Interactions of established risk factors and a GWAS-based genetic risk score on the risk of venous thromboembolism

Summary

Multiple genetic and environmental risk factors contribute to venous thromboembolism (VTE) risk. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of VTE and may identify opportunities for targeted prevention and treatment. It was our aim to examine the main effects and the potential effect-modification between single nucleotide polymorphisms (SNPs) at established loci and lifestyle risk factors for VTE. We performed a nested case-control study using data on 1,040 incident VTE cases and 16,936 controls from the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood, were selected as participants in a previous genome-wide association study (GWAS), and completed a biennial questionnaire at time of blood draw. We selected SNPs that were associated with VTE risk in previous GWAS studies. A genetic risk score (GRS) was constructed to evaluate the combined effect of the 16 SNPs that have reached genome-wide significance in previous GWAS of VTE. Interactions between SNPs and VTE risk factors (BMI and smoking) were also assessed. We found a significant association between our GRS and VTE risk. The risk of VTE among individuals in the highest GRS tertile was 2.02 times that of individuals in the lowest GRS tertile (p-trend = 9.69x10^-19). The OR was 1.52 (p=1.03x10^-8) for participants in the highest GRS tertile compared to those in the medium GRS tertile. However, while BMI and smoking were associated with VTE, and their effects were additive to each other we did not observe any significant multiplicative gene-environment interactions.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Body mass index - smoking - genetic susceptibility - gene-environment interactions - venous thromboembolism

