Q222R polymorphism in DNAse I gene is a risk factor for nephritis in South Indian SLE patients

Abstract

Objective

Systemic lupus erythematosus (SLE) is a multisystem disorder in which defective apoptotic clearance is considered to be an important factor in pathogenesis. DNAse I is associated with disposal of apoptotic nuclear debris. The defective enzyme production due to +2373 A to G (Q222R) in exon 8 is reported to be a genetic risk factor for SLE. SLE in Indians is reported to be severe. There are no genetic studies reported from India which have explored this aspect of DNAseI gene. This study aimed to analyze whether Q222R is a susceptibility factor for SLE and to study its influence on clinical manifestations and autoantibody production in South Indian Tamils.

Method

Three hundred SLE cases (based on ACR 1982 criteria) and 530 age, sex similar and ethnicity matched controls were recruited. All the cases and controls were genotyped for DNAse I Q222R polymorphism using PCR-RFLP method.

Results

DNAse I Q222R polymorphism is prevalent in our population. We observed higher frequency of Q/R in patients compared with controls (60% vs. 53%). This was found to be a genetic risk for SLE susceptibility (p = 0.04, odds ratio 1.5, 95% confidence interval 1–2.1). It also conferred a significant risk for development of nephritis (p = 0.007, odds ratio 1.93, 95% confidence interval 1.2–3.2).

Conclusion

DNAse I Q222R polymorphism is a potential genetic risk factor for SLE in South Indian Tamils. In addition, the mutant allele confers a significant risk for lupus nephritis.

Keywords

SLE ANA DNAse I apoptosis

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References

Wakeland

Liu

Graham

Behrens

. Delineating the genetic basis of SLE. Immunity 2001; 15: 397–408.

Antonio

. Anti cytokine therapies in systemic lupus erythematosus. Immunotherapy 2010; 2: 575–582.

Dieker

JWC

Van der Vlag

Berden

. Triggers for anti-chromatin autoantibody production in SLE. Lupus 2002; 11: 856–864.

Walport

. Lupus, DNase and defective disposal of cellular debris. Nat Genet 2000; 25: 135–136.

Kishi

Yasuda

Takeshita

. DNase I: Structure, function, and use in medicine and forensic science. Leg Med 2001; 3: 69–83.

Chitrabamrung

Rubin

Tan

. Serum deoxyribonuclease I and clinical activity in systemic lupus erythematosus. Rheumatol Int 1981; 1: 55–60.

Napirei

Karsunky

Zevnik

Stephan

Mannherz

Moroy

. Features of systemic lupus erythematosus in Dnase 1-deficient mice. Nat Genet 2000; 25: 177–181.

Yasutomo

Horiuchi

Kagami

. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 2001; 28: 313–314.

Chakraborty

Kacem

Makini-Karay

. The A/T mutation in exon 2 of DNase I gene is not present in Tunisian patients with systemic lupus erythematosus or in healthy subjects. Arthritis Rheum 2003; 48: 3295–3300.

10.

Bodano

Gonzalez

Vidal

. Association of non-synonymous single nucleotide polymorphism of DNASE 1 with SLE susceptibility. Rheumatology 2006; 45: 819–823.

11.

Shin

Park

Kim

Lee

Kim

Bae

. Common DNase I polymorphism associated with autoantibody production among systemic erythematosus patients. Hum Mol Genet 2004; 13: 2343–2350.

12.

Tan

Cohen

Fred

. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–1277.

13.

Miller

Dykes

Polesky

. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215–1215.

14.

Eilertsen GO, Becker-Merok A, Nossent JC. The influence of the 1997 updated classification criteria for systemic lupus erythematosus: epidemiology, disease presentation, and patient management. The Journal of Rheumatology. 2009; 36: 552--559.

15.

Yasuda

Ueki

Takeshita

. A biochemical and genetic study on all non-synonymous single nucleotide polymorphisms of the gene encoding human deoxyribonuclease I potentially relevant to autoimmunity. Int J Biochem Cell Biol 2010; 42: 1216–1225.

16.

Sebro

Lange

Laird

Rogus

Risch

. Differentiating population stratiﬁcation from genotyping error using family data. Ann Hum Genet 2012; 76: 42–52.

17.

Reich

Thangaraj

Patterson

Price

Singh

. Reconstructing Indian population history. Nature 2009; 461: 489–494.

18.

Malaviya

Chandrasekaran

Kumar

Shamar

. Systemic lupus erythematosus in India. Lupus 1997; 6: 690–700.

19.

Vanholder

De Keyser

Kips

Praet

Naeyaert

. The pathophysiology of lupus erythematosus. Eur J Dermatol 1998; 1: 4–7.

20.

Lande

Ganguly

Facchinetti

. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 2011; 3: 73ra19–73ra19.

21.

Van Bruggen

Walgreen

Rijke

. Antigen specificity of anti-nuclear antibodies complexed to nucleosomes determines glomerular basement membrane binding in vivo. Eur J Immunol 1997; 27: 1564–1569.

22.

Hakkim

Fürnrohr

Amann

. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA 2010; 107: 9813–9818.

23.

Martinez

Balada

Ordi-Ros

Bujan

Fernandez

Vilardell

. DNase1 activity in systemic lupus erythematosus patients with and without nephropathy. Rheumatol Int 2010; 30: 1601–1604.

24.

Lewis JE, Fu SM, Gaskin F. Autoimmunity, end organ damage, and the origin of autoantibodies and autoreactive T cells in systemic lupus erythematosus. Discov Med 2013; 15: 85--92.