Abstract
Arachidonate 5-lipoxygenase activating protein (ALOX5AP) has been reported to demonstrate linkage and association with ischemic stroke and myocardial infarction. However, replication studies have been conflicting and to date, a significant proportion of blacks have not been studied. We prospectively recruited cases of ischemic stroke from all 16 hospitals in the Greater Cincinnati/Northern Kentucky region and demographically matched them to stroke-free population-based controls. Single nucleotide polymorphisms (SNPs) were selected based on association with ischemic stroke in prior studies. Allelic, genotypic and haplotypic association testing was performed using HAPLOVIEW. Multiple logistic regression was used to control for the presence of traditional risk factors including hypertension, diabetes, hypercholesterolemia and smoking. A total of 357 cases and 482 controls were genotyped. The SNPs, rs9579646 and rs4769874 were found to be significantly associated at both allelic (P = 0.019 and P < 10−4, respectively) and genotypic level with ischemic stroke among whites after correction for multiple testing. Haplotype association was identified with ischemic stroke as well as ischemic stroke subtypes among whites. Although an overall haplotype association with ischemic stroke was identified among blacks no evidence of association among individual haplotypes, alleles or genotypes were observed. Allele frequencies for the SNPs examined were markedly different among whites and blacks. In conclusion, we report significant association of variants of ALOX5AP with ischemic stroke and ischemic stroke subtypes among whites. No significant association was identified among blacks.
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References
Armitage P (1955) Tests for linear trends in proportions and frequencies. Biometrics 11:375–386
van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM (2005) C-reactive protein and cerebral small-vessel disease: the Rotterdam scan study. Circulation 112:900–905
Elkind MS, Cheng J, Boden_Albala B, Paik MC, Sacco RL (2001) Elevated white blood cell count and carotid plaque thickness: the northern manhattan stroke study. Stroke 32:842–849
Elkind MS, Sciacca RR, Boden-Albala B, Rundek T, Paik MC, Sacco RL (2005) Relative elevation in baseline leukocyte count predicts first cerebral infarction. Neurology 64:2121–2125
Hakonarson H, Thorvaldsson S, Helgadottir A, Gudbjartsson D, Zink F, Andresdottir M, Manolescu A, Arnar DO, Andersen K, Sigurdsson A, Thorgeirsson G, Jonsson A, Agnarsson U, Bjornsdottir H, Gottskalksson G, Einarsson A, Gudmundsdottir H, Adalsteinsdottir AE, Gudmundsson K, Kristjansson K, Hardarson T, Kristinsson A, Topol EJ, Gulcher J, Kong A, Gurney M, Stefansson K (2005) Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA 293:2245–2256
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
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
Jiang Z, Dalton TP, Jin L, Wang B, Tsuneoka Y, Shertzer HG, Deka R, Nebert DW (2005) Toward the evaluation of function in genetic variability: characterizing human SNP frequencies and establishing BAC-transgenic mice carrying the human CYP1A1_CYP1A2 locus. Hum Mutant 25:196–206
Kajimoto K, Shioji K, Ishida C, Iwanaga Y, Kokubo Y, Tomoike H, Miyazaki S, Nonogi H, Goto Y, Iwai N (2005) Validation of the association between the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a Japanese population. Circ J 69:1029–1034
Kissela B, Schneider A, Kleindorfer D, Khoury J, Miller R, Alwell K, Woo D, Szaflarski J, Gebel J, Moomaw C, Pancioli A, Jauch E, Shukla R, Broderick J (2004) Stroke in a biracial population: the excess burden of stroke among blacks. Stroke 35:426–431
Lohmussaar E, Gschwendtner A, Mueller JC, Org T, Wichmann E, Hamann G, Meitinger T, Dichgans M (2005) ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke 36:731–736
Meschia JF, Brott TG, Brown RD, Crook R Jr, Worrall BB, Kissela B, Brown WM, Rich SS, Case LD, Evans EW, Hague S, Singleton A, Hardy J (2005) Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol 58:351–361
Silva EP, Fonseca FA, Ihara SS, Izar MC, Lopes IL, Pinto LE, Badimon JJ, Tuffik S, Paiva TB, Kasinski N, de Paola AV, Carvalho AC (2002) Early benefits of pravastatin to experimentally induced atherosclerosis. J Cardiovasc Pharmacol 39:389–395
Sun G, Kaushal R, Pal P, Wolujewicz M, Smelser D, Cheng H, Lu M, Chakraborty R, Jin L, Deka R (2005) Whole-genome amplification: relative efficiencies of the current methods. Leg Med 7:279–286
Woo D, Kaushal R, Kissela B, Sekar P, Wolujewicz M, Pal P, Alwell K, Haverbusch M, Ewing I, Miller R, Kleindorfer D, Flaherty M, Chakraborty R, Deka R, Broderick J (2006) Association of phosphodiesterase 4D with ischemic stroke: a population-based case-control study. Stroke 37:371–376
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
Zee RY, Cheng S, Hegener HH, Erlich HA, Ridker PM (2006) Genetic variants of arachidonate 5-lipoxygenase-activating protein, and risk of incident myocardial infarction and ischemic stroke: a nested case-control approach. Stroke 37:2007–2011
Acknowledgments
This study was funded by the National Institute of Neurological Disorders and Stroke (R-O1-NS36695; R-O1-NS30678), the National Institute of Environmental Health Sciences (R-O1-ES-06096), and Elizabeth B. Lips Memorial Fund of the Greater Cincinnati Foundation.
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Kaushal, R., Pal, P., Alwell, K. et al. Association of ALOX5AP with ischemic stroke: a population-based case-control study. Hum Genet 121, 601–607 (2007). https://doi.org/10.1007/s00439-007-0338-y
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DOI: https://doi.org/10.1007/s00439-007-0338-y