Elsevier

Atherosclerosis

Volume 219, Issue 1, November 2011, Pages 200-204
Atherosclerosis

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

https://doi.org/10.1016/j.atherosclerosis.2011.06.018Get rights and content

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-κB p50, was associated with a higher risk of CHD in three independent prospective studies of generally healthy Caucasians.

Introduction

Coronary heart disease (CHD) is a major cause of morbidity and mortality in the western world. The transcription factor NF-κB is a key regulator of many cellular processes and genes involved in modulation of inflammation. Thus, many genes that are relevant to the pathogenesis of atherosclerosis are regulated by NF-κB [1]. The p50 subunit of NF-κB encoded by NFKB1 seem to be specifically involved in anti-inflammatory effects [2]. Thus, the p50 homodimer represses transcription of pro-inflammatory cytokines like TNF and IL12 and stimulates transcription of the anti-inflammatory cytokine IL10 [2], [3].

The NFKB1 gene encodes both the subunits p105 and p50 of the transcription factor NF-κB by alternative splicing [4]. A functional ATTG insertion/deletion (ins/del) polymorphism in the promoter region of NFKB1 gene destroys a transcription factor binding site, resulting in differential expression [5], [6]. The del-allele results in lower transcript levels and protein levels of both p50 and p105. Consequently, carriers of the del-allele have lower levels of functional NF-κB p50 [5].

Thus, it may be that del-carriers are genetically determined towards a higher inflammatory response.

Our aim was to examine the associations of the NFKB1 promoter ATTG ins/del polymorphism with CHD risk in three independent studies of generally healthy Caucasians and the potential association with blood lipids and C-reactive protein (CRP).

We therefore hypothesized that the NFKB1 polymorphism would be associated with risk of CHD and that del-allele carriers, with a defective anti-inflammatory p50 NF-κB signalling pathway, would be at higher risk of CHD than homozygous carriers of the ins-allele.

Section snippets

Study populations

The Diet, Cancer, and Health (DCH) study was initiated in 1993–1997 when 57,053 Danish born residents, aged 50–64 years and free of cancer, participated in a clinical examination and detailed lifestyle survey [7]. Blood was sampled at baseline in the study clinic and stored as plasma, serum, lymphocytes, and erythrocytes at −150 °C. The Nurses’ Health Study (NHS) enrolled 121,701 female nurses aged 30–55 who returned a mailed questionnaire in 1976 regarding lifestyle and medical history. The

Results

Three independent prospective cohort studies were included. The Danish Diet, Cancer and Health (DCH) cohort included both men and women, whereas the US-based Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) were gender-specific. Table 1 shows baseline characteristics of cases and controls in the three study populations. The Danish participants on average drank more alcohol and smoked more than the US cohort members. The study populations had similar body weight but

Discussion

The present findings suggest that carriers of the del-allele of NFKB1 ATTG ins/del are at higher risk of CHD and have lower plasma levels of CRP.

NF-κB names a number of different transcription factors that are homo- or heterodimers of p65, p50, p105, C-rel and relB [2], [20]. The target gene specificity of NF-κB is determined by the subunit type. NF-κB is involved in both inflammatory and anti-inflammatory processes in atherogenesis [21]. The p50 subunit encoded by NFKB1 has both pro- and

Funding

This work was supported by the Danish Cancer Society, the Danish Ministry of Health, the Danish Ministry of Health, Research Centre for Environmental Health's Fund and grants from the National Institutes of Health (CA55075, HL35464, HL34594, CA87969).

Conflict of interest

None declared.

Acknowledgements

Anne-Karin Jensen is acknowledged for excellent technical support. We would like to thank Hardeep Ranu and Pati Soule from the DF/HCC Genotyping Core for genotyping and data management.

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