Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden

Bengt Zöller; Henrik Ohlsson; Jan Sundquist; Kristina Sundquist

doi:10.1160/TH12-10-0743

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 109(03): 458-463
DOI: 10.1160/TH12-10-0743

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden

Bengt Zöller

¹Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden

,

Henrik Ohlsson

¹Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden

²Stanford Prevention Research Center, Stanford University School of Medicine, Palo Alto, California, USA

,

Jan Sundquist

¹Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden

²Stanford Prevention Research Center, Stanford University School of Medicine, Palo Alto, California, USA

,

Kristina Sundquist

¹Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden

› Author Affiliations

Abstract

Summary

Venous thromboembolism (VTE) clusters in families, but the familial risk of VTE has only been determined in first-degree relatives. This nationwide study aimed to determine the familial risk of VTE in first-, second- and third-degree relatives of affected individuals. The Swedish Multi-Generation Register was linked to Hospital Discharge Register data for the period 1987–2009. This was a case-cohort study. Odds ratios (ORs) for VTE were calculated for individuals whose relatives were hospitalised for VTE, as determined by the International Classification of Diseases (ICD), and those whose relatives were unaffected by VTE. The familial OR for VTE was 2.49 in siblings (95% confidence interval [CI] 2.40–2.58), 2.65 in children (2.50–2.80), 2.09 in parents (2.03–2.15), 1.52 in maternal half-siblings (1.26–1.85), 2.34 in paternal half-siblings (2.00–2.73), 1.69 in nieces/nephews (1.57–1.82), 1.47 in cousins (1.33–1.64), and 1.14 in spouses of individuals diagnosed with VTE (1.09–1.18). Familial clustering was stronger at young ages. The familial transmission was slightly stronger for males compared with females but was only significant for siblings 1.13 (1.05–1.22) and parents 1.11 (1.05–1.78) of probands. The present data showing an increased VTE risk among not only first-degree relatives but also second- and third-degree relatives indicate that the genetic component of the familial clustering of VTE is strong. Family history is a potentially useful genetic surrogate marker for clinical VTE risk assessment, even in second- and third degree-relatives.

Keywords

Thrombophilia - deep venous thrombosis - risk factors - thrombosis - epidemiological studies

