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Prepublished online as a Blood First Edition Paper on December 12, 2002; DOI 10.1182/blood-2002-09-2888.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3037-3041
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Combined carrier status of prothrombin 20210A and factor
XIII-A Leu34 alleles as a strong risk factor for myocardial
infarction: evidence of a gene-gene interaction
Christopher Butt,
Hong Zheng,
Edward Randell,
Desmond Robb,
Patrick Parfrey, and
Ya-Gang Xie
From the Disciplines of Laboratory Medicine, Genetics,
Pediatrics, and Medicine, Memorial University of Newfoundland, St
John's, NF, Canada.
Studies associating the prothrombin 20210G>A (FII 20210A),
factor V Leiden (FVL), and factor XIII Leu34 (FXIII-A Leu34) alleles with myocardial infarction (MI) have yielded conflicting results. Complicated gene-gene interactions, small sample sizes, and
heterogeneous genetic and environmental backgrounds may contribute to
opposing findings. Simultaneous analysis of multiple gene variants in a large sample size from a genetically isolated population may overcome these weaknesses. Genotyping was performed in 500 MI patients and 500 control subjects from the genetically isolated Newfoundland population
to determine the prevalence of the FII 20210A, FVL, and FXIII-A Leu34
variants and their association with MI. Gene-gene interactions were
also analyzed. The prevalence of the FII 20210A allele was higher in MI
patients (3.2%) than in control subjects (1.0%;
P = .015). The FII 20210A allele was also 5.6-fold higher in MI patients younger than 51 years than in age-matched control subjects (P = .04). FVL showed 3.9-fold higher prevalence
in young patients than in patients older than 50 years
(P = .004) and 2.7-fold higher than in age-matched
control subjects (P = .007). Furthermore, the prevalence
of combined carriers of the FXIII-A L34 and FII 20210A alleles was
12-fold higher in MI patients than in control subjects
(P = .002) and with 92% penetrance. There was
disequilibrium of the FXIII-A Leu34 allele to MI patients carrying the
FII 20210A allele as a genetic background. Based on our data, we
determined that (1) the FII 20210A allele is a risk factor for MI,
possibly important for early onset; (2) FVL may predispose for
early-onset MI; (3) the FXIII-A Leu34 allele predisposes for MI in
males only; however, (4) interaction between the FII 20210A and FXIII-A
Leu34 alleles forms a synergistic coeffect that strongly predisposes for MI, placing combined carriers at high risk for MI.
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