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Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease

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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.

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References

  • Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74:106–120

    Article  PubMed  CAS  Google Scholar 

  • Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, Hunter DJ, Thomas G, Hirschhorn JN, Abecasis G, Altshuler D, Bailey-Wilson JE, Brooks LD, Cardon LR, Daly M, Donnelly P, Fraumeni JF Jr, Freimer NB, Gerhard DS, Gunter C, Guttmacher AE, Guyer MS, Harris EL, Hoh J, Hoover R, Kong CA, Merikangas KR, Morton CC, Palmer LJ, Phimister EG, Rice JP, Roberts J, Rotimi C, Tucker MA, Vogan KJ, Wacholder S, Wijsman EM, Winn DM, Collins FS (2007) Replicating genotype-phenotype associations. Nature 447:655–660

    Article  PubMed  CAS  Google Scholar 

  • Cipollone F, Mezzetti A, Fazia ML, Cuccurullo C, Iezzi A, Ucchino S, Spigonardo F, Bucci M, Cuccurullo F, Prescott SM, Stafforini DM (2005) Association between 5-lipoxygenase expression and plaque instability in humans. Arterioscler Thromb Vasc Biol 25:1665–1670

    Article  PubMed  CAS  Google Scholar 

  • Devlin B, Risch N (1995) A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29:311–322

    Article  PubMed  CAS  Google Scholar 

  • Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, Gillard JW, Miller DK (1990) Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 343:282–284

    Article  PubMed  CAS  Google Scholar 

  • Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, Lusis AJ, Mehrabian M (2004) Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med 350:29–37

    Article  PubMed  CAS  Google Scholar 

  • Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927

    PubMed  CAS  Google Scholar 

  • Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:1871–1875

    Article  PubMed  CAS  Google Scholar 

  • Funk CD (2005) Leukotriene modifiers as potential therapeutics for cardiovascular disease. Nat Rev Drug Discov 4:664–672

    Article  PubMed  CAS  Google Scholar 

  • Girelli D, Martinelli N, Trabetti E, Olivieri O, Cavallari U, Malerba G, Busti F, Friso S, Pizzolo F, Pignatti PF, Corrocher R (2007) ALOX5AP gene variants and risk of coronary artery disease: an angiography-based study. Eur J Hum Genet 15:959–966

    Article  PubMed  CAS  Google Scholar 

  • Go AS, Iribarren C, Chandra M, Lathon PV, Fortmann SP, Quertermous T, Hlatky MA (2006) Statin and beta-blocker therapy and the initial presentation of coronary heart disease. Ann Intern Med 144:229–238

    PubMed  CAS  Google Scholar 

  • Gonzalez P, Reguero JR, Lozano I, Moris C, Coto E (2007) A functional Sp1/Egr1-tandem repeat polymorphism in the 5-lipoxygenase gene is not associated with myocardial infarction. Int J Immunogenet 34:127–130

    Article  PubMed  CAS  Google Scholar 

  • Guo SW, Thompson EA (1992) Performing the exact test of Hardy–Weinberg proportion for multiple alleles. Biometrics 48:361–372

    Article  PubMed  CAS  Google Scholar 

  • Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, Samani NJ, Gudmundsson G, Grant SF, Thorgeirsson G, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Johannsson H, Gudmundsdottir O, Gurney ME, Sainz J, Thorhallsdottir M, Andresdottir M, Frigge ML, Topol EJ, Kong A, Gudnason V, Hakonarson H, Gulcher JR, Stefansson K (2004) The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 36:233–239

    Article  PubMed  CAS  Google Scholar 

  • Helgadottir A, Gretarsdottir S, St Clair D, Manolescu A, Cheung J, Thorleifsson G, Pasdar A, Grant SF, Whalley LJ, Hakonarson H, Thorsteinsdottir U, Kong A, Gulcher J, Stefansson K, MacLeod MJ (2005) Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet 76:505–509

    Article  PubMed  CAS  Google Scholar 

  • Hintze J (2006) NCSS, PASS, and GESS. NCSS, Kaysville

  • Holtby S, Zahnd E, Yen W, Lordi N, McCain C, SDiSogra C (2004) Health of California’s adults, adolescents and children: findings from CHIS 2001. UCLA Center for Health Policy Research, Los Angeles

    Google Scholar 

  • Hsieh FY, Lavori PW (2000) Sample-size calculations for the Cox proportional hazards regression model with nonbinary covariates. Control Clin Trials 21:552–560

    Article  PubMed  CAS  Google Scholar 

  • Hughes GH, Cutter G, Donahue R, Friedman GD, Hulley S, Hunkeler E, Jacobs DR Jr, Liu K, Orden S, Pirie P et al (1987) Recruitment in the coronary artery disease risk development in young adults (Cardia) study. Control Clin Trials 8:68S–73S

