Association of ficolin-2 gene polymorphisms and susceptibility to systemic lupus erythematosus in Egyptian children and adolescents: a multicenter study

Abstract

Background

Pediatric-onset SLE (pSLE) is a multisystem autoimmune disease. Recently, the ficolin-2 (FCN2) gene has emerged as a potential candidate gene for susceptibility to SLE.

Objectives

The objective of this study was to evaluate the association of the FCN2 gene polymorphisms at positions −986 (G/A), −602 (G/A), −4 (A/G) and SNP C/T (rs3124954) located in intron 1, with susceptibility to pSLE in Egyptian children and adolescents.

Methods

This was a multicenter study of 280 patients diagnosed with pSLE, and 280 well-matched healthy controls. The FCN2 promoter polymorphisms at –986 G/A (rs3124952), −602 G/A (rs3124953), −4 A/G (rs17514136) and SNP C/T (rs3124954) located in intron 1 were genotyped by polymerase chain reaction, while serum ficolin-2 levels were assessed using enzyme-linked immunosorbent assay.

Results

The frequencies of the FCN2 GG genotype and G allele at −986 and −602 positions were significantly more represented in patients with pSLE than in controls (p < 0.001). Conversely, the FCN2 AA genotype and A allele at position −4 were more common in patients than in controls (p < 0.001). Moreover, patients carrying the FCN2 GG genotype in −986 position were more likely to develop lupus nephritis (odds ratio: 2.6 (95% confidence interval: 1.4–4.78); p = 0.006). The FCN2 AA genotype at position −4 was also identified as a possible risk factor for lupus nephritis (odds ratio: 3.12 (95% confidence interval: 1.25–7.84); p = 0.024).

Conclusion

The FCN2 promoter polymorphisms may contribute to susceptibility to pSLE in Egyptian children and adolescents. Moreover, the FCN2 GG genotype at position −986 and AA genotype at position −4 were associated with low serum ficolin-2 levels and may constitute risk factors for lupus nephritis in pSLE.

Keywords

Adolescents children ficolin-2 gene pediatric-onset SLE polymorphism

Get full access to this article

View all access options for this article.

References

Kamphuis

Silverman

. Prevalence and burden of pediatric-onset systemic lupus erythematosus. Nat Rev Rheumatol 2010; 6: 538–546.

Tarr

Dérfalvi

Győri

et al.

Similarities and differences between pediatric and adult patients with systemic lupus erythematosus. Lupus 2015; 24: 796–803.

Choi

Kim

Craft

. The pathogenesis of systemic lupus erythematosus-an update. Curr Opin Immunol 2012; 24: 651–657.

Munoz

Gaipl

Franz

et al.

SLE—a disease of clearance deficiency?

Rheumatology (Oxford) 2005; 44: 1101–1107.

Runza

Schwaeble

Männel

. Ficolins: Novel pattern recognition molecules of the innate immune response. Immunobiology 2008; 213: 297–306.

Jensen

Honoré

Hummelshøj

Hansen

Madsen

Garred

. Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 2007; 44: 856–865.

Munthe-Fog

Hummelshoj

Honoré

et al.

Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation. Genes Immun 2012; 13: 515–522.

Watanabe

Saito

Asano

et al.

Serum L-ficolin levels in patients with systemic lupus erythematosus. Mod Rheumatol 2012; 22: 899–902.

Tanha

Pilely

Faurschou

Garred

Jacobsen

. Plasma ficolin levels and risk of nephritis in Danish patients with systemic lupus erythematosus. Clin Rheumatol 2017; 36: 335–341.

10.

Hein

Nielsen

et al.

Ficolins and the lectin pathway of complement in patients with systemic lupus erythematosus. Mol Immunol 2015; 63: 209–214.

11.

Colliard

Jourde-Chiche

Clavarino

et al.

Autoantibodies targeting ficolin-2 in systemic lupus erythematosus patients with active nephritis. Arthritis Care Res (Hoboken) 2018; 70: 1263–1268.

12.

Garred

Honoré

et al.

The genetics of ficolins. J Innate Immun 2010; 2: 3–16.

13.

Hummelshoj

Munthe-Fog

Madsen

Fujita

Matsushita

Garred

. Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2. Hum Mol Genet 2005; 14: 1651–1658.

14.

Addobbati

de Azevêdo Silva

Tavares

et al.

Ficolin gene polymorphisms in systemic lupus erythematosus and rheumatoid arthritis. Ann Hum Genet 2016; 80: 1–6.

15.

Petri

Orbai

Alarcón

et al.

Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677–2686.

16.

Ruperto

Bazso

Ravelli

et al.

Paediatric Rheumatology International Trials Organization (PRINTO). The Paediatric Rheumatology International Trials Organization (PRINTO). Lupus 2007; 16: 670–676.

17.

Uribe

Vilá

McGwin

Jr Sanchez

Reveille

Alarcón

. The Systemic Lupus Activity Measure-revised, the Mexican Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and a modified SLEDAI-2K are adequate instruments to measure disease activity in systemic lupus erythematosus. J Rheumatol 2004; 31: 1934–1940.

18.

Schwartz

. The pathology of lupus nephritis. Semin Nephrol 2007; 27: 22–34.

19.

Marzetti

Di Battista

Ferrante

et al.

MBL2 and FCN2 gene polymorphisms in a cohort of Italian children with rheumatic fever: A case–control study. Semin Arthritis Rheum 2017; 47: 264–268.

20.

Cedzynski

Atkinson

St. Swierzko

et al.

L-ficolin (ficolin-2) insufficiency is associated with combined allergic and infectious respiratory disease in children. Mol Immunol 2009; 47: 415–419.

21.

Świerzko

Szala-Poździej

Kilpatrick

et al.

Components of the lectin pathway of complement activation in paediatric patients of intensive care units. Immunobiology 2016; 221: 657–669.

22.

Faik

Oyedeji

Idris

et al.

Ficolin-2 levels and genetic polymorphisms of FCN2 in malaria. Hum Immunol 2011; 72: 74–79.

23.

Webb

Kelly

Somers

et al.

Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients. Ann Rheum Dis 2010; 70: 151–156.

24.

Østergaard

Nielsen

Iversen

et al.

Unique protein signature of circulating microparticles in systemic lupus erythematosus. Arthritis Rheum 2013; 65: 2680–2690.

25.

Nisihara

Magrini

Mocelin

Messias-Reason

. Deposition of the lectin pathway of complement in renal biopsies of lupus nephritis patients. Hum Immunol 2013; 74: 907–910.

26.

Hoang

Toan

Song le

et al.

Ficolin-2 levels and FCN2 haplotypes influence hepatitis B infection outcome in Vietnamese patients. PLoS One 2011; 6: e28113.

27.

Munthe-Fog

Hummelshøj

Hansen

et al.

The impact of FCN2 polymorphisms and haplotypes on the Ficolin-2 serum levels. Scand J Immunol 2007; 65: 383–392.

28.

Napirei

Karsunky

Zevnik

Stephan

Mannherz

Moroy

. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 2000; 25: 177–181.

29.

Stegert

Bock

Trendelenburg

. Clinical presentation of human C1q deficiency: How much of a lupus? Mol Immunol 2015; 67: 3–11.

30.

Rullo

Tsao

. Recent insights into the genetic basis of systemic lupus erythematosus. Ann Rheum Dis 2013; 72(Suppl. 2): ii56–ii61.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.74 MB