Polymorphism R92Q of the tumour necrosis factor receptor 1 gene is associated with myocardial infarction and carotid intima-media thickness – The ECTIM, AXA, EVA and GENIC Studies

Abstract

The TNFRSF1A gene was screened for polymorphisms in 95 subjects with premature myocardial infarction (MI), who also had one parent who had an MI. A total of 10 polymorphisms were found: three in the promoter region, two in exons and five in introns. All polymorphisms were genotyped in ECTIM, a case-control study of MI (1815 subjects). The nonsynonymous 92Q allele was found in 1.8, 1.0 and 1.7% of controls from Strasbourg, Belfast and Glasgow -respectively; in cases: 4.2, 2.2 and 3.2%. The populationadjusted odds ratio (OR) for MI associated with allele Q carrying was 2.15 (95% CI: 1.09 -4.23). To check its possible implication in atherosclerosis, this polymorphism was then genotyped in the AXA Study (ultrasound examinations of carotid and femoral arteries in the context of an employment medical examination, 733 subjects), the EVA Study (ultrasound examinations of carotid arteries in a study of cognitive and vascular ageing, 1092 subjects) and the GENIC Study (on brain infarction (BI), 912 subjects). In the AXA Study, among smokers, carrying the 92Q allele was positively associated with the presence of a carotid plaque (OR 5.07; 95% CI: 1.64 -15.63) and with a thickening of the carotid intima-media thickness (IMT) (0.59 (0.11) vs 0.54 (0.11), P ¼ 0.045). In the EVA Study, carriers of allele 92Q had an increased mean carotid IMT (0.70 (0.09) vs 0.67 (0.13), P ¼ 0.02). No significant association of the 92Q allele was found with BI in the GENIC Study. Overall, these results may suggest that carriers of the 92Q allele may be at increased risk of atherosclerosis.

Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies

“…Poirier et al used single-strand conformational polymorphism and sequencing analysis on only 26% of the total TNFR1 gene, predominantly on coding sequences, to identify CAD-associated TNFR1 SNPs, and subsequently found that the 92Q allele of TNFR1 (rs4149584) was associated with increased risk of MI among UK and French residents of European descent. Although we observed evidence of 92Q allele transmission to affected siblings in GENECARD, our CAD cases from CATHGEN and GENECARD did not demonstrate greater frequency of the 92Q allele than our controls, even though the absolute 92Q frequency in our cohorts was similar to that observed by Poirier et al in their control groups (1.6 -2%; Supplementary Material, Table S3) (11).…”

“…Although these tests suggested only modest evidence for the association of TNFR1 with CAD, it is notable, nonetheless, that they suggest evidence for the association between CAD and the TNFR1 R92Q polymorphism-the SNP originally associated with MI, as found by Poirier et al (11) (P , 0.05; Supplementary Material, Table S2). Together, data from GENECARD and Poirier et al (11) support the association between CAD and TNFR1 discerned in CATHGEN. Moreover, in conjunction with CATHGEN older normal controls, our GENECARD data also support the association found in CATHGEN between two TNFR1 SNPs and aging-associated atherosclerosis (Supplementary Material, Table S1).…”

“…In aged apolipoprotein E-deficient (Apoe 2/2 ) mice, the absence of TNFR1 reduces atherosclerosis of the aorta, but not the brachiocephalic artery (4); however, these studies could not evaluate the atherogenic role of aging, either systemically or in the arterial wall. Poirier et al (11) found that, in humans, TNFR1 polymorphisms were associated with MI; however, this study could not evaluate the role of TNFR1 variants in aging-related MI or atherosclerosis.…”

“…We built our human study on the findings of Poirier et al (11), by genotyping the same set of TNFR1 SNPs identified among premature MI patients by that group, and then extending that set of SNPs with tagSNPs so as to cover common genetic variation throughout the entire human TNFR1. Poirier et al used single-strand conformational polymorphism and sequencing analysis on only 26% of the total TNFR1 gene, predominantly on coding sequences, to identify CAD-associated TNFR1 SNPs, and subsequently found that the 92Q allele of TNFR1 (rs4149584) was associated with increased risk of MI among UK and French residents of European descent.…”

Role of tumour necrosis factor (TNF)-α and TNFRSF1A R92Q mutation in the pathogenesis of TNF receptor-associated periodic syndrome and multiple sclerosis

“…The R92Q mutation has also been associated with clinical phenotypes other than TRAPS, such as early arthritis [34], Behçet's disease with extracranial deep vein thrombosis [47], atherosclerosis [48] or recurrent pericarditis [49]. These findings support the known fact that different inflammatory diseases share genetic susceptibility loci.…”