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NFKB1 promoter –94 insertion/deletion ATTG polymorphism (rs28362491) is associated with severity and disease progression of rheumatoid arthritis through interleukin-6 levels modulation in Egyptian patients

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Abstract

Objective

Rheumatoid arthritis (RA) is an inflammatory autoimmune disorder, which can cause progressive and functional disability. Previous data suggests that some inflammatory cytokines are dysregulated in patients with RA. Polymorphisms in the NFKB1 gene were studied in different populations with RA. Specific studies showed that the NFKB1 promoter –94ins/delATTG (rs28362491) polymorphism appears to be correlated with alterations in the IL-6 expression and may lead to disease development. We aimed to evaluate the association between the NFKB1 –94ins/delATTG polymorphism and biochemical, and clinical markers for severity of RA in Egyptian patients.

Methods

Study subjects included 196 RA patients from the Egyptian population. NFKB1 –94ins/delATTG polymorphism was genotyped by real-time PCR using the TaqMan assay. Concentrations of plasma IL-6 were assessed using the ELISA method.

Results

The frequencies of (del/del + ins/del) genotype in cases with erosive arthritis were significantly increased as compared to cases with non-erosive arthritis (63.0% vs. 47.7%, OR = 1.86, 95% CI: 1.05–3.30, p: 0.043). Carriers of del allele had high activity and severity markers compared with those of ins/ins genotype. The del allele was significantly associated with higher IL-6 levels in a dose-dependent manner. Plasma levels of IL-6 were significantly higher in the del/del (41.4 ± 16.2 pg/ml) and ins/del (19.1 ± 12.4 pg/ml) genotype when compared with the ins/ins genotype (11.4 ± 4.21 pg/ml). In a multivariate analysis of variance, including confounding factors associated with higher IL-6 levels (RF, disease duration, and DAS28), the NFKB1 –94ins/delATTG polymorphism retained its role. Logistic regression analyses revealed that high IL-6 plasma levels independently associated with an increased risk of presenting erosive RA, while –94ins/delATTG polymorphism has no direct association with the progression of erosive arthritis.

Conclusion

Our data indicate that the NFKB1 –94ins/delATTG polymorphism contributes to the severity and progression of RA through IL-6 levels modulation in Egyptian patients.

Key Points

• Carriers of del allele had high activity and severity markers compared with those of ins/ins genotype.

• In RA patients, the del allele was significantly associated with higher IL-6 levels in a dose-dependent manner.

• IL-6 plasma levels are independently associated with an increased risk of presenting erosive arthritis.

• The NFKB1 –94ins/delATTG polymorphism contributes to the severity and progression of RA through IL-6 levels modulation in Egyptian patients.

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Abbreviations

RA:

Rheumatoid arthritis

NF-κB:

Nuclear factor-κB

NFKB1:

Nuclear factor-kappa B1

IL-6:

Interleukin-6

PCR:

Polymerase chain reaction

ELISA:

Enzyme-linked immunosorbent assay

SNP:

Single-nucleotide polymorphism

DAS28:

Disease activity score in 28 joints

VAS:

Visual analogue scale

HAQ:

Health Assessment Questionnaire

Anti-CCP:

Anti-cyclic citrullinated peptide

RF:

Rheumatoid factor

ins:

Insertion

del:

Deletion

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Authors and Affiliations

  1. Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Almokhayam Aldaem Street, 6th Province, Nasr City, Cairo, 13465, Egypt

    Samy Y. Elkhawaga, Maher H. Gomaa & Ahmed A. Ebeed

  2. Rheumatology, Rehabilitation and Physical Medicine Department, Faculty of Medicine (Boys), Al-Azhar University, Cairo, Egypt

    Mohsen M. Elsayed

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  1. Samy Y. Elkhawaga
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Correspondence to Samy Y. Elkhawaga.

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Elkhawaga, S.Y., Gomaa, M.H., Elsayed, M.M. et al. NFKB1 promoter –94 insertion/deletion ATTG polymorphism (rs28362491) is associated with severity and disease progression of rheumatoid arthritis through interleukin-6 levels modulation in Egyptian patients. Clin Rheumatol 40, 2927–2937 (2021). https://doi.org/10.1007/s10067-021-05584-z

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