Platelet glycoprotein gene Ia C807T,HPA-3,and Ibα VNTR polymorphisms are associated with increased ischemic stroke risk: Evidence from a comprehensive meta-analysis

Abstract

Background/aims

Platelet glycoproteins play a crucial role in the initial stage of thrombus formation and may contribute to the pathophysiology of atherosclerosis. Polymorphisms in glycoprotein genes alter the function of the protein, possibly leading to increased risk of ischemic stroke. However, previous genetic association studies that examined the relationship between glycoprotein genes polymorphisms and ischemic stroke have yielded inconsistent results. This study aimed to evaluate the association between glycoprotein genes and ischemic stroke by the application of meta-analysis.

Methods

Relevant studies were identified by an extensive search through databases. The quality of included studies was assessed independently using the Newcastle–Ottawa Scale. Allele and genotype frequencies for each included study were extracted. The odds ratio (OR) with 95% confidence interval (95%CI) was calculated using a random-effects or fixed-effects model. Q statistic was used to evaluate homogeneity, and a meta-regression model was used to explore the study-level variables and to describe the heterogeneity in included studies. Egger’s test and funnel plot were used to assess publication bias.

Results

A total of 60 studies (9 polymorphisms) were included and identified in the current meta-analysis. The Newcastle–Ottawa Scale scores ranged from 7 to 9 except for two studies with Newcastle–Ottawa Scale scores of 6. The T allele or TT genotype of the glycoprotein Ia C807T polymorphism were associated with an increased susceptibility to ischemic stroke in combined population (807T allele: OR, 95%CI: 1.24, 1.03–1.50, p = 0.02) or Asian populations (807T allele: OR, 95%CI: 1.31, 1.10–1.54, p = 0.002 and 807TT genotype: OR, 95%CI: 1.53, 1.13–2.08, p = 0.006, respectively), and the Ser allele of HPA-3 was associated with increased risk of ischemic stroke in combined population or in Asians (OR, 95%CI: 1.21, 1.04–1.40, p = 0.01 or 1.54, 1.18–2.01, p = 0.001). Of note, the Ser/Ser genotype was more common in Asians (OR, 95%CI: 2.09, 1.40–3.13, p < 0.001). For glycoprotein Ibα variable number tandem repeat, only B allele showed a mild significant association with ischemic stroke risk in combined population or in Caucasians (OR, 95%CI: 2.17, 1.04–4.55, p = 0.04 or 1.79, 1.02–3.13, p = 0.04). There was no significant association between HPA-1, HPA-2, HPA-4, HPA-5, glycoprotein Ibα-5 T/C as well as Ia G873A polymorphisms and increased risk of ischemic stroke.

Conclusions

We found that glycoprotein Ia C807T T allele or the TT genotype, the Ser-allele of HPA-3 and B allele of glycoprotein Ibα variable number tandem repeat polymorphisms were associated with increased risk for ischemic stroke. Future studies with larger sample sizes will be necessary to confirm the results. In addition, analyses of ischemic stroke subtypes and gene–gene and gene–environment interactions are warranted.

Keywords

Ischemic stroke cerebral infarction glycoprotein platelet glycoprotein meta-analysis systematic review

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References

Lozano

Naghavi

Foreman

. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 9859: 2095–2128.

Murray

Vos

Lozano

. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 9859: 2197–2223.

Liu

Wang

Lee

Zhang

Kong

. Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol 2007; 5: 456–464.

Rosengren

Hawken

Ounpuu

. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 2004; 9438: 953–962.

Dichgans

. Genetics of ischaemic stroke. Lancet Neurol 2007; 2: 149–161.

Humphries

Morgan

. Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. Lancet Neurol 2004; 3: 227–236.

Candore

Piazza

Crivello

. Association between platelet glycoprotein Ib-alpha and myocardial infarction: results of a pilot study performed in male and female patients from Sicily. Ann N Y Acad Sci 2006; 1089: 502–508.

