Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction*1

Edfeldt, Kristina; Bennet, Anna M.; Eriksson, Per; Frostegård, Johan; Wiman, Björn; Hamsten, Anders; Hansson, Göran K.; Fairé, Ulf dé; Yan, Zhenghua

doi:10.1016/j.ehj.2004.05.004

Cited by 149 publications

(94 citation statements)

References 29 publications

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“…9 In addition, several candidate gene studies have been conducted, testing variants in genes involved in inflammation, for example, CD14, TLR4 and VCAM1, for association with atherosclerosis and significant associations have been reported by some groups. 10,11 Notably, the majority of these studies were conducted in European populations and the results could not be replicated in Chinese Han populations. This suggests that there are substantial differences in the genetic contributors to CAD between these populations.…”

Section: Introductionmentioning

confidence: 99%

Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population

Wang

Xie

et al. 2010

J Hum Genet

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Coronary atherosclerosis is a complex and progressive condition that involves many biological pathways, including the oxidative stress and inflammatory response pathways. To investigate the association between common genetic variation within these two pathways and coronary atherosclerosis, we performed a comprehensive two-stage candidate gene association study in a Chinese Han population. In stage I, 936 tag single-nucleotide polymorphisms (SNPs) within 116 candidate genes were genotyped in 293 coronary atherosclerosis cases and 293 age-and gender-matched healthy controls. In stage II, 51 SNPs from stage I were selected and further genotyped in an additional 1030 cases and 764 controls. In allele-and genotype-based association tests of stage II and a meta-analysis across the two stages, we identified three SNPs within three genes significantly associated with the disease, namely rs3212556 in ITGA2 (P CMH ¼9.20Â10 À5 ), rs854563 in PON1 (P CMH ¼1.92Â10 À4 ) and rs9283851 in THBS2 (P CMH ¼3.00Â10 À3 ). Haplotype analysis provided further supporting evidence for the association of rs3212556 (P global o10 À4 ) and rs854563 (P global o10 À4 ). Our study has identified three SNPs within ITGA2, PON1 and THBS2 that are associated with coronary atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population

Wang

Xie

et al. 2010

J Hum Genet

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“…However, population-based studies designed to determine the impact of TLR4 polymorphism on the risk of myocardial infarction (MI) are so far inconclusive, and the data seem conflicting. Some studies suggest that individuals with the single nucleotide polymorphism of TLR4 Asp299Gly, who have an impaired host immune response toward LPS stimulation, have a lower risk of MI (9,15,54), whereas others suggest an increased (32) or the same level of risk (83) of MI in the polymorphism compared with the control population. In animal models of ischemic cardiac injury, the role of TLRs is incompletely defined.…”

mentioning

confidence: 99%

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Chao¹

2009

American Journal of Physiology-Heart and Circulatory Physiology

210

166

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Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.

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“…However, a larger study using myocardial infarction as a hard end point arrived at a different conclusion. 30 The 299Gly and 399Ile were significantly more common among 1213 survivors of a first myocardial infarction than in a matched control group of 1561 individuals in the Stockholm Heart Epidemiology Program (SHEEP). The reason for this discrepancy is unknown; one may speculate that TLR4-dependent activation of the AP-1 and NF-B pathways promote smooth muscle proliferation and the formation of a stable fibrous cap.…”

Section: See Pages 1213 and 1220mentioning

confidence: 99%

“…The reason for this discrepancy is unknown; one may speculate that TLR4-dependent activation of the AP-1 and NF-B pathways promote smooth muscle proliferation and the formation of a stable fibrous cap. 30 In the Dutch REGRESS study of myocardial infarction, 299Gly carriers had more severe coronary disease and gained more from statin treatment than those carrying the wild-type allele. 31 At balance, the clinical studies of TLR4 polymorphism suggest that (1) TLR4 activation promotes lesion growth; (2) it reduces the risk for myocardial infarction, possibly by promoting plaque stabilization; and (3) the TLR4 pathway interacts with statins.…”

Section: See Pages 1213 and 1220mentioning

confidence: 99%

Toll To Be Paid at the Gateway to the Vessel Wall

Hansson

Edfeldt

2005

ATVB

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Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction*1

Abstract: The association found between TLR4 genotype and risk of MI suggests that TLR4 genetic variants could potentially affect the susceptibility to MI and that TLR4-mediated innate immunity is implicated in the pathogenesis of MI.

Cited by 149 publications

References 29 publications

Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population

Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Toll To Be Paid at the Gateway to the Vessel Wall

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