CoChat
Sign Up
Cited by 82Blood Coagulation and Thrombosis MechanismsBlood properties and coagulationGenetic Associations and Epidemiology

Genetic Contribution to Circulating Levels of Hemostatic Factors in Healthy Families With Effects of Known Genetic Polymorphisms on Heritability

Freeman, M. S., Mansfield, M. W., Barrett, J. H., Grant, P. J.·2002·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/hq0302.104906
Open this paper in CoChat — free account

Abstract

Levels of fibrinogen, factor VII (FVII), factor XIII (FXIII), plasminogen activator inhibitor (PAI)-1, and tissue plasminogen activator have been associated with coronary artery disease as have genetic polymorphisms. Quantitative genetic analyses allow determination of the genetic contribution to phenotypic variation. We investigated familial influences on these hemostatic factors in 537 adults from 89 randomly ascertained healthy families of white North European origin. We used maximum likelihood analysis to estimate the heritabilities of these factors and effects of covariates on the factors in these families. After adjustment for age and sex, the factors showed considerable heritability, varying from 26% (PAI-1) to 47% (FXIII complex). The influence of known polymorphisms was negligible for fibrinogen and contributed 2% to the variance of the FXIII complex and PAI-1 and 11% to the variance of FVII coagulant activity. Age, sex, body mass index, lifestyle, and metabolic covariates explained between 10% (FXIII) and 44% (PAI-1) of phenotypic variance. Childhood household influences significantly affected FVII (11%) and FXIII (18%). A significant degree of phenotypic variance of several hemostatic factors can be explained by additive genes and known covariates. The impact of certain well-characterized polymorphisms to the heritability is small in this population of healthy families, indicating the need to localize new genes influencing hemostatic factor levels.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1161/hq0302.104906

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Genetic factors contribute to 47.3% of variation in plasma APP activity in the Leeds Family Study, a healthy population.

    “we have shown in a well established and large family study representative of a healthy population, the Leeds Family Study [Freeman et al., 2002a[Freeman et al., , 2002b]], that genetic factors contribute to 47.3% of variation in plasma APP activity.”

    From A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor‐induced angioedema (2011) · cites this paper as Freeman et al., 2002a

    The Abstract and Subject Recruitment sections describe a genetic study of healthy families recruited in Leeds, supporting the population and general genetic-contribution claim. But the Abstract assigns approximately 47% heritability to the FXIII complex, not plasma APP activity; the paper does not report the claimed 47.3% figure for APP activity. Page numbers were not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 37 · Cited by 82