Fredrickson

Dong

McIntire

López

. Shear-dependent rolling on von Willebrand factor of mammalian cells expressing the platelet glycoprotein Ib-IX-V complex. Blood 1998; 10: 3684–3693.

Furihata

Nugent

Kunicki

. Influence of platelet collagen receptor polymorphisms on risk for arterial thrombosis. Arch Pathol Lab Med 2002; 3: 305–309.

10.

Kaski

Kekomaki

Partanen

. Systematic screening for genetic polymorphism in human platelet glycoprotein 1balpha. Immunogenetics 1996; 44: 170–176.

11.

Murata

Furihata

Ishida

Russell

Ware

Ruggeri

. Genetic and structural characterization of an amino acid dimorphism in glycoprotein 1b alpha involved in platelet transfusion refractoriness. Blood 1992; 79: 3086–3090.

12.

Simsek

Bleeker

van der Schoot

von dem Borne

. Association of a variable number of tandem repeats (VNTR) in glycoprotein 1b alpha and HPA-2 alloantigens. Thromb Haemost 1994; 72: 757–761.

13.

Kunicki

Kritzik

Annis

Nugent

. Hereditary variation in platelet integrin alpha 2 beta 1 density is associated with two silent polymorphisms in the alpha 2 gene coding sequence. Blood 1997; 6: 1939–1943.

14.

Boden

McKay

. Optimal treatment of acute coronary syndromes—an evolving strategy. N Engl J Med 2001; 25: 1939–1942.

15.

Munafò

Flint

. Meta-analysis of genetic association studies. Trends Genet 2004; 20: 439–44.

16.

Xin

Song

. Gene polymorphisms and risk of adult early-onset ischemic stroke: a meta-analysis. Thromb Res 2009; 5: 619–624.

17.

Nikolopoulos

Tsantes

Bagos

Travlou

Vaiopoulos

. Integrin, alpha 2 gene C807T polymorphism and risk of ischemic stroke: a meta-analysis. Thromb Res 2007; 4: 501–510.

18.

Yao

. Genetic polymorphism of ITGA2 C807T can increase the risk of ischemic stroke. Int J Neurosci 2014; 11: 841–851.

19.

Bentley

Peck

Smeeth

Whittaker

Sharma

. Causal relationship of susceptibility genes to ischemic stroke: comparison to ischemic heart disease and biochemical determinants. PLoS One 2010; 2: e9136.

20.

Floyd

Ellis

Ferro

. The PlA1/A2 polymorphism of glycoprotein IIIa as a risk Factor for stroke: a systematic review and meta-analysis. PLoS One 2014; 7: e100239.

21.

Maguire

Thakkinstian

Sturm

. Polymorphisms in platelet glycoprotein 1balpha and factor VII and risk of ischemic stroke: a meta-analysis. Stroke 2008; 6: 1710–1716.

22.

Kopyta

Sarecka-Hujar

Sordyl

. The role of genetic risk factors in arterial ischemic stroke in pediatric and adult patients: a critical review. Mol Biol Rep 2014; 7: 4241–4251.

23.

Little J and Higgins JPT (eds) The HuGENet™ HuGE review handbook, version 1.0, http://www.hugenet.ca (accessed 28 February 2006).

24.

Liu

Xia

Liu

. PON gene polymorphisms and ischaemic stroke: a systematic review and meta analysis. Int J Stroke 2013; 2: 111–123.

25.

Wells G, Shea B, O’Connell D, Peterson J, Welch V, and Losos M. The Newcastle–Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses, http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed 1 February 2016).

26.

DerSimonian

Laird

. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

27.

Berman

Parker

. Meta-analysis: neither quick nor easy. BMC Med Res Methodol 2002; 2: 10.

28.

Zintzaras

Lau

. Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol 2008; 61: 634–645.

29.

Egger

Davey Smith

Schneider

Minder

. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

30.

