Association between a literature-based genetic risk score and cardiovascular events in women.
BACKGROUND
While multiple genetic markers associated with cardiovascular disease have been identified by genome-wide association studies, their aggregate effect on risk beyond traditional factors is uncertain, particularly among women.


OBJECTIVE
To test the predictive ability of a literature-based genetic risk score for cardiovascular disease.


METHODS
Prospective cohort of 19,313 initially healthy white women in the Women's Genome Health Study followed up over a median of 12.3 years (interquartile range, 11.6-12.8 years). Genetic risk scores were constructed from the National Human Genome Research Institute's catalog of genome-wide association study results published between 2005 and June 2009.


METHODS
Incident myocardial infarction, stroke, arterial revascularization, and cardiovascular death.


RESULTS
A total of 101 single nucleotide polymorphisms reported to be associated with cardiovascular disease or at least 1 intermediate cardiovascular disease phenotype at a published P value of less than 10(-7) were identified and risk alleles were added to create a genetic risk score. During follow-up, 777 cardiovascular disease events occurred (199 myocardial infarctions, 203 strokes, 63 cardiovascular deaths, 312 revascularizations). After adjustment for age, the genetic risk score had a hazard ratio (HR) for cardiovascular disease of 1.02 per risk allele (95% confidence interval [CI], 1.00-1.03/risk allele; P = .006). This corresponds to an absolute cardiovascular disease risk of 3% over 10 years in the lowest tertile of genetic risk (73-99 risk alleles) and 3.7% in the highest tertile (106-125 risk alleles). However, after adjustment for traditional factors, the genetic risk score did not improve discrimination or reclassification (change in c index from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [ATP III] risk score, 0; net reclassification improvement, 0.5%; [P = .24]). The genetic risk score was not associated with cardiovascular disease risk (ATP III-adjusted HR/allele, 1.00; 95% CI, 0.99-1.01). In contrast, self-reported family history remained significantly associated with cardiovascular disease in multivariable models.


CONCLUSIONS
After adjustment for traditional cardiovascular risk factors, a genetic risk score comprising 101 single nucleotide polymorphisms was not significantly associated with the incidence of total cardiovascular disease.
Center for Cardiovascular Disease Prevention and the Divisions of Preventive Medicine and Cardiovascular Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. npaynter@partners.org
Nina P
NP
Paynter
Daniel I
DI
Chasman
Guillaume
G
Paré
Julie E
JE
Buring
Nancy R
NR
Cook
Joseph P
JP
Miletich
Paul M
PM
Ridker
D000483:Alleles; D002318:Cardiovascular Diseases / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012306:Risk
D005819:Genetic Markers