Association of ALOX5AP with ischemic stroke in eastern Chinese

doi:10.5847/wjem.j.issn.1920-8642.2012.02.005

Abstract

Abstract:

BACKGROUND: 5-lipoxygenase protein (ALOX5AP) has been recognized as a susceptibility gene for stroke and coronary artery diseases. The present study was to explore the role of this gene in the eastern Chinese patients with ischemic stroke.

METHODS: Using a case-control design, we studied 658 patients with ischemic stroke and 704 unrelated population-based controls who were age- and sex-matched. The 658 patients were classified by the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Two single-nucleotide polymorphisms (SNPs) covering ALOX5AP were genotyped.

RESULTS: The genotype frequencies of TG of the SNPs rs17222919 located in the promoter of the ALOX5AP gene were significantly higher in patients with ischemic stroke than in controls (OR^*=1.34, 95%CI^*=1.02-1.75), especially in patients with ischemic stroke caused by small-artery occlusion (SAO) (OR^*=1.40, 95%CI^*=1.02-1.93). Meanwhile, the genotype frequencies of TG and TG/GG were higher in female patients than in the controls. After specification, the genotype frequencies of TG and TG/GG were higher in the patients than in controls with hypertension. The genotype frequencies of AG and AG/GG of the SNPs rs9579646 located in the intron of the ALOX5AP gene were higher in the controls than in the patients. After specification, the genotype frequencies of TG were higher in the controls than patients without hypertension.

CONCLUSION: The present study suggests that sequence variants in the ALOX5AP gene are significantly associated with ischemic stroke.

Key words: 5-lipoxygenase activating protein (ALOX5AP), Leukotrienes (LTs), Trial of Org 10172 in Acute Stroke Treatment (TOAST), Single nucleotide polymorphisms (SNPs), Ischemic stroke

Yao Wang, Gan-nan Wang, Hao Sun, Chen Chen, Hang Xiao, Jin-song Zhang. Association of ALOX5AP with ischemic stroke in eastern Chinese[J]. World Journal of Emergency Medicine, 2012, 3(2): 108-113.

