Interactions of established risk factors and a GWAS-based genetic risk score on the risk of venous thromboembolism.
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 = 9.69×10(-19)). The OR was 1.52 (p=1.03×10(-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.
Marta
M
Crous-Bou
Immaculata
I
De Vivo
Carlos A
CA
Camargo
Raphaëlle
R
Varraso
Francine
F
Grodstein
Majken K
MK
Jensen
Peter
P
Kraft
Samuel Z
SZ
Goldhaber
Sara
S
Lindström
Christopher Kabrhel, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, USA, Tel.: +1 617 7265824, Fax: +1 617 7240917, E-mail: ckabrhel@partners.org.
Christopher
C
Kabrhel
D000328:Adult; D015992:Body Mass Index; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D054556:Venous Thromboembolism / Q000235:genetics*
Body mass index; gene-environment interactions; genetic susceptibility; smoking; venous thromboembolism