Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes.
BACKGROUND
Cardiovascular disease (CVD) and its most common manifestations--including coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF)--are major causes of morbidity and mortality. In many industrialized countries, cardiovascular disease (CVD) claims more lives each year than any other disease. Heart disease and stroke are the first and third leading causes of death in the United States. Prior investigations have reported several single gene variants associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association study of major CVD outcomes.


METHODS
In 1345 Framingham Heart Study participants from the largest 310 pedigrees (54% women, mean age 33 years at entry), we analyzed associations of 70,987 qualifying SNPs (Affymetrix 100K GeneChip) to four major CVD outcomes: major atherosclerotic CVD (n = 142; myocardial infarction, stroke, CHD death), major CHD (n = 118; myocardial infarction, CHD death), AF (n = 151), and HF (n = 73). Participants free of the condition at entry were included in proportional hazards models. We analyzed model-based deviance residuals using generalized estimating equations to test associations between SNP genotypes and traits in additive genetic models restricted to autosomal SNPs with minor allele frequency > or =0.10, genotype call rate > or =0.80, and Hardy-Weinberg equilibrium p-value > or = 0.001.


RESULTS
Six associations yielded p < 10(-5). The lowest p-values for each CVD trait were as follows: major CVD, rs499818, p = 6.6 x 10(-6); major CHD, rs2549513, p = 9.7 x 10(-6); AF, rs958546, p = 4.8 x 10(-6); HF: rs740363, p = 8.8 x 10(-6). Of note, we found associations of a 13 Kb region on chromosome 9p21 with major CVD (p 1.7-1.9 x 10(-5)) and major CHD (p 2.5-3.5 x 10(-4)) that confirm associations with CHD in two recently reported genome-wide association studies. Also, rs10501920 in CNTN5 was associated with AF (p = 9.4 x 10(-6)) and HF (p = 1.2 x 10(-4)). Complete results for these phenotypes can be found at the dbgap website http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.


CONCLUSIONS
No association attained genome-wide significance, but several intriguing findings emerged. Notably, we replicated associations of chromosome 9p21 with major CVD. Additional studies are needed to validate these results. Finding genetic variants associated with CVD may point to novel disease pathways and identify potential targeted preventive therapies.
Larson
Martin G
MG
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA. mlarson@bu.edu
Atwood
Larry D
LD
Benjamin
Emelia J
EJ
Cupples
L Adrienne
LA
D'Agostino
Ralph B
RB
Fox
Caroline S
CS
Govindaraju
Diddahally R
DR
Guo
Chao-Yu
CY
Heard-Costa
Nancy L
NL
Hwang
Shih-Jen
SJ
Murabito
Joanne M
JM
Newton-Cheh
Christopher
C
O'Donnell
Christopher J
CJ
Seshadri
Sudha
S
Vasan
Ramachandran S
RS
Wang
Thomas J
TJ
Wolf
Philip A
PA
Levy
Daniel
D
D000328:Adult; D002318:Cardiovascular Diseases / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9; D015331:Cohort Studies; D004198:Disease Susceptibility; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D016896:Treatment Outcome
D005819:Genetic Markers