Figures/Tables 4

Table 1

Table 2

Table 3

Table 4

References 27

1	Feigin VL. Stroke epidemiology in the developing world. Lancet 2005; 365:2160-2161. doi: 10.1016/S0140-6736(05)66755-4 pmid: 15978910
2	Markus HS. Stroke genetics. Hum medGenet 2011; 20:R124-131.
3	Matarin M, Singleton A, Hardy J, Meschia J. The genetics of ischaemic stroke. J Intern Med 2010; 267:139-155. doi: 10.1111/j.1365-2796.2009.02202.x pmid: 20175863
4	Flossmann E, Schulz UG, Rothwell PM. Potential confounding by intermediate phenotypes in studies of the genetics of ischaemic stroke. Cerebrovasc Dis 2005; 19:1-10.Epub 2004 Nov 3.
5	Flossmann E, Schulz UG, Rothwell PM. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke 2004; 35:212-227.Epub 2003 Dec 18. Review. Review.
6	Dichgans M. Genetics of ischaemic stroke. Lancet Neurol 2007; 6:149-161. doi: 10.1016/S1474-4422(07)70028-5 pmid: 17239802
7	Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U. et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nature Genetics 2004; 36:233-239. doi: 10.1038/ng1311 pmid: 14770184
8	De Caterina R. From athma to atherosclerosis 5-lipoxygenase, leukotrienes, and information. N Engl J Med 2004; 350:4-7. doi: 10.1056/NEJMp038190 pmid: 14702420
9	Brezinski DA, Nesto RW, Serhan CN. Angioplasty triggers intracoronary leukotrienes and lipoxin A4. Impact of aspirin therapy. Circulation 1992; 86:56-63. doi: 10.1161/01.cir.86.1.56 pmid: 1617790
10	Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF. et al. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 1990; 343:282-284. doi: 10.1038/343282a0 pmid: 2300173
11	Mehrabian M, Allayee H, Wong J, Shi W, Wang XP, Shaposhnik Z. et al. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res 2002; 91:120-126. doi: 10.1161/01.res.0000028008.99774.7f pmid: 12142344
12	Spanbroek R, Grabner R, Lotzer K, Hildner M, Urbach A, Ruhling K. et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci USA 2003; 100:1238-1243. doi: 10.1073/pnas.242716099 pmid: 12552108
13	Kajimoto K, Shioji K, Ishida C, Iwanaga Y, Kokubo Y, Tomoike H. et al. Validation of the association between the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a Japanese population. Circ J 2005; 69:1029-1034. doi: 10.1253/circj.69.1029 pmid: 16127181
14	Meschia JF, Brott TG, Brown RD Jr, Crook R, Worrall BB, Kissela B. et al. Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol 2005; 58:351-361. doi: 10.1002/ana.20585 pmid: 16130105
15	Liu J, Sun K, Bai Y, Zhang W, Wang X, Wang Y. et al. Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case-control study. Hum Genet 2009; 125:649-56.Epub 2009 Apr 17. doi: 10.1007/s00439-009-0659-0 pmid: 19373490
16	Quarta G, Stanzione R, Evangelista A, Zanda B, Di Angelantonio E, Marchitti S. et al. Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians. Eur J Hum Genet 2009; 17:1448-53.Epub 2009 May 6. doi: 10.1038/ejhg.2009.71 pmid: 19417766
17	Helgadottir A, Gretarsdottir S, St Clair D, Manolescu A, Cheung J, Thorleifsson G. et al. Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet 2005; 76:505-514. doi: 10.1086/428066 pmid: 15640973
18	Lõhmussaar E, Gschwendtner A, Mueller JC, Org T, Wichmann E, Hamann G. et al. ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke 2005; 36:731-736. doi: 10.1161/01.STR.0000157587.59821.87 pmid: 15731479
19	Zee, RYL. Genetic Variants of arachidonate 5-lipoxygenase-activating protein, and risk of incident myocardial infarction and ischemic stroke: A nested case-control approach. Stroke 2006; 37:2007-2011. doi: 10.1161/01.STR.0000229905.25080.01 pmid: 16778124
20	Kaushal R, Pal P, Alwell K, Haverbusch M, Flaherty M, Moomaw C. et al. Association of ALOX5AP with ischemic stroke: a population-based case-control study. Human Genetics 2007; 121:601-607. doi: 10.1007/s00439-007-0338-y pmid: 17387518
21	Zintzaras E, Rodopoulou, Sakellaridis. Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of stroke: A Huge gene-disease association review and meta-analysis. Am J Epidemiol 2008; 169:523-532. doi: 10.1093/aje/kwn368 pmid: 19126581
22	Domingues-Montanari S, Fernández-Cadenas I, del Rio-Espinola A, Corbeto N, Krug T, Manso H. et al. Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: A case-control, meta-analysis and functional study. Cerebrovascular Dis 2010; 29:528-537.
23	Sun H, Wu H, Zhang J, Wang J, Lu Y, Ding H. et al. A tagging SNP in ALOX5AP and risk of stroke: a haplotype-based analysis among eastern Chinese Han population. Molecular Biology Reports 2011; 38:4731-4739. doi: 10.1007/s11033-010-0610-4 pmid: 21153769
24	Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL. et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment. Stroke 1993; 24:35-41. doi: 10.1161/01.str.24.1.35 pmid: 7678184
25	Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21:263-265. doi: 10.1093/bioinformatics/bth457 pmid: 15297300
26	Kim DH, Ahn WY, Kim DK, Choe BK, Kim SK, Jo DJ. et al. A Promoter polymorphism (rs17222919,-1316T/G) of ALOX5AP is associated with intracerebral hemorrhage in Korean population. Prostaglandins Leukot Essent Fatty Acids 2011; 85:115-120. doi: 10.1016/j.plefa.2011.07.004 pmid: 21816595
27	Bondarenko EA, Slominskiĭ PA, Limborskaia SA, Shetova IM, Timofeev DY, Skvortsova VI. Polymorphic variants of ALOX5AP gene and the risk of acute stroke development in the Russian population. Genetika 2011; 47:570-573. pmid: 21675249

Parameters	Patients (n=658)		Controls (n=704)		P^*
Parameters	Number	%	Number	%	P^*
Age (average ± SD, year)	69.42±10.58		69.22 ±9.04		0.070
Gender					0.096
Male	392	59.97	388	55.11
Female	266	40.03	316	44.89
BMI (kg/m²)	24.20 ±3.18		23.27±2.38		<0.001
Smoking	164	24.92	179	25.43	0.831
Drinking	111	16.87	136	19.32	0.241
Coronary artery disease	128	19.45	17	2.41	<0.001
Hypertension	514	78.12	218	30.97	<0.001
Diabetes	223	33.89	89	12.64	<0.001
TIA	168	25.53	8	1.14	<0.001
Blood glucose (mmol/L)	6.42±2.64		5.90±2.41		0.000
TC (mmol/L)	4.67±1.17		4.44±1.18		0.001
TG (mmol/L)	1.68±1.25		1.37±0.92		<0.001
HDL (mmol/L)	1.28±3.04		1.26±0.35		0.893