Full Text

References

References
1 Silverstein MD, Heit JA, Mohr DN. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585-593.
2 Heit JA, Silverstein MD, Mohr DN. et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001; 86: 452-463.
3 Anderson Jr FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933-938.
4 Kniffin Jr WD, Baron JA, Barrett J. et al. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994; 154: 861-866
5 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107: I4-I8.
6 Cohen AT, Agnelli G, Anderson FA. et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98: 756-764.
7 Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost 1999; 82: 610-619.
8 Dowling NF, Austin H, Dilley A. et al. The epidemiology of venous thromboembolism in Caucasians and African-Americans: the GATE Study. J Thromb Haemost 2003; 1: 80-87.
9 Noboa S, Le Gal G, Lacut K. et al. Family history as a risk factor for venous thromboembolism. Thromb Res 2008; 122: 624-629.
10 Bezemer ID, van der Meer FJ, Eikenboom JC. et al. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med 2009; 169: 610-615.
11 Zöller B, Li X, Sundquist J. et al. Parental history and venous thromboembolism: a nationwide study of age and sex-specific familial risks in Sweden. J Thromb Haemost 2011; 9: 64-70.
12 van Sluis GL, Söhne M, El Kheir DY. et al. Family history and inherited thrombophilia. J Thromb Haemost 2006; 4: 2182-7.
13 Risch N. The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches. Cancer Epidemiol Biomarkers Prev 2001; 10: 733-741.
14 Frisell T, Pawitan Y, Långström N. et al. Heritability, assortative mating and gender differences in violent crime: results from a total population sample using twin, adoption, and sibling models. Behav Genet 2012; 42: 3-18.
15 Couturaud F, Leroyer C, Julian JA. et al. Factors that predict risk of thrombosis in relatives of patients with unprovoked venous thromboembolism. Chest 2009; 136: 1537-1545.
16 Sørensen HT, Riis AH, Diaz LJ. et al. Familial risk of venous thromboembolism: a nationwide cohort study. J Thromb Haemost 2011; 9: 320-324.
17 Zöller B, Li X, Sundquist J. et al. Familial risks for unusual forms of venous thrombosis: a nationwide epidemiological study in Sweden. J Intern Med 2010; 270: 158-165.
18 Zöller B, Li X, Sundquist J. et al. Determination of age-specific and sex-specific familial risks for the different manifestations of venous thromboembolism: a nationwide family study in Sweden. Thromb Haemost 2011; 106: 102-112.
19 Zöller B, Li X, Sundquist J. et al. Age- and gender-specific familial risks for venous thromboembolism: a nationwide epidemiological study based on hospitalizations in Sweden. Circulation 2011; 124: 1012-1020.
20 Zöller B, Li X, Sundquist J. et al. Shared familial aggregation of susceptibility to different manifestations of venous thromboembolism: a nationwide family study in Sweden. Br J Haematol. 2011; epub ahead of print
21 Zöller B, Li X, Sundquist J. et al. A nationwide family study of pulmonary embolism: Identification of high risk families with increased risk of hospitalized and fatal pulmonary embolism. Thromb Res 2012; 130: 178-182.
22 Prandoni P, Prins MH, Ghirarduzzi A. et al. Family history of venous thrombosis or sudden death as a risk factor for venous thromboembolism. Thromb Haemost 2012; 107: 1191-1192.
23 Mili FD, Hooper WC, Lally C. et al. The impact of co-morbid conditions on family history of venous thromboembolism in Whites and Blacks. Thromb Res 2011; 127: 309-316.
24 Hron G, Eichinger S, Weltermann A. et al. Family history for venous thromboembolism and the risk for recurrence. Am J Med 2006; 119: 50-53.
25 Gauthier K, Kovacs MJ, Wells PS. et al. Family history of venous thromboembolism (VTE) as a predictor for recurrent VTE in unprovoked VTE patients. J Thromb Haemost. 2012; Epub ahead of print.
26 Christiansen SC, Cannegieter SC, Koster T. et al. Thrombophilia, clinical factors, and recurrent venous thrombotic events. J Am Med Assoc 2005; 293: 2352-2361.
27 Baglin T, Luddington R, Brown K. et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362: 523-526.
28 Statistics Sweden.. The Swedish Multigeneration Register (1960–1990): Registret över totalbefolkningen/RTB3. In Swedish. Stockholm; Statistics Sweden: 2005: 29.
29 The National Board of Health and Welfare.. Validity of the diagnoses from the Swedish In-Care Register 1987 and 1995. In Swedish. Stockholm: Epidemiologiskt Centrum, Socialstyrelsen; 2000
30 Rosen M, Hakulinen T. Use of disease registers. In: Handbook of epidemiology. Berlin:Springer-Verlag 2005; pp. 231-251
31 Ludvigsson JF, Otterblad-Olausson P, Pettersson BU. et al. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 2009; 24: 659-667.
32 Ludvigsson JF, Andersson E, Ekbom A. et al. External review and validation of the Swedish national inpatient register. BMC Public Health 2011; 11: 450.
33 Rosengren A, Fredén M, Hansson PO. et al. Psychosocial factors and venous thromboembolism: a long-term follow-up study of Swedish men. J Thromb Haemost 2008; 6: 558-564.
34 Breslow NE, Day NE. Statistical methods in cancer research. Volume I - The analysis of case-control studies. IARC Sci Publ 1980; 32: 5-338.
35 Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost 2009; 7 (Suppl. 01) 301-304.
36 Trégouët DA, Heath S, Saut N. et al. Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. Blood 2009; 113: 5298-5303.
37 Morange PE, Bezemer I, Saut N. et al. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1. Am J Hum Genet 2010; 86: 592-595.
38 Buil A, Trégouët DA, Souto JC. et al. C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies. Blood 2010; 115: 4644-4650.
39 Morange PE, Saut N, Antoni G. et al. Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels. J Thromb Haemost 2011; 9: 229-231.
40 Bezemer ID, Bare LA, Doggen CJ. et al. Gene variants associated with deep vein thrombosis. J Am Med Assoc 2008; 299: 1306-1314.
41 Germain M, Saut N, Greliche N. et al. Genetics of venous thrombosis: insights from a new genome wide association study. PLoS One 2011; 6: e25581.
42 Zöller B, Li X, Sundquist J. et al. Socioeconomic and occupational risk factors for venous thromboembolism in Sweden: a nationwide epidemiological study. Thromb Res 2012; 129: 577-582.
43 Zöller B, Li X, Sundquist J. et al. Neighborhood deprivation and hospitalization for venous thromboembolism in Sweden. J Thromb Thrombolysis 2012; 34: 374-382.
44 Charchar FJ, Bloomer LD, Barnes TA. et al. Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome. Lancet 2012; 379: 915-922.