A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease.
OBJECTIVE
The purpose of this study was to identify genetic variants associated with severe coronary artery disease (CAD).


RESULTS
We used 3 case-control studies of white subjects whose severity of CAD was assessed by angiography. The first 2 studies were used to generate hypotheses that were then tested in the third study. We tested 12,077 putative functional single nucleotide polymorphisms (SNPs) in Study 1 (781 cases, 603 controls) and identified 302 SNPs nominally associated with severe CAD. Testing these 302 SNPs in Study 2 (471 cases, 298 controls), we found 5 (in LPA, CALM1, HAP1, AP3B1, and ABCG2) were nominally associated with severe CAD and had the same risk alleles in both studies. We then tested these 5 SNPs in Study 3 (554 cases, 373 controls). We found 1 SNP that was associated with severe CAD: LPA I4399M (rs3798220). LPA encodes apolipoprotein(a), a component of lipoprotein(a). I4399M is located in the protease-like domain of apolipoprotein(a). Compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (confidence interval 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels (P=0.003).


CONCLUSIONS
The LPA I4399M SNP is associated with severe CAD and plasma lipoprotein(a) levels.
Luke
May M
MM
Celera, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA. may.luke@celera.com
Kane
John P
JP
Liu
Dongming M
DM
Rowland
Charles M
CM
Shiffman
Dov
D
Cassano
June
J
Catanese
Joseph J
JJ
Pullinger
Clive R
CR
Leong
Diane U
DU
Arellano
Andre R
AR
Tong
Carmen H
CH
Movsesyan
Irina
I
Naya-Vigne
Josephina
J
Noordhof
Curtis
C
Feric
Nicole T
NT
Malloy
Mary J
MJ
Topol
Eric J
EJ
Koschinsky
Marlys L
ML
Devlin
James J
JJ
Ellis
Stephen G
SG
D000368:Aged; D053241:Apoprotein(a) / Q000235:genetics*; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D053241:Apoprotein(a)