Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease.
BACKGROUND
Low plasma HDL cholesterol (HDL-C) is associated with an increased risk of coronary artery disease (CAD). We recently identified the ATP-binding cassette transporter 1 (ABCA1) as the major gene underlying the HDL deficiency associated with reduced cholesterol efflux. Mutations within the ABCA1 gene are associated with decreased HDL-C, increased triglycerides, and an increased risk of CAD. However, the extent to which common variation within this gene influences plasma lipid levels and CAD in the general population is unknown.


RESULTS
We examined the phenotypic effects of single nucleotide polymorphisms in the coding region of ABCA1. The R219K variant has a carrier frequency of 46% in Europeans. Carriers have a reduced severity of CAD, decreased focal (minimum obstruction diameter 1.81+/-0.35 versus 1.73+/-0.35 mm in noncarriers, P:=0.001) and diffuse atherosclerosis (mean segment diameter 2.77+/-0.37 versus 2.70+/-0.37 mm, P:=0.005), and fewer coronary events (50% versus 59%, P:=0.02). Atherosclerosis progresses more slowly in carriers of R219K than in noncarriers. Carriers have decreased triglyceride levels (1.42+/-0.49 versus 1.84+/-0.77 mmol/L, P:=0.001) and a trend toward increased HDL-C (0.91+/-0.22 versus 0.88+/-0.20 mmol/L, P:=0.12). Other single nucleotide polymorphisms in the coding region had milder effects on plasma lipids and atherosclerosis.


CONCLUSIONS
These data suggest that common variation in ABCA1 significantly influences plasma lipid levels and the severity of CAD.
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
S M
SM
Clee
A H
AH
Zwinderman
J C
JC
Engert
K Y
KY
Zwarts
H O
HO
Molhuizen
K
K
Roomp
J W
JW
Jukema
M
M
van Wijland
M
M
van Dam
T J
TJ
Hudson
A
A
Brooks-Wilson
J
J
Genest
J J
JJ
Kastelein
M R
MR
Hayden
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000367:Age Factors; D000368:Aged; D019943:Amino Acid Substitution; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000378:metabolism; D015331:Cohort Studies; D003327:Coronary Disease / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D016019:Survival Analysis; D014280:Triglycerides / Q000097:blood
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D008055:Lipids; D008074:Lipoproteins; D014280:Triglycerides