Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and coronary heart disease risk in familial hypercholesterolemia.
OBJECTIVE
To investigate the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene as a potential modifier gene for coronary heart disease (CHD) in patients with familial hypercholesterolemia (FH).


BACKGROUND
The ALOX5AP gene is required for the synthesis of leukotrienes, a protein family involved in inflammatory responses. Recently, genetic variation in this gene was shown to be associated with myocardial infarction in an Icelandic and British population. Since FH is characterized by severely increased levels of plasma low-density lipoprotein (LDL) cholesterol levels, chronic inflammation of the arterial wall, and subsequent premature CHD, the ALOX5AP gene could be an important modifier gene for CHD in FH.


METHODS
In a cohort of 1817 FH patients, we reconstructed two four-marker haplotypes, previously defined in Icelandic (HapA) and British (HapB) individuals. The haplotypes were inferred with PHASE and the associations between the haplotypes and CHD were analyzed with a Cox proportional hazards model, adjusted for year of birth, sex, and smoking.


RESULTS
HapB had a frequency of 6.9% and 8.2% in the group without and with CHD, respectively, conferring a hazard ratio of 1.48 (95% CI 1.17-1.89, p=0.001). This association was predominantly found in patients with LDL cholesterol levels above the median (HR 1.82, 95% CI 1.20-2.76, p=0.005). HapA was not associated with CHD.


CONCLUSIONS
We conclude that genetic variation in the ALOX5AP gene contributes to CHD risk in patients with FH. Our findings emphasize the important role of inflammation in the pathogenesis of early CHD in this disorder, particularly in patients with more severely raised LDL cholesterol levels.
van der Net
Jeroen B
JB
Department of Internal Medicine, Erasmus MC - University Medical Center, Rotterdam, The Netherlands.
Versmissen
Jorie
J
Oosterveer
Daniëlla M
DM
Defesche
Joep C
JC
Yazdanpanah
Mojgan
M
Aouizerat
Bradley E
BE
Steyerberg
Ewout W
EW
Malloy
Mary J
MJ
Pullinger
Clive R
CR
Kane
John P
JP
Kastelein
John J P
JJ
Sijbrands
Eric J G
EJ
D058927:5-Lipoxygenase-Activating Proteins; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D015331:Cohort Studies; D003327:Coronary Disease / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000235:genetics*; D007249:Inflammation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D016016:Proportional Hazards Models; D012306:Risk
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D008078:Cholesterol, LDL; D008565:Membrane Proteins