finding unique filter sets in plato: a precursor to efficient interaction analysis in gwas data. Pac Symp Biocomput 2010; 315-326.
    PubMedGoogle Scholar
  • 33 Barrett JC, Fry B, Maller J. et al. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263-265.
    CrossrefPubMedGoogle Scholar
  • 34 Pendergrass SA, Dudek S, Crawford DCC. et al. Synthesis-View: visualization and interpretation of SNP association results for multi-cohort, multi-phenotype data and meta-analysis. BioData Mining 2010; 3: 10.
    CrossrefPubMedGoogle Scholar
  • 35 Reiner AP, Carty CL, Carlson CS. et al. Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study. J Thromb Haemost 2006; 4: 1279-1287.
    CrossrefPubMedGoogle Scholar
  • 36 Wassel CL, Lange LA, Keating BJ. et al. Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate gene Association Resource (CARe). Blood 2011; 117: 268-275.
    CrossrefPubMedGoogle Scholar
  • 37 Dehghan A, Yang Q, Peters A. et al. Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. Circ Cardiovasc Genet 2009; 2: 125-133.
    CrossrefPubMedGoogle Scholar
  • 38 Kottke-Marchant K. Genetic polymorphisms associated with venous and arterial thrombosis: an overview. Arch Pathol Lab Med 2011; 126: 295-304.
    PubMedGoogle Scholar
  • 39 Wagner GP, Zhang J. The pleiotropic structure of the genotype-phenotype map: the evolvability of complex organisms. Nat Rev Genet 2011; 12: 204-213.
    PubMedGoogle Scholar
  • 40 Pendergrass SA, Brown-Gentry K, Dudek SM. et al. The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery. Genet Epidemiol 2011; 35: 410-422.
    CrossrefPubMedGoogle Scholar
  • 41 David Ginsburg. Genetic Risk Factors for Arterial Thrombosis and Inflammation. Hematology 2005; 442-444.
    PubMedGoogle Scholar
  • 42 Feinbloom D, Bauer KA. Assessment of hemostatic risk factors in predicting arterial thrombotic events. Arterioscler Thromb Vasc Biol 2005; 25: 2043-2053.
    CrossrefPubMedGoogle Scholar
  • 43 Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000; 95: 1517-1532.
    PubMedGoogle Scholar
  • 44 Lowe GD. Common risk factors for both arterial and venous thrombosis. Br J Haematol 2008; 140: 488-495.
    CrossrefPubMedGoogle Scholar
  • 45 Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451: 914-918.
    CrossrefPubMedGoogle Scholar