Research works printed but not linked: 35

  1. de Lange M, Sneider H, Ariens RAS, Spector TD, Grant PJ. The Genetics of Haemostasis: a twin study. Lancet. 2001;357:101-105.
  2. Bo S, Cavallo-Perin P, Scaglione L, Pagano G. Heritability of cardiovascular risk parameters in subjects with increased susceptibility to non-insulin- dependent diabetes mellitus. Acta Diabetol. 1997;34:280 -284.
  3. Souto JC, Almasy L, Borrell M, Gari M, Martinez E, Mateo J, Stone WH, Blangero J, Fontcuberta J. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation. 2000;101:1546 -1551.
  4. Margaglione M, Cappucci G, Colaizzo D, Pirro L, Vecchione G, Grandone E, Di Minno G. Fibrinogen plasma levels in an apparently healthy general population: relation to environmental and genetic determinants. Thromb Haemost. 1998;80:805-810.
  5. Dawson SJ, Hamsten A, Wiman B, Henney A, Humphries SE. Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity. Arte- rioscler Thromb. 1991;11:183-190.
  6. Bernardi F, Marchetti G, Pinotti M, Arcieri P, Baroncini C, Papacchini M, Zepponi E, Ursicino N, Chiarotti J, Mariani G. Factor VII gene poly- morphisms contribute about one third of the factor VII level variation in plasma. Arterioscler Thromb Vasc Biol. 1996;16:72-76.
  7. van't Hoof F, Silveira A, Tornvall P. Two common functional poly- morphisms in the promotor region of coagulation factor VII determining plasma factor VII activity and mass concentration. Blood. 1993;93: 3432-3441.
  8. Clauss A. Gerinnungsphysiologische schnell methode zur bestimmung des fibrinogens. Acta Haematol. 1952;17:237-246.
  9. Komanasin N, Futers TS, Ariens RAS, Grant PJ. A novel polymorphism in the factor XIII B subunit (His95Arg) relates to the dissociation of the A2B2 tetramer. Thromb Haemost. 1999;82:111a. Abstract.
  10. Thomas A, Lamlum H, Humphris S, Green F. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A-455 (HaeIII), CT-148 (HindIII/AluI), T/G-1689 (AvaII) and Bcl1 (B-fibrinogen) and taq1 (a-fibrinogen), and their detection by PCR. Hum Mutat. 1994;3:79-81.
  11. O'Hara PJ, Grant FJ, Haldeman BA, Gray CL, Insley MY, Hagen FS, Murray MJ. Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation. Proc Natl Acad Sci U S A. 1987;84:5158 -5162.
  12. Margaglione M, Grandone E, Cappucci G, Collaizzo D, Giuliani N, Vecchione G, d'Addedda M, Di Minno G. An alternative method for PAI-1 promotor polymorphism (4G/5G) typing. Thromb Haemost. 1997;77:605-606.
  13. Kohler HP, Stickland MH, Ossei-Gerning N, Carter A, Mikkola H, Grant PJ. Association of a common polymorphism in the factor XIII gene with myo- cardial infarction. Thromb Haemost. 1998;79:8 -13.
  14. Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998;62:1198 -1211.
  15. Lee AJ, Lowe GDO, Woodward M, Tunstall-Pedoe H. Fibrinogen in relation to personal history of prevalent hypertension, diabetes, stroke, intermittent claudication, coronary heart disease, and family history: the Scottish Heart Health Study. Br Heart J. 1993;69:338 -342.
  16. Livshits G, Schettler G, Graff E, Blettner M, Wahrendorf J, Brunner D. Tel Aviv-Heidelberg three-generation offspring study: genetic determinants of plasma fibrinogen level. Am J Med Genet. 1996;63:509 -517.
  17. Friedlander Y, Elkana Y, Sinnreich R, Kark JD. Genetic and environmental sources of fibrinogen variability in Israeli families: the Kibbutzim Family Study. Am J Hum Genet. 1995;56:1194 -1206.
  18. Reed T, Tracy RP, Fabsitz RR. Minimal genetic influences on plasma fibrinogen level in adult males in the NHLBI twin study. Clin Genet. 1994; 45:71-77.
  19. van't Hooft FM, von Bahr SJ, Silveira A, Iliadou A, Eriksson P, Hamsten A. Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concen- tration. Arterioscler Thromb Vasc Biol. 1999;19:3063-3070.
  20. Tybjaerg-Hansen A, Agerholm-Larsen B, Humphries SE, Abildgaard S, Schnohr P. A common mutation (G-4553A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease: a study of 9,127 individuals based on the Copenhagen City Heart Study. J Clin Invest. 1997;99:3034 -3039.
  21. Iso H, Folsom AR, Winkelmann JC, Koike K, Harada S, Greenberg B, Sato S, Shimamoto T, Iida M, Komachi Y. Polymorphisms of the beta fibrinogen gene and plasma fibrinogen concentration in Caucasian and Japanese popu- lation samples. Thromb Haemost. 1995;73:106 -111.
