The NFKB1 ATTG ins/del polymorphism and risk of coronary heart disease in three independent populations
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.
References (27)
- et al.
NF-kappaB -94Ins/Del ATTG polymorphism modifies the association between dietary polyunsaturated fatty acids and HDL-cholesterol in two distinct populations
Atherosclerosis
(2009) - et al.
Nuclear factor-kappaB1: regulation and function
Int J Biochem Cell Biol
(2008) - et al.
NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages
J Biol Chem
(2006) - et al.
Cotranslational biogenesis of NF-kappaB p50 by the 26S proteasome
Cell
(1998) - et al.
Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis
Hum Mol Genet
(2004) - et al.
NFKB1 promoter variation implicates shear-induced NOS3 gene expression and endothelial function in prehypertensives and stage I hypertensives
Am J Physiol Heart Circ Physiol
(2007) - et al.
Study design, exposure variables, and socioeconomic determinants of participation in Diet, Cancer and Health: a population-based prospective cohort study of 57,053 men and women in Denmark
Scand J Public Health
(2007) - et al.
Predictive values of acute coronary syndrome discharge diagnoses differed in the Danish National Patient Registry
J Clin Epidemiol
(2009) - et al.
The Nurses’ Health Study: 20-year contribution to the understanding of health among women
J Womens Health
(1997) - et al.
Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals
Am J Epidemiol
(1992)
Prospective study of alcohol consumption and risk of coronary disease in men
Lancet
The analysis of failure times in the presence of competing risks
Biometrics
The T111I variant in the endothelial lipase gene and risk of coronary heart disease in three independent populations
Eur Heart J
Cited by (42)
Association of NFKB1 -94 ins/del variants with BMI in patients with myocardial infarction
2019, Obesity MedicineCitation Excerpt :Previous reports suggest that the rs2275913 (G197A) from IL-17A gene promoter is markedly associated with inflammatory diseases (Geng et al., 2014; Arisawa et al., 2008, 2012). Moreover, rs28362491 from NFKB1 gene is associated with increased risk of coronary artery disease (Yang et al., 2014; Vogel et al., 2011). Since NF-κB1 works downstream of IL-17 signaling, we aimed to study functional polymorphisms in the IL-17A and NFKB1 gene promoters in patients who were hospitalized after myocardial infarction and also in a group of healthy blood donors in the same geographic region.
Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and their association with type 2 diabetes and impaired renal function
2018, Human ImmunologyCitation Excerpt :Given the tumor-promoting role of p50 and NF-kappaB, it is biologically plausible that the −94del allele (linked to reduced promoter activity) would confers a decreased cancer susceptibility. In contrast, the Del allele has been associated with increased risk for coronary artery disease [23–25,36–38]. In our cohort the deletion allele was at a higher frequency in the eGFR < 60 and T2DM group, but the genotype frequencies were only significantly associated with T2DM in a dominant model (ID + DD vs. II).
Mutant DD genotype of NFKB1 gene is associated with the susceptibility and severity of coronary artery disease
2017, Journal of Molecular and Cellular CardiologyInteractions between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases among the Japanese population
2017, Journal of EpidemiologyCitation Excerpt :DNA was extracted from the buffy coat fraction using the standard method and the QIAamp Blood Mini Kit (Qiagen, Valencia, CA, USA), GenElute Blood Genomic DNA Kit (Sigma–Aldrich, St. Louis, MO, USA), or Blood-Animal-Plant DNA Preparation Kit (Jena Bioscience, Jena, Germany). We selected three single-nucleotide polymorphisms (SNPs) with minor allele frequencies (MAF) greater than 0.05 from the common genes for cytokines that have important roles in the immune-inflammatory processes of HTLV-I infection, cancers, and atherosclerosis, including TNF-α 1031T/C [rs1799964], IL-10 819T/C [rs1800871], and NF-κB1 94ATTG ins/del [rs28362491].23–37 These SNPs were genotyped using TaqMan allelic discrimination kits (Applied Biosystems, Foster City, CA, USA) and real-time polymerase chain reaction (StepOne, Applied Biosystems).
Cardiovascular risk assessment in patients with rheumatoid arthritis: The relevance of clinical, genetic and serological markers
2016, Autoimmunity ReviewsCitation Excerpt :The latter plays a central role in inflammation through the regulation of genes encoding pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors, and inducible enzymes such as inducible nitric oxide synthase [104]. Because of that, the inappropriate activation of NF-kB predisposes to the development of a variety of human diseases and pathologic conditions [105,106]. With respect to this, the NFKB1 − 94 insertion/deletion ATTG (rs28362491) promoter polymorphism, that shows functional effects on the transcription of NFKB1, has been related to several immune-mediated disorders [107].
NFKB1 variants were associated with the risk of Parkinson´s disease in male
2024, Journal of Neural Transmission