Functional Genetic Variation in<i>NFKBIA</i>and Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

Ali, Shirook M.; Hirschfeld, Aaron F.; Mayer, Matthew L.; Fortuno, Edgardo S.; Corbett, Nathan; Kaplan, Maia; Wang, Shirley; Schneiderman, Julia; Fjell, Christopher D.; Jin, Yan; Akhabir, Loubna; Aminuddin, Farzian; Marr, Nico; Lacaze‐Masmonteil, Thierry; Hegele, Richard G.; Becker, Allan B.; Chan‐Yeung, Moira; Hancock, Robert E. W.; Kollmann, Tobias R.; Daley, Denise; Sandford, Andrew J.; Lavoie, Pascal M.; Turvey, Stuart E.

doi:10.4049/jimmunol.1201015

Cited by 66 publications

(52 citation statements)

References 63 publications

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“…A small number of genes were found to be differentially expressed in cord blood from infants who went on to be hospitalized with RSV versus those that experienced a mild infection, including TNFRSF25 , which is involved in activation of NF-κB (29). Consistent with this, NFKBIA promoter variants which increase toll-like receptor (TLR)-mediated inflammatory cytokine production are associated with severe RSV bronchiolitis and AHR in children with RSV in the first year of life (30). Together this suggests that the immune response to RSV is key to determining the outcome of infection in the very young (Figure 2).…”

Section: Clinical Disease and Treatmentmentioning

confidence: 73%

“…A recent twin study in Denmark concluded that severe RSV bronchiolitis was a marker for genetic predisposition to asthma (184). Furthermore, a genetic polymorphism in the gene encoding IκBα, a negative regulator of NF-κB, was recently identified to be associated with both RSV and asthma (30). In addition, Gern et al showed that infants whose cord blood responded with a stronger IFN-γ secretion to RSV stimulation had reduced risk of early PBW, although the infants in this study were all already at increased risk of wheeze with an atopic background (185).…”

Section: Delayed Sequelae Of Rsv Bronchiolitismentioning

confidence: 99%

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Immunity to RSV in Early-Life

et al. 2014

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Respiratory Syncytial Virus (RSV) is the commonest cause of severe respiratory infection in infants, leading to over 3 million hospitalizations and around 66,000 deaths worldwide each year. RSV bronchiolitis predominantly strikes apparently healthy infants, with age as the principal risk factor for severe disease. The differences in the immune response to RSV in the very young are likely to be key to determining the clinical outcome of this common infection. Remarkable age-related differences in innate cytokine responses follow recognition of RSV by numerous pattern recognition receptors, and the importance of this early response is supported by polymorphisms in many early innate genes, which associate with bronchiolitis. In the absence of strong, Th1 polarizing signals, infants develop T cell responses that can be biased away from protective Th1 and cytotoxic T cell immunity toward dysregulated, Th2 and Th17 polarization. This may contribute not only to the initial inflammation in bronchiolitis, but also to the long-term increased risk of developing wheeze and asthma later in life. An early-life vaccine for RSV will need to overcome the difficulties of generating a protective response in infants, and the proven risks associated with generating an inappropriate response. Infantile T follicular helper and B cell responses are immature, but maternal antibodies can afford some protection. Thus, maternal vaccination is a promising alternative approach. However, even in adults adaptive immunity following natural infection is poorly protective, allowing re-infection even with the same strain of RSV. This gives us few clues as to how effective vaccination could be achieved. Challenges remain in understanding how respiratory immunity matures with age, and the external factors influencing its development. Determining why some infants develop bronchiolitis should lead to new therapies to lessen the clinical impact of RSV and aid the rational design of protective vaccines.

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Section: Clinical Disease and Treatmentmentioning

confidence: 73%

Section: Delayed Sequelae Of Rsv Bronchiolitismentioning

confidence: 99%

Immunity to RSV in Early-Life

et al. 2014

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“…In line with this, a genetic variant of the best known NF-kB inhibitor, IkBa (NFΚBIA), has been shown to contain inactivating mutations in Hodgkin's lymphoma cell lines and in ∼20% of patients, which leads to strong constitutive NF-kB activity that is thought to contribute to malignant transformation (26,27). Other IkBa variants resulting in decreased expression of the inhibitor have been described in inflammation-associated disorders including asthma and bronchiolitis (28). The existence of regulatory proteins that lead to inactivation of NF-kB provides a rationale to consider that a genetic variant that reduces their inhibitory activity may be clinically relevant in chronic inflammatory disorders where NFkB is constitutively active.…”

Section: Discussionmentioning

confidence: 99%

A Truncated Variant of ASCC1, a Novel Inhibitor of NF-κB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis

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Álvarez-Rodríguez

Grande

et al. 2015

The Journal of Immunology

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Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-κB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-κB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-κB target genes (TRAIL, TNF-α, cIAP-1, IL8) and blocks activation of a NF-κB–luciferase reporter construct in five different human cell lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78*) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-κB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-κB and the secretion of TNF-α in response to inflammatory stimuli. We analyzed the clinical impact of p.S78* variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheumatic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-κB activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA.

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“…Genotyping was performed by real time PCR assays using allele-specific Taqman probes (Fig. 1) as previously described [27], [28].…”

Section: Methodsmentioning

confidence: 99%

Assessment of Genetic Associations between Common Single Nucleotide Polymorphisms in RIG-I-Like Receptor and IL-4 Signaling Genes and Severe Respiratory Syncytial Virus Infection in Children: A Candidate Gene Case-Control Study

et al. 2014

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The majority of cases of severe pediatric respiratory syncytial virus (RSV) infection occur in otherwise healthy infants who have no identifiable risk factors, suggesting that additional subclinical factors, such as population genetic variation, influence the course of RSV infection. The objective of this study was to test if common single nucleotide polymorphisms (SNPs) in genes encoding for immune signalling components of the RIG-I-like receptor (RLR) and IL-4-signalling pathways affect the outcome of RSV infection in early life. We genotyped 8 SNPs using allele-specific probes combined with real-time PCR. Each of the SNPs tested had previously been established to have a functional impact on immune responsiveness and two of the SNPs in the IL4 and IL4R genes had previously been associated with severe RSV bronchiolitis. Association with susceptibility to severe RSV infection was tested by statistically comparing genotype and allele frequencies in infants and young children hospitalized with severe RSV bronchiolitis (n = 140) with two control groups—children who tested positive for RSV but did not require hospitalization (n = 100), and a general population control group (n = 285). Our study was designed with sufficient power (>80%) to detect clinically-relevant associations with effect sizes ≥1.5. However, we detected no statistically significant differences in allele and genotype frequencies of the investigated SNPs between the inpatient and control groups. To conclude, we could not replicate the previously reported association with SNPs in the IL4 and IL4R genes in our independent cohort, nor did we find that common SNPs in genes encoding for RLRs and the downstream adapter MAVS were associated with susceptibility to severe RSV infections. Despite the existing evidence demonstrating a functional immunological impact of these SNPs, our data suggest that the biological effect of each individual SNP is unlikely to affect clinical outcomes of RSV infection.

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Functional Genetic Variation inNFKBIAand Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

Cited by 66 publications

References 63 publications

Immunity to RSV in Early-Life

Immunity to RSV in Early-Life

A Truncated Variant of ASCC1, a Novel Inhibitor of NF-κB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis

Assessment of Genetic Associations between Common Single Nucleotide Polymorphisms in RIG-I-Like Receptor and IL-4 Signaling Genes and Severe Respiratory Syncytial Virus Infection in Children: A Candidate Gene Case-Control Study

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