• References

• 1 Heit JA, Phelps MA, Ward SA. et al. Familial segregation of venous thromboembolism. J Thromb Haemost 2004; 02: 731-736.
• 2 Vossen CY, Conard J, Fontcuberta J. et al. Familial thrombophilia and lifetime risk of venous thrombosis. J Thromb Haemost 2004; 02: 1526-1532.
• 3 Vossen CY, Conard J, Fontcuberta J. et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005; 03: 459-464.
• 4 Souto JC, Almasy L, Borrell M. et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia. Am J Hum Genet 2000; 67: 1452-1459.
• 5 Souto JC, Almasy L, Borrell M. et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101: 1546-1551.
• 6 Couturaud F, Kearon C, Leroyer C. et al. Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. Thromb Haemost 2006; 96: 744-749.
• 7 Rosendaal FR, Reitsma PH.. Genetics of venous thrombosis. J Thromb Haemost 2009; 07 (01) 301-304.
• 8 Zoller 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.
• 9 Gohil R, Peck G, Sharma P.. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost 2009; 102: 360-370.
• 10 Ageno W, Squizzato A, Garcia D. et al. Epidemiology and risk factors of venous thromboembolism. Semin Thromb Hemost 2006; 32: 651-658.
• 11 Goldhaber SZ.. Risk factors for venous thromboembolism. J Am Coll Cardiol 2010; 56: 1-7.
• 12 Rosendaal FR.. Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program 2005; 1-12.
• 13 Rosendaal FR.. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
• 14 Kabrhel C, Varraso R, Goldhaber SZ. et al. Prospective study of BMI and the risk of pulmonary embolism in women. Obesity 2009; 17: 2040-2046.
• 15 Goldhaber SZ, Grodstein F, Stampfer MJ. et al. A prospective study of risk factors for pulmonary embolism in women. J Am Med Assoc 1997; 277: 642-645.
• 16 Wolpin BM, Kabrhel C, Varraso R. et al. Prospective study of ABO blood type and the risk of pulmonary embolism in two large cohort studies. Thromb Haemost 2010; 104: 962-971.
• 17 Kraft P, Hunter D.. Integrating epidemiology and genetic association: the challenge of gene-environment interaction. Philos Trans R Soc Lond B Biol Sci 2005; 360: 1609-1616.
• 18 Kraft P, Yen YC, Stram DO. et al. Exploiting gene-environment interaction to detect genetic associations. Hum Hered 2007; 63: 111-119.
• 19 van Boven HH, Vandenbroucke JP, Briet E. et al Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood 1999; 94: 2590-2594.
• 20 Colditz GA.. The nurses' health study: a cohort of US women followed since 1976. Journal of the American Medical Women's Association 1995; 50: 40-44.
• 21 Colditz GA, Martin P, Stampfer MJ. et al. Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am J Epidemiol 1986; 123: 894-900.
• 22 Hankinson SE, Manson JE, Spiegelman D. et al. Reproducibility of plasma hormone levels in postmenopausal women over a 2–3-year period. Cancer Epidemiol Biom Prevent 1995; 04: 649-654.
• 23 Colditz GA, Hankinson SE.. The Nurses' Health Study: lifestyle and health among women. Nature Rev Cancer 2005; 05: 388-396.
• 24 Tworoger SS, Sluss P, Hankinson SE.. Association between plasma prolactin concentrations and risk of breast cancer among predominately premenopausal women. Cancer Res 2006; 66: 2476-2482.
• 25 Giovannucci E, Rimm EB, Liu Y. et al. A prospective study of cruciferous vegetables and prostate cancer. Cancer Epidemiol Biom Prevent 2003; 12: 1403-1409.
• 26 Giovannucci E, Rimm EB, Liu Y. et al. Body mass index and risk of prostate cancer in U. S. health professionals. J Natl Cancer Inst 2003; 95: 1240-1244.
• 27 Hankinson SE, Colditz GA, Hunter DJ. et al. Reproductive factors and family history of breast cancer in relation to plasma estrogen and prolactin levels in postmenopausal women in the Nurses' Health Study (United States). Cancer Causes Control 1995; 06: 217-224.
• 28 Lindstrom S, Chen C, Huang H. et al. A comprehensive survey of genetic variation in 20,769 subjects from the Harvard Cohorts (Abstract #1796). Presented at the 64th Annual Meeting of The American Society of Human Genetics, October 21, 2014. San Diego, CA: 2014
• 29 Rimm EB, Stampfer MJ, Colditz GA. et al. Validity of self-reported waist and hip circumferences in men and women. Epidemiology 1990; 01: 466-473.
• 30 Rimm EB, Giovannucci EL, Stampfer MJ. et al. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol 1992; 135: 1114-1136.
• 31 Pun VC, Hart JE, Kabrhel C. et al. Prospective Study of Ambient Particulate Matter Exposure and Risk of Pulmonary Embolism in the Nurses' Health Study Cohort. Environ Health Perspect. 2015 Epub ahead of print.
• 32 A Catalog of Published Genome-Wide Association Studies. National Human Genome Research Institute. https://www.genome.gov/26525384 [updated July 2015
• 33 Germain M, Chasman DI, de Haan H. et al. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. Am J Hum Genet 2015; 96: 532-542.
• 34 Tang W, Teichert M, Chasman DI. et al. A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. Genet Epidemiol 2013; 37: 512-521.
• 35 Greliche N, Germain M, Lambert JC. et al. A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis. BMC medical Genet 2013; 14: 36.
• 36 Heit JA, Armasu SM, Asmann YW. et al. A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q. J Thromb Haemost 2012; 10: 1521-1531.
• 37 Germain M, Saut N, Greliche N. et al. Genetics of venous thrombosis: insights from a new genome wide association study. PLoS One 2011; 06: e25581.
• 38 Tregouet 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.
• 39 Team RDC. R: A language and environment for statistical computing.. R Foundation for Statistical Computing. Vienna, Austria: 2009
• 40 Howie B, Fuchsberger C, Stephens M. et al. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 2012; 44: 955-959.
• 41 Li Y, Willer CJ, Ding J. et al. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 2010; 34: 816-834.
• 42 Soria JM, Morange PE, Vila J. et al. Multilocus genetic risk scores for venous thromboembolism risk assessment. J Am Heart Assoc 2014; 03: e001060.
• 43 de Haan HG, Bezemer ID, Doggen CJ. et al Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 2012; 120: 656-663.