Thompson

Higgins

. How should meta-regression analyses be undertaken and interpreted? Stat Med 2002; 11: 1559–1573.

31.

Corral

González-Conejero

Rivera

Iniesta

Lozano

Vicente

. HPA-1 genotype in arterial thrombosis—role of HPA-1b polymorphism in platelet function. Blood Coagul Fibrinolysis 1997; 5: 284–290.

32.

Carter

Catto

Bamford

Grant

. Platelet GP IIIa PlA and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke. Arterioscler Thromb Vasc Biol 1998; 7: 1124–1131.

33.

Wagner

Giles

Johnson

. Platelet glycoprotein receptor IIIa polymorphism P1A2 and ischemic stroke risk: the Stroke Prevention in Young Women Study. Stroke 1998; 3: 581–585.

34.

Carter

Catto

Bamford

Grant

. Association of the platelet glycoprotein IIb HPA-3 polymorphism with survival after acute ischemic stroke. Stroke 1999; 12: 2606–2611.

35.

Kekomäki

Hämäläinen

Kauppinen-Mäkelin

Palomäki

Kaste

Kontula

. Genetic polymorphism of platelet glycoprotein IIIa in patients with acute myocardial infarction and acute ischaemic stroke. J Cardiovasc Risk 1999; 1: 13–17.

36.

Chen

Jian

Xie

Xiao

Han

. Polymorphism of human platelet alloantigen in Chinese patients with acute myocardial infarction and acute ischemic stroke. Chin Med J (Engl) 2000; 8: 702–705.

37.

Reiner

Kumar

Schwartz

. Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke 2000; 7: 1628–1633.

38.

Sonoda

Murata

Ito

. Association between platelet glycoprotein Ibalpha genotype and ischemic cerebrovascular disease. Stroke 2000; 2: 493–497.

39.

Baker

Eikelboom

Lofthouse

. Platelet glycoprotein Ibalpha Kozak polymorphism is associated with an increased risk of ischemic stroke. Blood 2001; 1: 36–40.

40.

Frank

Reiner

Schwartz

. The Kozak sequence polymorphism of platelet glycoprotein Ibalpha and risk of nonfatal myocardial infarction and nonfatal stroke in young women. Blood 2001; 4: 875–879.

41.

Shi

Gao

Bai

Xing

Yun

Ruan

. The relationship between platelet glycoprotein Ibα VNTR variants and cerebral infarction (Chinese). Chin J Neurol 2002; 6: 364–364.

42.

Cole

Staton

Eikelboom

. Collagen platelet receptor polymorphisms integrin alpha2beta1 C807T and GPVI Q317L and risk of ischemic stroke. J Thromb Haemost 2003; 5: 963–970.

43.

Wang

Liu

. The polymorphisms of ischemic stroke related genes in Chinese population (Chinese). Chin J Hypertens 2003; 2: 116–120.

44.

Shi

Gao

. Research on collagen receptor-GP Ia C807T polymorphism in patients with acute cerebral infarction and myocardial infarction (Chinese). Chin J Cardiol 2003; 11: 852–854.

45.

Szolnoki

Somogyvári

Kondacs

. Increased prevalence of platelet glycoprotein IIb/IIIa PLA2 allele in ischaemic stroke associated with large vessel pathology. Thromb Res 2003; 5–6: 265–269.

46.

Chen

. Platelet glycoprotein Ia C807T, Ib C3550T, and IIIa Pl(A1/A2) polymorphisms and ischemic stroke in young Taiwanese. J Neurol Sci 2004; 1: 1–5.

47.

Slowik

Dziedzic

Turaj

. A2 alelle of GpIIIa gene is a risk factor for stroke caused by large-vessel disease in males. Stroke 2004; 7: 1589–1593.

48.

Yeh

Lin

. Prognosis of young ischemic stroke in Taiwan: impact of prothrombotic genetic polymorphisms. Thromb Haemost 2004; 3: 583–589.