    Article  PubMed  CAS  Google Scholar 

  • In KH, Asano K, Beier D, Grobholz J, Finn PW, Silverman EK, Silverman ES, Collins T, Fischer AR, Keith TP, Serino K, Kim SW, De Sanctis GT, Yandava C, Pillari A, Rubin P, Kemp J, Israel E, Busse W, Ledford D, Murray JJ, Segal A, Tinkleman D, Drazen JM (1997) Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest 99:1130–1137

    Article  PubMed  CAS  Google Scholar 

  • Iribarren C, Go AS, Husson G, Sidney S, Fair JM, Quertermous T, Hlatky MA, Fortmann SP (2006) Metabolic syndrome and early-onset coronary artery disease: is the whole greater than its parts? J Am Coll Cardiol 48:1800–1807

    Article  PubMed  CAS  Google Scholar 

  • Lotzer K, Funk CD, Habenicht AJ (2005) The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis. Biochim Biophys Acta 1736:30–37

    PubMed  Google Scholar 

  • Ma J, Folsom AR, Shahar E, Eckfeldt JH (1995) Plasma fatty acid composition as an indicator of habitual dietary fat intake in middle-aged adults. The atherosclerosis risk in communities (ARIC) study investigators. Am J Clin Nutr 62:564–571

    PubMed  CAS  Google Scholar 

  • Mehrabian M, Wong J, Wang X, Jiang Z, Shi W, Fogelman AM, Lusis AJ (2001) Genetic locus in mice that blocks development of atherosclerosis despite extreme hyperlipidemia. Circ Res 89:125–130

    Article  PubMed  CAS  Google Scholar 

  • Mehrabian M, Allayee H, Wong J, Shi W, Wang XP, Shaposhnik Z, Funk CD, Lusis AJ (2002) Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res 91:120–126

    Article  PubMed  CAS  Google Scholar 

  • Miller DK, Gillard JW, Vickers PJ, Sadowski S, Leveille C, Mancini JA, Charleson P, Dixon RA, Ford-Hutchinson AW, Fortin R et al (1990) Identification and isolation of a membrane protein necessary for leukotriene production. Nature 343:278–281

    Article  PubMed  CAS  Google Scholar 

  • Morgan TM, Krumholz HM, Lifton RP, Spertus JA (2007) Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. JAMA 297:1551–1561

    Article  PubMed  CAS  Google Scholar 

  • Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959

    PubMed  CAS  Google Scholar 

  • Purcell S, Cherny SS, Sham PC (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150

    Article  PubMed  CAS  Google Scholar 

  • Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, Dixon RJ, Meitinger T, Braund P, Wichmann HE, Barrett JH, Konig IR, Stevens SE, Szymczak S, Tregouet DA, Iles MM, Pahlke F, Pollard H, Lieb W, Cambien F, Fischer M, Ouwehand W, Blankenberg S, Balmforth AJ, Baessler A, Ball SG, Strom TM, Braenne I, Gieger C, Deloukas P, Tobin MD, Ziegler A, Thompson JR, Schunkert H (2007) Genomewide association analysis of coronary artery disease. N Engl J Med 357:443–453

    Google Scholar 

  • Spanbroek R, Grabner R, Lotzer K, Hildner M, Urbach A, Ruhling K, Moos MP, Kaiser B, Cohnert TU, Wahlers T, Zieske A, Plenz G, Robenek H, Salbach P, Kuhn H, Radmark O, Samuelsson B, Habenicht AJ (2003) Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci USA 100:1238–1243

    Article  PubMed  CAS  Google Scholar 

  • Stevens J, Tyroler HA, Cai J, Paton CC, Folsom AR, Tell GS, Schreiner PJ, Chambless LE (1998) Body weight change and carotid artery wall thickness. The atherosclerosis risk in communities (ARIC) study. Am J Epidemiol 147:563–573

    PubMed  CAS  Google Scholar 

  • Strachan T, Read AP (1999) Human molecular genetics 2, 2nd edn. Wiley-Liss, New York

    Google Scholar 

  • Subbarao K, Jala VR, Mathis S, Suttles J, Zacharias W, Ahamed J, Ali H, Tseng MT, Haribabu B (2004) Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms. Arterioscler Thromb Vasc Biol 24:369–375

    Article  PubMed  CAS  Google Scholar 

  • Symons MJ, Moore DT (2002) Hazard rate ratio and prospective epidemiological studies. J Clin Epidemiol 55:893–899

    Article  PubMed  CAS  Google Scholar 

  • Tabibiazar R, Wagner RA, Ashley EA, King JY, Ferrara R, Spin JM, Sanan DA, Narasimhan B, Tibshirani R, Tsao PS, Efron B, Quertermous T (2005a) Signature patterns of gene expression in mouse atherosclerosis and their correlation to human coronary disease. Physiol Genomics 22:213–226

