Assessment of the association between TNIP1 polymorphism with clinical features and risk of systemic lupus erythematosus

Abstract

Objective

Over the past decades, TNIP1 has been identified as a strong risk locus in multiple genome-wide association studies (GWAS), spanning multiple populations and various autoimmune diseases. TNIP1 is a polyubiquitin-binding protein that works as a physiological inhibitor of NF-κB and maintains immune homeostasis. Some studies have confirmed that TNIP1 is downregulated in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In the current study, for the first time, we evaluated the possible association between rs6889239 polymorphism in the TNIP1 gene with the risk and clinical characteristics of RA and SLE in the Iranian population.

Method

In this case–control study, 115 patients with RA, 115 patients with SLE, and 115 unrelated healthy subjects were enrolled to estimate rs6889239 genotypes with real-time PCR high resolution melting (HRM) method.

Results

Our results demonstrated considerable associations between CC genotype and C allele of rs6889239 with augmented risk of SLE (OR for CC genotype= 2.23; 95%CI [1.175–4.307], OR for C allele= 1.84; 95%CI [1.254–2.720]). However, there was an insignificant association between genotypes and allele frequencies of rs6889239 with the occurrence risk of RA in the population under study (p > 0.05). Additionally, stratification analysis specified that the C allele in rs6889239 was linked with the incidence of renal involvement in SLE patients and lower age of onset in the RA group (p < 0.05).

Conclusion

These findings propose a significant association between TNIP1 polymorphism and higher risk of SLE and some clinical characteristics of RA and SLE.

Keywords

Rheumatoid arthritis systemic lupus erythematosus single nucleotide polymorphism TNIP1 rs6889239

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References

Wang

Xie

Zhang

, et al. Rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren’s syndrome shared megakaryocyte expansion in peripheral blood. Ann Rheum Dis 2021; 81(3), 379–385.

Scherer

Häupl

Burmester

. The etiology of rheumatoid arthritis. J Autoimmunity 2020; 110: 102400.

Firestein

McInnes

. Immunopathogenesis of rheumatoid arthritis. Immunity 2017; 46: 183–196.

Mohan

Putterman

. Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. Nat Rev Nephrol 2015; 11: 329–341.

Zhang

Jiang

, et al. Detection of genetic overlap between rheumatoid arthritis and systemic lupus erythematosus using GWAS summary statistics. Front Genetics 2021; 12: 389.

Wang

Y-F

Zhang

Lin

, et al. Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups. Nat Commun 2021; 12: 772.

Onuora

. New insights into RA genetics from GWAS meta-analysis. Nat Rev Rheumatol 2021; 17: 128–128.

Taniguchi

Karin

. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 2018; 18: 309–324.

Barnabei

Laplantine

Mbongo

, et al. NF-κB: at the borders of autoimmunity and inflammation. Front Immunol 2021; 12: 716469.

10.

Mishra

. Involvement of NF-κB signaling pathway in the pathogenesis of systemic lupus erythematosus. Nephrol - Open J 2016; 2: 9–13.

11.

Samimi

Farhadi

Tahmasebi

, et al. NF-κB signaling in rheumatoid arthritis with focus on fibroblast-like synoviocytes. Autoimmun Highlights 2020; 11: 1–10.

12.

Sun

S-C

Chang

J-H

Jin

. Regulation of nuclear factor-κB in autoimmunity. Trends Immunol 2013; 34: 282–289.

13.

Brady

Korte

Caster

, et al. TNIP1/ABIN1 and lupus nephritis: review. Lupus Sci Med 2020; 7: e000437.

14.

Verstrepen L, Carpentier I, Beyaert R. The biology of A20-binding inhibitors of NF-κB activation (ABINs). Adv Exp Med Biol. 2014;809:13–31.

15.

G’Sell

Gaffney

Powell

. ABIN1 a physiological inhibitor of NF–κB: A molecular switch for inflammation and autoimmunity. Arthritis Rheumatology (Hoboken, NJ) 2015; 67: 2292.

16.

Hövelmeyer

Reissig

Thi Xuan

, et al. A20 deficiency in B cells enhances B‐cell proliferation and results in the development of autoantibodies. Eur Journal Immunology 2011; 41: 595–601.

17.

Yang

Liu

, et al. Investigation of 20 non-HLA (human leucocyte antigen) psoriasis susceptibility loci in Chinese patients with psoriatic arthritis and psoriasis vulgaris. Br J Dermatol 2013; 168: 1060–1065.

18.

Allanore

Saad

Dieudé

, et al. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genetics 2011; 7: e1002091.

19.

Bowes

Budu-Aggrey

Huffmeier

, et al. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nat Communications 2015; 6: 6046.

20.

López-Isac

Acosta-Herrera

Kerick

, et al. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways. Nat Commun 2019; 10: 4955.

21.

Sun

Cheng

Wang

, et al. Association analyses identify six new psoriasis susceptibility loci in the Chinese population. Nat Genet 2010; 42: 1005–1009.

22.

Nair

Duffin

, et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat Genetics 2009; 41: 199–204.

23.

Gateva

Sandling

Hom

, et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genetics 2009; 41: 1228–1233.

24.

Han

Zheng

Cui

, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 2009; 41: 1234–1237.

25.

Adrianto

Wang

Wiley

, et al. Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus. Arthritis Rheumatism 2012; 64: 3695–3705.

26.

Graham

DSC

Morris

Bhangale

, et al. Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genetics 2011; 7: e1002341.

27.

Zhang

D-M

Cheng

L-Q

Zhai

Z-F

, et al. Single-nucleotide polymorphism and haplotypes of TNIP1 associated with systemic lupus erythematosus in a Chinese Han population. J Rheumatology 2013; 40: 1535–1544.

28.

Bolin

Sandling

Zickert

, et al. Association of STAT4 polymorphism with severe renal insufficiency in lupus nephritis. PloS One 2013; 8: e84450.

29.

Aringer

Costenbader

Daikh

, et al. 2019 European league against rheumatism/american college of rheumatology classification criteria for systemic lupus erythematosus. Ann Rheumatic Diseases 2019; 78: 1151–1159.

30.

Ehtesham

Zare Rafie

Esmaeilzadeh

, et al. Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus. Lupus 2021; 30: 1273–1282.

31.

Ramirez

Gurevich

Aneskievich

. Emerging roles for TNIP1 in regulating post-receptor signaling. Cytokine Growth Factor Rev 2012; 23: 109–118.

32.

Shamilov

Aneskievich

. TNIP1 in autoimmune diseases: regulation of toll-like receptor signaling. J Immunol Res 2018; 2018: 3491269.

33.

Chu

Vahl

Kumar

, et al. B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood 2011; 117: 2227–2236.

34.

Chen

Yan

Song

, et al. Downregulation of TNIP1 expression leads to increased proliferation of human keratinocytes and severer psoriasis-like conditions in an imiquimod-induced mouse model of dermatitis. PloS One 2015; 10: e0127957.

35.

Zhu

Wang

, et al. Characteristics of A20 gene polymorphisms and clinical significance in patients with rheumatoid arthritis. J Translational Med 2015; 13: 215.

36.

Yang

, et al. TNFAIP3 genetic polymorphisms reduce ankylosing spondylitis risk in Eastern Chinese Han population. Scientific Reports 2019; 9: 1–9.