49.

Gao

Huo

Liu

Teng

. Gene polymorphism of platelet glycoprotein I balpha in Chinese patients with large- and small-artery subtypes of ischemic stroke. Eur Neurol 2005; 2: 73–77.

50.

Liu

Jia

. Association between the polymorphisms of platelet membrane glycoprotein Ibα HPA-2 and ischemic cerebrovascular disease. J Cap Univ Med Sci 2005; 4: 418–421.

51.

Rubattu

Di Angelantonio

Nitsch

. Polymorphisms in prothrombotic genes and their impact on ischemic stroke in a Sardinian population. Thromb Haemost 2005; 6: 1095–1100.

52.

Rubattu

Speranza

Ferrari

. A role of TNF-a gene variant on juvenile ischemic stroke: a case–control study. Eur J Neurol 2005; 12: 989–993.

53.

Liu

Jia

. Association between the Kozak sequence polymorphisms of platelet membrane glycoprotein receptor Ibα and ischemic cerebrovascular disorders (Chinese). Chin J Nerv Ment Dis 2006; 6: 527–531.

54.

Liu

Zhao

. Association between polymorphism of platelet membrane glycoprotein IIb gene HPA-3 and cerebral infarction (Chinese). Nerv Dis Ment Health 2006; 2: 104–107.

55.

Yan

Shao

Zhao

Zhang

Wang

. Relationship between the polymorphism of platelet membrane glycoprotein Ibα gene and stroke (Chinese). J Clin Int Med 2006; 1: 21–23.

56.

Yang

Huang

Zhou

. Association of platelet glycoprotein Ia C807T gene polymorphism with platelet function in acute cerebral infarction (Chinese). Med J Qilu 2006; 2: 111–113.

57.

Berge

Haug

Sandset

Haugbro

Turkovic

Sandset

. The factor V Leiden, prothrombin gene 20210GA, methylenetetrahydrofolate reductase 677CT and platelet glycoprotein IIIa 1565TC mutations in patients with acute ischemic stroke and atrial fibrillation. Stroke 2007; 3: 1069–1071.

58.

de Oliveira

André

Spector

Luiz

de Castro Souza

Gadelha

. 807C/T polymorphism in the platelet glycoprotein Ia gene in young patients with ischemic stroke of undetermined etiology. Blood Coagul Fibrinolysis 2007; 7: 599–602.

59.

Lanni

Santulli

Izzo

. The Pl (A1/A2) polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients. J Hypertens 2007; 3: 551–556.

60.

Zhao

Chen

. Relation of platelet membrane glycoprotein Ib Kozak sequence—5 T/C gene and beta fibrinogen—148 C/T gene polymorphism with cerebral infarction (Chinese). Chin J Geriatr Heart Brain Vessel Dis 2007; 11: 745–748.

61.

Zhao

Chen

. The association of platelet glycoprotein IIIa PIA polymorphism with cerebral infarction (Chinese). J Apoplexy Nerv Dis 2007; 1: 52.

62.

Liu

. Relationship between the polymorphism of platelet membrane glycoprotein GP IIIa and cerebral thrombosis (Chinese). Chin J Hemorheol 2007; 2: 185–187.

63.

Sun

Wang

Feng

Yang

Chen

. Relationship between platelet glycoprotein Ia C807T gene polymorphism and cerebral infarction in Anhui Han nationality (Chinese). Modern Health 2007; 5: 1–2.

64.

Zhang

Wang

. Platelet glycoprotein polymorphisms: risk, in vivo expression and severity of atherothrombotic stroke in Chinese. Clin Chim Acta 2007; 1–2: 99–104.

65.

Saidi

Mahjoub

Slamia

Ammou

Al-Subaie

Almawi

. Polymorphisms of the human platelet alloantigens HPA-1, HPA-2, HPA-3, and HPA-4 in ischemic stroke. Am J Hematol 2008; 7: 570–573.

66.