    Article  PubMed  CAS  Google Scholar 

  • Tabibiazar R, Wagner RA, Spin JM, Ashley EA, Narasimhan B, Rubin EM, Efron B, Tsao PS, Tibshirani R, Quertermous T (2005b) Mouse strain-specific differences in vascular wall gene expression and their relationship to vascular disease. Arterioscler Thromb Vasc Biol 25:302–308

    Article  PubMed  CAS  Google Scholar 

  • Taylor-Piliae RE, Norton LC, Haskell WL, Mahbouda MH, Fair JM, Iribarren C, Hlatky MA, Go AS, Fortmann SP (2006) Validation of a new brief physical activity survey among men and women aged 60–69 years. Am J Epidemiol 164(6):598–606

    Article  PubMed  Google Scholar 

  • The ARIC Investigators (1989) The atherosclerosis risk in communities (ARIC) study: design and objectives Am J Epidemiol 129:687–702

    Google Scholar 

  • The ARIC Study Group (1991) High-resolution B-mode ultrasound scanning methods in the atherosclerosis risk in communities study (ARIC) J Neuroimaging 1:68–73

    Google Scholar 

  • The International HapMap Consortium (2003) The International HapMap Project Nature 426:789–796

    Article  Google Scholar 

  • Volcik KA, Ballantyne CM, Coresh J, Folsom AR, Wu KK, Boerwinkle E (2006) P-selectin Thr715Pro polymorphism predicts P-selectin levels but not risk of incident coronary heart disease or ischemic stroke in a cohort of 14595 participants: the atherosclerosis risk in communities study. Atherosclerosis 186:74–79

    Article  PubMed  CAS  Google Scholar 

  • White AD, Folsom AR, Chambless LE, Sharret AR, Yang K, Conwill D, Higgins M, Williams OD, Tyroler HA (1996) Community surveillance of coronary heart disease in the atherosclerosis risk in communities (ARIC) study: methods and initial two years’ experience. J Clin Epidemiol 49:223–233

    Article  PubMed  CAS  Google Scholar 

  • Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG (2002) Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 53:79–91

    Article  PubMed  Google Scholar 

  • Zhao L, Funk CD (2004) Lipoxygenase pathways in atherogenesis. Trends Cardiovasc Med 14:191–195

    Article  PubMed  CAS  Google Scholar 

  • Zhao JH, Curtis D, Sham PC (2000) Model-free analysis and permutation tests for allelic associations. Hum Hered 50:133–139

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The ADVANCE investigators wish to thank the many participants and staff who contributed to the ADVANCE study. The ADVANCE study was supported by a grant from the Donald W. Reynolds Foundation, Las Vegas, NV. JWK is supported by Post-Doctoral Research Fellowships from the Stanford University School of Medicine as well as the American Heart Association and the Integrated Therapeutics Group, Inc through investigator initiated research grants. Role of the Sponsor: The funding agency had no role in the design or conduct of the study; collection, management, analysis or interpretation of the data; or in preparation, review, or approval of the manuscript. The CARDIA study is supported by contracts N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, and N01-HC-95095 from the National Heart, Lung, and Blood Institute. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022. The authors thank the staff and participants of the ARIC study for their important contributions. This study was also supported, in part, by NIH grant HL079353 (HA) and a portion of the work was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 (RR10600-01, CA62528-01, RR14514-01) from the National Center for Research Resources.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Themistocles L. Assimes, Joshua W. Knowles, James R. Priest, Mark Hlatky & Thomas Quertermous

  2. Institute for Human Genetics, University of California, San Francisco, USA

    Analabha Basu & Neil Risch

  3. Human Genetics Center, University of Texas Houston Health Science Center, Houston, TX, USA

    Kelly A. Volcik, Megan L. Grove & Eric Boerwinkle

  4. Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA

    Audrey Southwick, Holly K. Tabor & Richard Myers

  5. Department of Preventive Medicine, General Clinical Research Center, USC Keck School of Medicine, Los Angeles, CA, USA

    Jaana Hartiala & Hooman Allayee

  6. Bay City Capital, San Francisco, CA, USA

    Raymond Tabibiazar

  7. Division of Research, Kaiser Permanente, Oakland, CA, USA

    Stephen Sidney, Alan Go, Carlos Iribarren & Neil Risch

  8. Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA

    Stephen P. Fortmann

  9. Department of Epidemiology and Biostatistics, University of California, San Francisco, USA

    Alan Go, Carlos Iribarren & Neil Risch

  10. Department of Medicine, University of California, San Francisco, USA

    Alan Go

  11. Falk Cardiovascular Research Building, 300 Pasteur Drive, Stanford, CA, 94305-5406, USA

    Themistocles L. Assimes

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  1. Themistocles L. Assimes
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  2. Joshua W. Knowles
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Correspondence to Themistocles L. Assimes.

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Themistocles L. Assimes and Joshua W. Knowles contributed equally to this work.

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Assimes, T.L., Knowles, J.W., Priest, J.R. et al. Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease. Hum Genet 123, 399–408 (2008). https://doi.org/10.1007/s00439-008-0489-5

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