  22. Green F, Hamsten A, Blomback M, Humphries SE. The role of beta- fibrinogen genotype in determining plasma fibrinogen levels in young sur- vivors of myocardial infarction and healthy controls from Sweden. Thromb Haemost. 1993;70:915-920.
  23. Woodhouse PR, Khaw KT, Plummer M, Foley A, Meade TW. Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease. Lancet. 1994;343:435-439.
  24. Saha N, Liu Y, Heng CK, Hong S, Low PS, Tay JS. 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: 1923-1927.
  25. Kohler HP, Ariens RA, Whitaker P, Grant PJ. A common coding poly- morphism in the FXIII A-subunit gene (FXIIIVal34Leu) affects cross-linking activity. Thromb Haemost. 1998;80:704.
  26. Pankow JS, Folsom A, Province MA, Rao DC, Williams RR, EckfeldtJ, Sellers TA. Segregation analysis of plasminogen activator inhibitor-1 and fibrinogen levels in the NHLBI Family Heart Study. Arterioscler Thromb Vasc Biol. 1998;18:1559 -1567.
  27. Cesari M, Sartori MT, Patrassi GM, Vettore S, Rossi GP. Determinants of plasma levels of plasminogen activator inhibitor-1: a study of normotensive twins. Arterioscler Thromb Vasc Biol. 1999;19:316 -320.
  28. Henry M, Tregouet DA, Alessi MC Aillaud MF, Visvikis S, Siest G, Tiret L, Juhan-Vague I. Metabolic determinants are much more important than genetic polymorphisms in determining the PAI-1 activity and antigen plasma concentrations: a family study with part of the Stanislas Cohort. Arterioscler Thromb Vasc Biol. 1998;18:84 -91.
  29. Ossei-Gerning N, Mansfield MW, Stickland MH, Wilson IJ, Grant PJ. Plas- minogen activator inhibitor-1 promoter 4G/5G genotype and plasma levels in relation to a history of myocardial infarction in patients characterized by coronary angiography. Arterioscler Thromb Vasc Biol. 1997;17:33-37.
  30. Ridker PM, Vaughen DE, Stampfer MJ, Manson JE, Hennekens CH. En- dogenous tissue-type plasminogen activator and the risk of myocardial infarction. Lancet. 1993;341:1165-1168.
  31. Jern C, Ladenvall P, Wall U, Jern S. Gene polymorphism of t-PA is asso- ciated with forearm vascular release rate of t-PA. Arterioscler Thromb Vasc Biol. 1999;19:454 -459.
  32. Chandler WL, Trimble SL, Loo SC, Mornin D. Effect of PAI-1 levels on the molar concentrations of active tissue plasminogen activator (t-PA) and t-PA/PAI-1 complex in plasma. Blood. 1990;76:930 -937.
  33. Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood. 2000;95:1517-1532.
  34. Hong Y, Pedersen NL, Egberg N, de Faire U. Genetic effects for plasma factor VII levels independent of and in common with triglycerides. Thromb Haemost. 1999;81:382-386.
  35. Hong Y, Pedersen NL, Egberg N, de Faire U. Moderate genetic influences on plasma levels of plasminogen activator inhibitor-1 and evidence of genetic and environmental influences shared by plasminogen activator inhibitor-1, triglycerides, and body mass index. Arterioscler Thromb Vasc Biol. 1995;17: 2776 -2782.

Authors
Freeman, M. S., Mansfield, M. W., Barrett, J. H., & Grant, P. J.
Affiliations
University of Leeds (GB)
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2002-03
Volume
22
Issue
3
Pages
506-510
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/hq0302.104906
OpenAlex
W2050943729
Cited by
82
References
37
Citations by year
2025: 2 · 2024: 1 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2016: 2 · 2014: 2 · 2013: 1 · 2012: 2
FWCI
4.37
Type
journal article
Language
en
Open access
closed
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
hemostatic factors, heritability, genetic polymorphism, fibrinogen, factor VII coagulant activity, plasminogen activator inhibitor-1, tissue plasminogen activator, coronary artery disease, family influence, phenotypic variance, additive genetic effects, healthy family
MeSH terms
Adult, Blood Coagulation Factors, Factor VII, Factor XIII, Family Health, Female, Fibrinogen, Humans, Male, Tissue Plasminogen Activator, Polymorphism, Genetic, Risk Factors, Vascular Diseases, Likelihood Functions, Plasminogen Activator Inhibitor 1

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review