Saidi

Mahjoub

Slamia

Ammou

Al-Subaie

Almawi

. Association of human platelet alloantigen 1 through 5 polymorphisms with ischemic stroke. Cerebrovasc Dis 2008; 1–2: 81–86.

67.

Jin

Wang

Cui

Xin

. Variable number of tandem repeats polymorphism of platelet glycoprotein Ib alpha in Chinese people and CC genotype with aspirin sensitivity in patients with cerebral infarction. J Clin Pharm Ther 2009; 2: 239–243.

68.

Dai

. VNTR polymorphism in platelet glycoprotein Ibα gene with thrombotic diseases (Chinese). Chin J Thromb Hemost 2009; 2: 75–77, 79.

69.

Chen

Wei

Liang

Liu

. Relationship between integrin alpha-2 gene polymorphisms and cerebral infarction and its effect on plasma lipid levels (Chinese). Shandong Med J 2010; 41: 1–3.

70.

Hou

Liu

Yuan

Zheng

. Study on relationship between cerebral infarction and polymorphisms of Ia and Ibα genes of platelet membrane glycoprotein (Chinese). Chin J Geriatr Heart Brain Vessel Dis 2010; 2: 132–135.

71.

Liu

Guang

Zheng

. Polymorphism of platelet glycoprotein Ia C807T gene in Han population of Henan province and its effect on platelet aggregation (Chinese). Neural Injury Funct Reconstr 2010; 1: 35–37.

72.

Long

Wang

Pan

Huang

. The relationship of integrin alpha-2 and beta-3 gene polymorphisms with ischemic stroke (Chinese). Chin J Laborat Diag 2010; 8: 1234–1237.

73.

Zhai

. Study on the correlation platelet of glycoprotein Ibα gene polymorphism and cerebral infarction (Chinese). Chin J Pract Nerv Dis 2010; 15: 1–4.

74.

Luk

Wang

Tam

Lam

. Predictive role of polymorphisms in interleukin-5 receptor alpha-subunit, lipoprotein lipase, integrin A2 and nitric oxide synthase genes on ischemic stroke in type 2 diabetes—an 8-year prospective cohort analysis of 1327 Chinese patients. Atherosclerosis 2011; 1: 130–135.

75.

Zhu

Song

Xiong

Wang

. Relationship between the gene polymorphisms with expressions of platelet glycoprotein CD41/CD61 and cerebral infarction (Chinese). J Apoplexy Nerv Dis 2011; 7: 605–607.

76.

Maguire

Thakkinstian

Levi

. Impact of COX-2 rs5275 and rs20417 and GP IIIa rs5918 polymorphisms on 90-day ischemic stroke functional outcome: a novel finding. J Stroke Cerebrovasc Dis 2011; 2: 134–144.

77.

Wang

Han

. The association of progressive ischemic stroke with platelet glycoprotein Ia C807T polymorphism (Chinese). Chin J Gerontol 2011; 14: 2624–2626.

78.

Zhang

Ouyang

Mei

Zhang

Che

Tai

. Investigation of VNTR polymorphism on GP Ibα gene of patients with acute ischemic cerebral infarction in some district (Chinese). Int J Lab Med 2011; 3: 322–323.

79.

Duan

Cai

Sun

. Platelet glycoprotein IIb/IIIa polymorphism HPA-3 b/b is associated with increased risk of ischemic stroke in patients under 60 years of age. Med Sci Monit 2012; 1: CR19–CR24.

80.

Esen

Hancer

Küçükkaya

. Glycoprotein Ib-alpha Kozak polymorphism in ischemic stroke. Neurol Res 2012; 1: 68–71.

81.

Shang

Bai

. VNTR polymorphisms of platelet membrane glycoprotein Ibα gene in Henan Han population with atherothrombotic brain infarction (Chinese). J Zhengzhou Univ 2012; 4: 466–469.

82.

