Association between Toll-like receptor 4 Asp299Gly polymorphism and coronary heart disease susceptibility

Wu, B.W.; Zhu, J.; Shi, H.M.; Jin, B.; Wen, Z.C.

doi:10.1590/1414-431X20176306

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Brazilian Journal of Medical and Biological Research

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Research Articles • Braz. J. Med. Biol. Res. 50 (9) • 2017 • https://doi.org/10.1590/1414-431X20176306 copy

Association between Toll-like receptor 4 Asp299Gly polymorphism and coronary heart disease susceptibility

Authorship SCIMAGO INSTITUTIONS RANKINGS

Published data on the association between Toll-like receptor 4 (TLR4) Asp299Gly polymorphism and coronary heart disease (CHD) susceptibility are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. English-language studies were identified by searching PubMed and Embase databases (up to November 2016). All epidemiological studies were regarding Caucasians because no TLR4 Asp/Gly and Gly/Gly genotypes have been detected in Asians. A total of 20 case-control studies involving 14,416 cases and 10,764 controls were included in the meta-analysis. Overall, no significant associations were found between TLR4 Asp299Gly polymorphism and CHD susceptibility in the dominant model (OR=0.89; 95%CI=0.74 to 1.06; P=0.20) pooled in the meta-analysis. In the subgroup analysis by CHD, non-significant associations were found in cases compared to controls. When stratified by control source, no significantly decreased risk was found in the additive model or dominant model. The present meta-analysis suggests that the TLR4 Asp299Gly polymorphism was not associated with decreased CHD risk in Caucasians.