SNP	Patients		Controls		P value	OR^*	95% CI^*
SNP	n	%	n	%	P value	OR^*	95% CI^*
rs17222919^a
TT	417	63.37	469	66.81		1.00	—
TG	219	33.28	207	29.49		1.34	1.02-1.75
GG	22	3.34	26	3.70		0.83	0.42-1.66
rs9579646^a
TG/GG	241	36.63	233	33.19	0.184	1.28	0.98-1.65
AA	171	26.03	169	24.25	0.681	1.00	—
AG	325	49.47	360	51.65		0.78	0.58-1.05
GG	161	24.51	168	24.10		0.95	0.67-1.36
AG/GG	486	73.97	528	75.75	0.450	0.83	0.62-1.11

SNP	LAA		CE		SAO		OC		SUD		P value
SNP	OR	95% CI^*	OR	95% CI^*	OR	95% CI^*	OR	95% CI^*	OR	95% CI^*	P value
TT	1.00		1.00		1.00		1.00		1.00		0.80
TG	1.36	(0.91-2.02)	1.17	(0.64-2.12)	1.40	(1.02-1.93)	2.57	(0.87-7.57)	0.66	(0.31-1.38)
GG	0.39	(0.13-1.20)	0.84	(0.18-3.98)	0.89	(0.41-1.96)			0.85	(0.11-6.67)
TG/GG	1.17	(0.79-1.72)	1.31	(0.64-2.02)	1.35	(0.99-1.84)	2.07	(0.70-6.10)	1.78	(0.85-3.74)	0.49

Variables	rs17222919 OR^* (95% CI^* )^a				rs9579646 OR^* (95% CI^* )^b
Variables	TT	TG	GG	TG/GG	AA	AG	GG	AG/GG
Gender
Male	1.00	1.08 (0.75-1.55)	0.86 (0.38-1.95)	1.04 (0.74-1.48)	1.00	0.69 (0.49-0.97)	1.07 (0.72-1.60)	0.65 (0.44-0.96)
Female	1.00	1.88 (1.24-2.85)	0.46 (0.12-1.84)	1.71 (1.13-2.57)	1.00	0.95 (0.65-1.39)	1.26 (0.82-1.94)	1.19 (0.76-1.87)
Hypertension
Yes	1.00	1.61 (1.11-2.32)	0.60 (0.25-1.45)	1.45 (1.02-2.06)	1.00	0.93 (0.67-1.29)	0.99 (0.67-1.45)	0.89 (0.60-1.31)
No	1.00	1.08 (0.71-1.62)	0.88 (0.36-2.37)	1.05 (0.70-1.56)	1.00	0.64 (0.44-0.95)	1.32 (0.86-2.03)	0.76 (0.50-1.16)

[1]	Jing-fen Jin, Zhi-ting Guo, Yu-ping Zhang, Yuan-yuan Chen. Prediction of motor recovery after ischemic stroke using diffusion tensor imaging: A meta-analysis [J]. World Journal of Emergency Medicine, 2017, 8(2): 99-105.
[2]	Harun Gunes, Hayati Kandis, Ayhan Saritas, Suber Dikici, Ramazan Buyukkaya. The relationship between ischemic stroke and weather conditions in Duzce, Turkey [J]. World Journal of Emergency Medicine, 2015, 6(3): 207-211.
[3]	Seyran Bozkurt, Engin Deniz Arslan, Ataman Köse, Cüneyt Ayrık, Arda Yılmaz, Güllü Akbaydoğan Dündar. Lingual angioedema after alteplase treatment in a patient with acute ischemic stroke [J]. World Journal of Emergency Medicine, 2015, 6(1): 74-76.
[4]	Lin Li, Lin-hong Zhang, Wu-ping Xu, Jun-min Hu. Risk assessment of ischemic stroke associated pneumonia [J]. World Journal of Emergency Medicine, 2014, 5(3): 209-213.
[5]	Gan-nan Wang, Jin-song Zhang, Wei-juan Cao, Hao Sun, Jing Zhang, Yao Wang, Hang Xiao. Association of ALOX5, LTA4H and LTC4S gene polymorphisms with ischemic stroke risk in a cohort of Chinese in east China [J]. World Journal of Emergency Medicine, 2013, 4(1): 32-37.
[6]	Misbahuddin Mohammad, Anish F. James, Raheel S. Qureshi, Sapan Saraf, Tina Ahluwalia, Joy Dev Mukherji, Tamorish Kole. Acute ischemic stroke in a child with cyanotic congenital heart disease due to non-compliance of anticoagulation [J]. World Journal of Emergency Medicine, 2012, 3(2): 154-156.
[7]	Jing Zhang, Yao Wang, Gan-nan Wang, Hao Sun, Tao Sun, Jian-quan Shi, Hang Xiao, Jin-song Zhang. Clinical factors in patients with ischemic versus hemorrhagic stroke in East China [J]. World Journal of Emergency Medicine, 2011, 2(1): 18-23.