Retrospective analysis of coagulation factor II receptor (F2R) sequence variation and coronary heart disease in hypertensive patients

Objectives: The purpose of this study was to evaluate the role of genetic variants within the coagulation factor II receptor (F2R) in the occurrence of coronary heart disease (CHD).

Methods and results: Four SNPs (-1738 G/A, 2860 G/A, 2930 T/C, and 9113 C/A) and an ins/del polymorphism -506-/GGCCGCGGGAAGC (D/I), replicating a consensus sequence for Ets-1 transcription factor, and their related haplotypes were tested for association to CHD in 1600 hypertensive patients divided in 2 groups according to presence (cases, n=559) and absence (controls, n=1041) of CHD. Allele I at -506 locus was associated with increased risk of CHD under additive, dominant, and recessive models of inheritance (all P<0.01). Three haplotypes carrying I allele were consistently associated with an increased risk of CHD (all P<0.05). Patients homozygous for the C allele at the 2930 locus also showed an increased risk of CHD (P<0.05). To test the functionality of -506 locus, nuclear extracts were incubated with -506D and -506I sequences by EMSA and F2R promoter activity (F2R-A) were assessed in HUVECs transfected with vectors carrying -506D and -506I sequences and exposed to hypoxia. Presence of the -506I sequence was associated with a 26% reduction of affinity binding to nuclear proteins and to blunted F2R-A in response to hypoxia as compared with the -506D sequence (all P<0.05).

Conclusions: F2R genetic variants may influence the natural history of CHD in patients at high risk of cardiovascular events.