Toll-like receptor 4; Polymorphism; Coronary heart disease; Meta-analysis

Authors	Year	Region	Matching criteria	Cases	Controls	Case/Control	Genotyping method
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Boekholdt et al. (¹³13. Boekholdt SM, Agema WR, Peters RJ, Zwinderman AH, van der Wall EE, Reitsma PH, et al. Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation 2003; 107: 2416–2421, doi: 10.1161/01.CIR.0000068311.40161.28. https://doi.org/10.1161/01.CIR.000006831... )	2003	Netherlands	Age	MI	Non-MI subjects	312/343	AS-PCR
Džumhur et al. (¹⁴14. Džumhur A, Zibar L, Wagner J, Simundić T, Dembić Z, Barbić J. Association studies of gene polymorphisms in toll-like receptors 2 and 4 in Croatian patients with acute myocardial infarction. Scand J Immunol 2012; 75: 517–523, doi: 10.1111/j.1365-3083.2012.02681.x. https://doi.org/10.1111/j.1365-3083.2012... )	2012	Croatia	Age and sex	MI	Healthy subjects	119/120	TaqMan
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Enquobahrie et al. (¹⁶16. Enquobahrie DA, Smith NL, Bis JC, Carty CL, Rice KM, Lumley T, et al. Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and Toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke. Am J Cardiol 2008; 101: 1683–1688, doi: 10.1016/j.amjcard.2008.02.052. https://doi.org/10.1016/j.amjcard.2008.0... )	2008	USA	Age and sex	MI	Non-MI subjects	848/2682	AS-PCR
Golovkin et al. (¹⁷17. Golovkin AS, Ponasenko AV, Khutornaya MV, Kutikhin AG, Salakhov RR, Yuzhalin AE, et al. Association of TLR and TREM-1 gene polymorphisms with risk of coronary artery disease in a Russian population. Gene 2014; 550: 101–109, doi: 10.1016/j.gene.2014.08.022. https://doi.org/10.1016/j.gene.2014.08.0... )	2014	Russia	Age and sex	CHD	Healthy subjects	702/300	TaqMan
Guven et al. (¹⁸18. Guven M, Ismailoglu Z, Batar B, Unal S, Onaran I, Karadag B, et al. The effect of genetic polymorphisms of TLR2 and TLR4 in Turkish patients with coronary artery disease. Gene 2015; 558: 99–102, doi: 10.1016/j.gene.2014.12.047. https://doi.org/10.1016/j.gene.2014.12.0... )	2015	Turkey	–	CHD	CHD-free subjects	150/150	PCR-RFLP
Hamann et al. (¹⁹19. Hamann L, Gomma A, Schröder NW, Stamme C, Glaeser C, Schulz S, et al. A frequent toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J Mol Med 2005; 83: 478–485, doi: 10.1007/s00109-005-0643-7. https://doi.org/10.1007/s00109-005-0643-... )	2005	UK	Age and sex	CHD	Healthy subjects	388/189	TaqMan
Hernesniemi et al. (²⁰20. Hernesniemi J, Lehtimäki T, Rontu R, Islam MS, Eklund C, Mikkelsson J, et al. Toll-like receptor 4 polymorphism is associated with coronary stenosis but not with the occurrence of acute or old myocardial infarctions. Scand J Clin Lab Invest 2006; 66: 667–675, doi: 10.1080/00365510600933011. https://doi.org/10.1080/0036551060093301... )	2006	Finland	–	CHD	CHD-free subjects	333/299	AS-PCR
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Koch et al. (²²22. Koch W, Hoppmann P, Pfeufer A, Schömig A, Kastrati A.Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population. Eur Heart J 2006; 27: 2524–2529, doi: 10.1093/eurheartj/ehl231. https://doi.org/10.1093/eurheartj/ehl231... )	2006	Germany	–	MI	CHD-free subjects	3657/1211	TaqMan
Kolek et al. (²³23. Kolek MJ, Carlquist JF, Muhlestein JB, Whiting BM, Horne BD, Bair TL, et al. Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes. Am Heart J 2004; 148: 1034–1040, doi: 10.1016/j.ahj.2004.05.049. https://doi.org/10.1016/j.ahj.2004.05.04... )	2004	USA	–	CHD	CHD-free subjects	1375/519	TaqMan
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Morange et al. (²⁵25. Morange PE, Tiret L, Saut N, Luc G, Arveiler D, Ferrieres J, et al. TLR4/Asp299Gly, CD14/C-260T, plasma levels of the soluble receptor CD14 and the risk of coronary heart disease: The PRIME Study. Eur J Hum Genet 2004; 12: 1041–1049, doi: 10.1038/sj.ejhg.5201277. https://doi.org/10.1038/sj.ejhg.5201277... )	2004	France/Ireland	Age	CHD	CHD-free subjects	247/490	AS-PCR
Nebel et al. (²⁶26. Nebel A, Flachsbart F, Schäfer A, Nothnagel M, Nikolaus S, Mokhtari NE, et al. Role of the toll-like receptor 4 polymorphism Asp299Gly in longevity and myocardial infarction in German men. Mech Ageing Dev 2007; 128: 409–411, doi: 10.1016/j.mad.2007.04.001. https://doi.org/10.1016/j.mad.2007.04.00... )	2007	Germany	Age	MI	Healthy subjects	606/323	TaqMan
O’Halloran et al. (²⁷27. O'Halloran AM, Stanton A, O'Brien E, Shields DC. The impact on coronary artery disease of common polymorphisms known to modulate responses to pathogens. Ann Hum Genet 2006; 70: 934–945, doi: 10.1111/j.1469-1809.2006.00281.x. https://doi.org/10.1111/j.1469-1809.2006... )	2006	Ireland	–	CHD	Healthy subjects	1598/386	AS-PCR
Yang et al. (²⁸28. Yang IA, Holloway JW, Ye S, Southampton Atherosclerosis Study (SAS) Group. TLR4 Asp299Gly polymorphism is not associated with coronary artery stenosis. Atherosclerosis 2003; 170: 187–190, doi: 10.1016/S0021-9150(03)00286-7. https://doi.org/10.1016/S0021-9150(03)00... )	2003	UK	–	CHD	CHD-free subjects	1078/322	ARMS-PCR
Zee et al. (²⁹29. Zee RY, Hegener HH, Gould J, Ridker PM. Toll-like receptor 4 Asp299Gly gene polymorphism and risk of atherothrombosis. Stroke 2005; 36: 154–157, doi: 10.1161/01.STR.0000149948.31879.f0. https://doi.org/10.1161/01.STR.000014994... )	2005	USA	Age and smoking	MI	CHD-free subjects	370/695	AS-PCR

Comparison	Study	Asp/Gly vs Asp/Asp		Gly/Gly vs Asp/Asp		Dominant model
Comparison	Study	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value
Total	20	0.89 (0.71; 1.13)	0.35	1.12 (0.60; 2.07)	0.72	0.89 (0.74; 1.06)	0.20
Category
ACS (MI/UA)	11	0.90 (0.68; 1.20)	0.48	0.94 (0.42; 2.08)	0.88	0.95 (0.77; 1.19)	0.68
CHD (mixed)	9	0.86 (0.56; 1.32)	0.49	1.44 (0.54; 3.85)	0.47	0.82 (0.60; 1.11)	0.20
Control source
Hospital	11	0.78 (0.46; 1.30)	0.34	1.28 (0.52; 3.17)	0.59	0.82 (0.65; 1.05)	0.11
Population	9	0.93 (0.70; 1.24)	0.64	0.99 (0.42; 2.30)	0.98	0.97 (0.75; 1.26)	0.83

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[1] Correspondence: B. Jin: <jinbo7711@aliyun.com> | Z.C. Wen: <wzchsh@aliyun.com>