C(−260)→T Polymorphism in the Promoter of the CD14 Monocyte Receptor Gene as a Risk Factor for Myocardial Infarction

Abstract

Background-The CD14 receptor of monocytes is an important mediator for the activation of monocytes/macrophages by endotoxins from the envelope of Gram-negative bacteria (lipopolysaccharides). We identified a polymorphism in the CD14 receptor and examined whether this genetic marker influenced the expression of the CD14 receptor on monocytes and affected the predisposition to myocardial infarction. Methods and Results-We identified a C(Ϫ260)3 T nucleotide change, creating a HaeIII polymorphism in the promoter of the CD14 gene. The polymorphism was determined in 178 male patients Ͻ65 years old (cases; average age, 55.9Ϯ6.3 years) at the time of their first myocardial infarction and in 135 representative selected male control subjects (controls; average age, 55.2Ϯ11.5 years). The frequency of the T allele (absence of the cutting site) was 0.49 in cases and 0.35 in controls (Pϭ0.0005; OR, 1.781; 95% CI, 1.286 to 2.465). Subsequently, we measured the expression of monocyte CD14 by flow cytometry in 18 volunteers with different CD14 genotypes. A significantly higher density of the CD14 receptor was shown in the T/T homozygotes than in the others (Pϭ0.0028). Conclusions-A higher frequency of allele T(Ϫ260) in the promoter of the CD14 receptor gene was found in myocardial infarction survivors than in controls. At the same time, this variation was associated with a higher density of CD14 receptors in healthy volunteers. Therefore, we can conclude that in addition to the well-established risk factors, a genetically determined reaction of monocytes/macrophages to infectious stimuli could play an important role in the process of atherosclerosis. (Circulation. 1999;99:3218-3220.)

Effect of CD14 promoter polymorphism andH. pyloriinfection and its clinical outcomes on circulating CD14

“…Whether moderately elevated sCD14 in H. pylori infection contributes to lipid metabolism remains to be settled. Interestingly, an association between the TT genotype of the CD14 gene and myocardial infarction has been recently reported in three different studies [23,39,40].…”

“…An additional mismatch was inserted at the penultimate 3¢ nucleotide (underlined) of the allele-specific primers to increase the specificity of the PCR reaction. Additionally, two previously described outer primers were used [23]. The primer sequences were as follows:…”

“…cfors: 5¢-CTC CAG AAT CCT TCC TGT TAC GAC-3¢ trevs: 5¢-TGT AGG ATG TTT CAG GGA GGG GTA-3¢ cdp1: 5¢-TTG GTG CCA ACA GAT GAG GTT CAC-3¢ [23] cdp2: 5¢-TTC TTT CCT ACA CAG CGG CAC CC-3¢ [23] PCR was performed in a total volume of 10 ml (50-100 ng genomic DNA, 1 ¥ PCR buffer with 1·5 mM MgCl, 0·2 mM nucleotides, 0·5 U Taq polymerase and 0·5 mM CD14 primers). The following reaction conditions were used: an initial denaturation at 95°C for 5 min followed by 30 cycles at 95°C for 30 s, at 60°C for 30 s, and at 72°C for 1 min.…”

Multi-locus interactions predict risk for post-PTCA restenosis: an approach to the genetic analysis of common complex disease

“…[15][16][17][18][19][20][21][22][23][24][25][26][27][28] To confirm genotype assignments, the PCR procedure was performed in replicate on all samples. Scoring was carried out by two independent observers.…”

NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?

“…35 Membrane-bound CD14 is expressed on monocytes and macrophages, and the expression of CD14 on mucosal macrophages is upregulated in active IBD. 36,37 A common functional promoter region polymorphism (T-159C) of the CD14 gene has been identified 38 and a weak association with both CD and UC has been demonstrated. [39][40][41] In the present study, we have investigated the contribution of the three common NOD2/CARD15 variants in determining susceptibility and phenotype in a large cohort of Scottish patients with well-characterised CD and UC.…”