The NFKB1 ATTG ins/del polymorphism and risk of coronary heart disease in three independent populations

Abstract

Aim Inflammation is a risk factor for coronary heart disease (CHD). A common deletion-allele in the promoter region of NFKB1 results in lower protein levels of the NF-κB p50 subunit. Recent evidence suggests that the NF-κB p50 dimer has anti-inflammatory effects. We aimed to investigate the association of the functional ATTG NFKB1 insertion/deletion variant with risk of CHD in three independent prospective studies of generally healthy men and women. Methods and Results The NFKB1 ins/del polymorphism was genotyped in studies of CHD nested within the Diet, Cancer and Health (DCH) study, the Health Professionals Follow-up (HPFS) and the Nurses’ Health (NHS) studies, totaling 1008, 428 and 439 cases, respectively. The minor allele frequency in the combined sample was 0.38 among controls. In a pooled analysis, the relative risk (RR) among heterozygous men and women was 1.22 (95% CI: 1.07–1.40), compared to the most common ins/ins genotype. The RR among homozygotes was 1.20 (95% CI: 0.94–1.53). There was no evidence of an allele-dosage effect, and in a dominant model the RR among del-allele carriers was 1.22 (95% CI: 1.07–1.39). The risk was similar in women and men (RR was 1.20 in women and 1.23 in men, respectively). The NFKB1 variant was not associated with plasma lipid levels, but del-carriers had lower levels of C-reactive protein. Conclusions The NFKB1 promoter variant, previously shown to cause partial depletion of NF-kB p50, was associated with a higher risk of CHD in three independent prospective studies of generally healthy Caucasians.

Extracellular HSP27 acts as a signaling molecule to activate NF-κB in macrophages

“…In humans, there is evidence that a genetic deletion in the promoter of the NFKB1 gene results in decreased levels of the p50 subunit and is associated with a higher risk for coronary heart disease (Karban et al 2004;Park et al 2007;Vogel et al 2011). These studies suggest that there are protective roles for NF-κB signaling in atherosclerosis and exemplifies the importance of macrophages in balancing pro-and anti-inflammatory signals in the developing lesion.…”

Association between NF-κBI and NF-κBIA polymorphisms and coronary artery disease

“…Cha-Molstad et al (26) reported that the p50 dimer of NF-κB activates transcription of CRP. Vogel et al (22) identified that the del-allele carriers had lower CRP levels. There was a statistically significant difference between case and controls for hypertension in the comparison of the WW genotype and WD and DD genotypes (P<0.001 and P=0.023).…”

“…Karban et al (21) stated that, when compared with the W allele in vitro, the NF-ĸB1 gene with the D allele exhibited reduced transcription activity. Vogel et al (22) identified that the p50 depletion of the del-allele affects the anti-inflammatory response. The study identified that patients with the del-allele have a higher risk of CAD.…”

“…Individuals with the DD genotype have a 3-fold higher risk of CAD compared to WW (OR=3.35) (Table III). Hypertension, diabetes and hypercholesterolaemia are intermediate variables between inflammation and CAD (22).…”

Polymorphisms in the nuclear factor kappa B gene association with recurrent embryo implantation failure

“…The NF-κB1 -94ins/del ATTG promoter polymorphism is an insertion/deletion of four bases in the promoter region of the NF-κB gene that encodes for the p50 subunit, and the variant allele containing this deletion produces lower transcript levels of the p50 subunit (Karban et al, 2004). The NF-κB1 rs28362491 promoter polymorphism is the only known functional polymorphism in the NF-ΚB family (van der Heiden et al, 2010;Vogel et al, 2011), and this polymorphism has been shown to be associated with both inflammation and coronary syndrome (Tjønneland et al, 2007). In the current study, we found a significant difference in the genotype distribution of rs28362491 between those with RIF and controls.…”