Identification of Genetic Interaction with Risk Factors Using a Time-To-Event Model

Int J Environ Res Public Health. 2017 Oct 15;14(10):1228. doi: 10.3390/ijerph14101228.


Background: Certain diseases can occur with and without a trigger. We use Venous Thromboembolism (VTE) as our example to identify genetic interaction with pregnancy in women with VTE during pre- or postpartum. Pregnancy is one of the major risk factors for VTE as it accounts for 10% of maternal deaths.

Methods: We performed a whole genome association analysis using the Cox Proportional Hazard (CoxPH) model adjusted for covariates to identify genetic variants associated with the time-to-event of VTE related to pre- or postpartum during the childbearing age of 18-45 years using a case-only design in a cohort of women with VTE. Women with a VTE event after 45 years of age were censored and contributed only follow-up time.

Results: We identified two intragenic single nucleotide polymorphisms (SNPs) at genome-wide significance in the PURB gene located on chromosome 7, and two additional intragenic SNPs, one in the LINGO2 gene on chromosome 9 and one in RDXP2 on chromosome X.

Conclusions: We showed that the time-to-event model is a useful approach for identifying potential hazard-modification of the genetic variants when the event of interest (VTE) occurs due to a risk factor (pre- or post-partum).

Keywords: genetic variation; genome-wide association study; pregnancy complications; risk factors; venous thromboembolism.

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Female
  • Genome-Wide Association Study
  • Humans
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Postpartum Period / genetics
  • Pregnancy / genetics
  • Pregnancy Complications, Cardiovascular / epidemiology
  • Pregnancy Complications, Cardiovascular / genetics*
  • Proportional Hazards Models
  • Risk Factors
  • Venous Thromboembolism / epidemiology
  • Venous Thromboembolism / genetics*
  • Young Adult