Polymorphism in the beta2-adrenergic receptor and lipoprotein lipase genes as risk determinants for idiopathic venous thromboembolism: a multilocus, population-based, prospective genetic analysis.
BACKGROUND
Candidate genes in inflammation, thrombosis, coagulation, and lipid metabolism pathways have been implicated in venous thromboembolism (VTE).


RESULTS
Using DNA samples collected at baseline in the Physicians' Health Study cohort, we genotyped 92 polymorphisms from 56 candidate genes among 304 individuals who subsequently developed VTE (144 idiopathic, 156 secondary cases) and among 2070 individuals who remained free of reported vascular disease over a mean follow-up of 13.2 years to prospectively determine whether these gene polymorphisms contribute to the risk of VTE. For idiopathic VTE, in addition to the factor V (Leiden) mutation (odds ratio [OR], 5.13; 95% confidence interval [CI], 3.24 to 8.14; P<0.0001; false discovery rate [FDR], P<0.0001), an N291S lipoprotein lipase gene polymorphism (OR, 3.09; 95% CI, 1.56 to 6.09; P=0.001; FDR, P=0.036) and a Q27E beta2-adrenergic receptor gene polymorphism (OR, 1.40; 95% CI, 1.09 to 1.79; P=0.006; FDR, P=0.036) were found to be significantly associated with increased risk. For secondary VTE, a Q360H apolipoprotein A4 gene polymorphism (OR, 0.34; 95% CI, 0.18 to 0.65; P=0.001; FDR, P=0.07) and an I50V interleukin-4 receptor polymorphism (OR, 0.66; 95% CI, 0.52 to 0.84; P=0.0009; FDR, P=0.07) were moderately, but not statistically and significantly, associated with reduced risk after adjustment for multiple comparisons.


CONCLUSIONS
These present findings are hypothesis generating and require replication and confirmation in an independent investigation.
Zee
Robert Y L
RY
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. rzee@rics.bwh.harvard.edu
Cook
Nancy R
NR
Cheng
Suzanne
S
Erlich
Henry A
HA
Lindpaintner
Klaus
K
Ridker
Paul M
PM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001054:Apolipoproteins A / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005165:Factor V / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010820:Physicians / Q000706:statistics & numerical data; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011655:Pulmonary Embolism / Q000453:epidemiology / Q000235:genetics; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D019948:Receptors, Interleukin-4 / Q000235:genetics; D012307:Risk Factors; D013923:Thromboembolism / Q000453:epidemiology / Q000235:genetics*; D019851:Thrombophilia / Q000453:epidemiology / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D020246:Venous Thrombosis / Q000453:epidemiology / Q000235:genetics*
D001054:Apolipoproteins A; D018343:Receptors, Adrenergic, beta-2; D019948:Receptors, Interleukin-4; C022205:apolipoprotein A-IV; C095381:factor V Leiden; D005165:Factor V; D008071:Lipoprotein Lipase