Shang

Bai

. HPA-2 polymorphisms of platelet membrane glycoprotein Ibα gene in Henan Han population with atherothrombotic brain infarction (Chinese). J Zhengzhou Univ 2012; 5: 605–607.

83.

Zhang

Huang

Yang

. Platelet glycoprotein Ia C807T polymorphisms and ischemic stroke in young Chinese Han population. Eur Rev Med Pharmacol Sci 2012; 12: 1691–1695.

84.

Shen

Shi

Chen

Dai

. The study on platelet glycoprotein Ia C807T polymorphism and function of platelet in patients with acute cerebral infarction (Chinese). Chin J Microcirculat 2013; 1: 28–30.

85.

Rivera-García

Esparza-García

Aceves-Chimal

Leaños-Miranda

Majluf-Cruz

Isordia-Salas

. Platelet glycoprotein IIIA PIA1/A2 polymorphism in young patients with ST elevation myocardial infarction and idiopathic ischemic stroke. Mol Cell Biochem 2013; 1: 163–171.

86.

Zhang

Zhi

Chen

Wang

. Polymorphism in integrin ITGA2 is associated with ischemic stroke and altered serum cholesterol in Chinese individuals. Balkan Med J 2014; 1: 55–59.

87.

Lv ME and Ruan CD. Research on the association of the platelet glycoprotein gene polymorphism and stroke (Chinese). Master Degree Thesis, Suzhou University, Suzhou, China, 2003, p. 4.

88.

Li H and Yang LH. Investigate the polymorphism of matrix metalloproteinase-9 and platelet glycoprotein IIIa with cerebral infarction (Chinese). Master Degree Thesis. Shanxi Medical University, Taiyuan, China, 2004, p. 6.

89.

Zhang QZ, Bin W and Zhang C. Correlation between the polymorphism of platelet glycoprotein GP Ibα Kozak gene and ischemic cerebrovascular disease (Chinese). Master Degree Thesis. Qingdao University, Qingdao, China, 2005, p. 9.

90.

Wang DL and Li X. Study on the relationship between platelet membrane glycoprotein IIb gene polymorphism and ischemic stroke (Chinese). Master Degree Thesis. Tianjin Medical University, Tianjin, China, 2011, p. 5.

91.

Jackson

. Arterial thrombosis—insidious, unpredictable and deadly. Nat Med 2011; 11: 1423–1436.

92.

Kunicki

Orchekowski

Annis

Honda

. Variability of integrin alpha 2 beta 1 activity on human platelets. Blood 1993; 9: 2693–2703.

93.

Moshfegh

Wuillemin

Redondo

. Association of two silent polymorphisms of platelet glycoprotein Ia/IIa receptor with risk of myocardial infarction: a case-control study. Lancet 1999; 9150: 351–354.

94.

Mikkelson

Perola

Penttila

Karhunen

. Platelet glycoprotein Ib (alpha) HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden death. Circulation 2001; 104: 876–880.

95.

Lekakis

Bisti

Tsougos

. Platelet glycoprotein IIb HPA-3 polymorphism and acute coronary syndromes. Int J Cardiol 2008; 1: 46–50.

96.

Michelson

Furman

Goldschmidt-Clermont

. Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. Circulation 2000; 9: 1013–1018.

97.

Weiss

Bray

Tayback

. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 17: 1090–1094.

98.

Liu

Higgins

. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet 2006; 9511: 651–658.

99.

Bray

. Platelet glycoprotein polymorphisms as risk factors for thrombosis. Curr Opin Hematol 2000; 5: 284–289.

100.

Casorelli

De Stefano

Leone

. The C807T/G873A polymorphism in the platelet glycoprotein Ia gene and the risk of acute coronary syndrome in the Italian population. Br J Haematol 2001; 1: 150–154.

101.

Chopra

Anand

Hickner

. Risk of venous thromboembolism associated with peripherally inserted central catheters: a systematic review and meta-analysis. Lancet 2013; 9889: 311–325.