Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease |
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| Authors: | Themistocles L Assimes Joshua W Knowles James R Priest Analabha Basu Kelly A Volcik Audrey Southwick Holly K Tabor Jaana Hartiala Hooman Allayee Megan L Grove Raymond Tabibiazar Stephen Sidney Stephen P Fortmann Alan Go Mark Hlatky Carlos Iribarren Eric Boerwinkle Richard Myers Neil Risch Thomas Quertermous |
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| Institution: | (1) Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA;(2) Institute for Human Genetics, University of California, San Francisco, USA;(3) Human Genetics Center, University of Texas Houston Health Science Center, Houston, TX, USA;(4) Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA;(5) Department of Preventive Medicine, General Clinical Research Center, USC Keck School of Medicine, Los Angeles, CA, USA;(6) Bay City Capital, San Francisco, CA, USA;(7) Division of Research, Kaiser Permanente, Oakland, CA, USA;(8) Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA;(9) Department of Epidemiology and Biostatistics, University of California, San Francisco, USA;(10) Department of Medicine, University of California, San Francisco, USA;(11) Falk Cardiovascular Research Building, 300 Pasteur Drive, Stanford, CA 94305-5406, USA |
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| Abstract: | Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and
subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including
a subset of participants of the coronary artery risk development in young adults study. A nominally significant association
was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model,
1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at
the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced
in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our
power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk
of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.
Themistocles L. Assimes and Joshua W. Knowles contributed equally to this work. |
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