A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease.
OBJECTIVE
Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene (ALOX15) alter the risk of symptomatic coronary artery disease (CAD).


RESULTS
We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P=0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P=0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P=0.63 and HR, 0.93; P=0.9).


CONCLUSIONS
A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout studies.
Assimes
Themistocles L
TL
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5406, USA. tassimes@cvmed.stanford.edu
Knowles
Joshua W
JW
Priest
James R
JR
Basu
Analabha
A
Borchert
Astrid
A
Volcik
Kelly A
KA
Grove
Megan L
ML
Tabor
Holly K
HK
Southwick
Audrey
A
Tabibiazar
Raymond
R
Sidney
Steve
S
Boerwinkle
Eric
E
Go
Alan S
AS
Iribarren
Carlos
C
Hlatky
Mark A
MA
Fortmann
Stephen P
SP
Myers
Richard M
RM
Kuhn
Hartmut
H
Risch
Neil
N
Quertermous
Thomas
T
D000368:Aged; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics*; D045744:Cell Line, Tumor; D003324:Coronary Artery Disease / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012307:Risk Factors
C475064:12-15-lipoxygenase; D001092:Arachidonate 12-Lipoxygenase; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase