Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach.
BACKGROUND
Recurrent venous thromboembolism (VTE) is a common, complex disorder; however, genetic factors have been suggested to play a role in the disease development. We therefore conducted a multi-locus genetic study examining the potential associations of candidate gene variants in inflammation, thrombosis, coagulation, and lipid metabolism pathways, individually or interactively, with risk of recurrent VTE.


METHODS
Using DNA samples collected at baseline in the Prevention of Recurrent Venous Thromboembolism trial (PREVENT), we genotyped 86 candidate genes polymorphisms among 43 individuals who subsequently developed recurrent VTE and among 396 individuals who remained free of recurrent event over a mean follow-up period of 2.1 years to prospectively determine whether these gene polymorphisms contribute to the risk of recurrent VTE.


RESULTS
Using a single-marker 'uncorrected' analysis, CCR5 A(-2459)G [rs1799864], MMP3 5A(-1171)6A [rs3025058] and PON1 gln192arg [rs662] gene variants were associated with increased risk, and CETP C(-629)A [rs1800775] gene variant with reduced risk of recurrent VTE, respectively. Furthermore, potentially important gene-gene-interactions were detected by the Monte Carlo Markov chain Logic Regression method.


CONCLUSIONS
Although the present findings are hypothesis-generating and require confirmation in an independent investigation, our study provides a practical example of detecting epistasis in common, complex diseases.
Zee
Robert Y L
RY
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. rzee@rics.bwh.harvard.edu
Bubes
Vadim
V
Shrivastava
Sanjay
S
Ridker
Paul M
PM
Glynn
Robert J
RJ
D000368:Aged; D000483:Alleles; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009010:Monte Carlo Method; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D054556:Venous Thromboembolism / Q000453:epidemiology* / Q000235:genetics*
D005819:Genetic Markers