SREBP-2 and SCAP isoforms and risk of early onset myocardial infarction.
BACKGROUND
Cholesterol metabolism is mediated, in part, by the sterol-regulatory element binding proteins (SREBPs) that are activated by a SREBP cleavage-activating protein (SCAP). We examined whether coding variations in the interacting domains of both genes, are related to early-onset MI risk in a population-based case-control study from western Washington State.


METHODS
Cases were 257 women, aged 18-59 years, and 320 men, aged 18-49 years, with first acute non-fatal MI; controls were 353 women and 311 men, similar in age, identified from the community who had no history of clinical CHD or stroke. Genotyping of the SREBF-2 G1784C polymorphism (SREBP-2-595A/G isoforms), and the SCAP A2386G polymorphism (SCAP-796I/V isoforms), were performed.


RESULTS
After adjustment for age and race, the SREBP-2-595A isoform was associated with increased MI risk among men (OR=1.63, 95% CI=1.26-2.12). In contrast, there was little evidence for an association among women in a multiplicative model. However, compared to SREBP-2-595G homozygotes, homozygote women for the SREBP-2-595A isoform were at nearly two-fold increased risk (OR=1.95, 95% CI=1.07-3.54). Overall, SCAP genotypes were neither associated with MI in men nor in women. However, in men, SCAP genotypes were found to modify the association between SREBF-2 and MI (p-value for interaction=0.01).


CONCLUSIONS
The SREBP-2-595A isoform was associated with an increased risk of early-onset MI in U.S. men. The SCAP polymorphism appeared to modify the associations of SREBF-2 genotype with MI risk among men. These novel findings require confirmation in other populations.
Friedlander
Yechiel
Y
Unit of Epidemiology, Hebrew University-Hadassah School of Public Health, Jerusalem, Israel.
Schwartz
Stephen M
SM
Durst
Ronen
R
Meiner
Vardiella
V
Robertson
Andrea S
AS
Erez
Gilli
G
Leitersdorf
Eran
E
Siscovick
David S
DS
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics; D012306:Risk; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; D051782:Sterol Regulatory Element Binding Protein 2