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Human Molecular Genetics Advance Access originally published online on August 27, 2004
Human Molecular Genetics 2004 13(20):2343-2350; doi:10.1093/hmg/ddh275
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Human Molecular Genetics, Vol. 13, No. 20 © Oxford University Press 2004; all rights reserved

Common DNase I polymorphism associated with autoantibody production among systemic lupus erythematosus patients

Hyoung Doo Shin1, Byung Lae Park1, Lyoung Hyo Kim1, Hye-Soon Lee2, Think-You Kim3 and Sang-Cheol Bae2,*

1Department of Genetic Epidemiology, SNP Genetics, Inc., 11th Floor, MaeHun B/D, 13 Chongro 4 Ga, Chongro-Gu, Seoul 10-834, South Korea, 2Department of Internal Medicine, Division of Rheumatology and 3Department of Diagnostic Immunology, Laboratory Medicine, The Hospital for Rheumatic Diseases, Hanyang University, Seoul 133-792, South Korea

Received June 13, 2004; Revised July 27, 2004; Accepted August 20, 2004


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
DNase I could be the most important nuclease for the removal of DNA from nuclear antigens at sites of high cell turnover, and thus may also prevent systemic lupus erythematosus (SLE). Sixteen SNPs were identified by direct DNA sequencing, among which six were selected for genotyping in a larger investigation on the basis of linkage disequilibria among SNPs, their frequency, location and haplotype tagging status. Genetic associations of polymorphisms in DNase I with the risk of SLE and the production of common autoantibodies were examined in a Korean population (350 SLE patients and 330 controls). Although no significant associations with the risk of SLE were found, logistic regression analyses revealed that one non-synonymous SNPs in exon 8, +2373A>G(Gln244Arg), was significantly associated with an increased risk of the production of anti-RNP and anti-dsDNA antibodies among SLE patients. The frequency of the homozygous minor allele (Arg/Arg) was much higher in patients who had the anti-RNP antibody (31.3%) than in patients who did not have this antibody (14.4%) (P=0.0006, OR=2.86). In addition, the A/T mutation in exon 2 of DNase reported in two Japanese SLE patients was not present in SLE patients (n=350) or controls (n=330) in our Korean population, which combined with the results of previous reports strongly suggests that the mutation is not present in three major ethnic groups: Caucasian, African and Asian.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation that leads to a high level of autoantibody (auto-Ab) production, immune-complex deposition and tissue injury. Patients with SLE manifest with a diverse array of clinical symptoms that can involve multiple organ systems. The etiology of SLE is complex, involving environmental and genetic factors both independently and, most probably, synergistically. Genetic factors are likely to play a significant role in the susceptibility to SLE, in determining the disease expression and in the auto-Ab profile exhibited by individuals with SLE (1).

Lower serum DNase activity observed in SLE patients could be causing abnormalities in the function of enzymes responsible for clearance of postapoptotic products and, consequently, could be an important pathogenesis of SLE (2). DNase I and DNase II are the primary enzymes involved in the metabolism and clearance of DNA.

One nonsense mutation in exon 2 of DNase I, with decreased DNase I activity and an extremely high immunoglobulin G titer against nucleosomal antigens, has been reported in two Japanese SLE patients (3). However, analyses of 1516 chromosomes of Caucasian (4) and 260 chromosomes of African, including SLE patients (5), showed the absence of this mutation. To confirm the absence or presence of this mutation in the Korean population, whose genetic background is very similar to that of the Japanese population (6), we explored the A/T mutation of DNase I in SLE patients and controls (n=680).

Furthermore, to investigate the possible involvement of genetic polymorphisms of DNase I in SLE, additional polymorphisms were scrutinized by direct DNA sequencing of the whole gene, including ~1500 bp of the 5' flanking region. The genetic associations of additional polymorphisms (identified in this study) with the risk of SLE and production of auto-Abs were examined in Korean patients with SLE.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Genotyping and direct DNA sequencing revealed that neither Korean SLE patients (n=350) nor Korean controls (n=330) carried any A/T mutation in exon 2 of DNase I reported in two Japanese SLE patients (3).

We then investigated the possible existence of polymorphisms in DNase I by direct DNA sequencing of the whole gene, including ~1500 bp of the 5' flanking region, in 12 SLE patients and 12 healthy subjects. Fifteen SNPs, including three known SNPs, were identified: three in the 5' regulatory region, five in introns and seven in exons (four non-synonymous SNPs) (Fig. 1). The frequencies of the minor alleles of DNase I SNPs are shown in Figure 1A. Pair-wise comparisons among SNPs revealed one set of absolute linkage disequilibria (LDs) (|D'|=1 and r2=1):–2125A>C : –1900T>C : –1494C>G : –778G>A : –637G>A : –16C>T. Several complete LDs (|D'|=1 and r2=1) were also found (Fig. 1C). LDs among SNPs and haplotypes inferred by PHASE software (7) are also shown in Figure 1B and C. Only two common (frequency>0.05) haplotypes (ht1 and ht2) were used for haplotype association analysis.



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  		Figure 1. Gene map and haplotypes of DNase I. (A) Map of DNase I gene on chromosome 16p13.3. Coding exons are marked by black blocks, and 5' and 3' UTRs by white blocks. The first base of the translational start site is denoted as nucleotide +1. Asterisks indicate polymorphisms genotyped in our total study (n=680). The frequencies of polymorphisms without larger scale genotyping were based on sequencing data (n=24). (B) Haplotypes of DNase I. (C) Measurement of LDS (based on |D'| and r2 values) among DNase I SNPs.

 
Six of these SNPs [–2125A>C, +273C>T, +1649C>G (Pro154Ala), +2035C>G, +2120C>T and +2373A>G (Gln244Arg)] were selected for genotyping in a larger investigation (350 SLE patients and 330 controls) on the basis of LDs among SNPs, their frequency, location and haplotype tagging status. For comparison of allele frequencies with those in other major ethnic groups, we also genotyped 50 Caucasian and 50 African-American DNA samples obtained from the Human Genetic Cell Repository (http://locus.umdnj.edu/nigms/) (Fig. 1B). The genotype distributions of DNase I SNPs in SLE patients and normal subjects were analyzed with multiple logistic regression models. No significant genetic associations were found between DNase I polymorphisms and the risk of SLE (Table 1). The genetic associations with the production of three common auto-Abs [anti-Ro, -RNP (ribonucleoprotein) and -dsDNA Abs] were also tested. One non-synonymous SNP [+2373A>G(Gln244Arg)], one nearby intronic SNP (+2035C>G) and two common haplotypes (ht1 and ht2) were significantly associated with an increased risk of anti-RNP (P=0.003, 0.003, 0.0007 and 0.001, respectively) and anti-dsDNA Abs production (P=0.02, 0.04, 0.03 and 0.11, respectively) among SLE patients (Table 2). It is more likely that the significant associations of ht1[A–C–C–C–C–C–A] and ht2[A–C–C–C–G–C–G] come from +2373A>G(Gln244Arg) and +2035C>G, considering that ht1 and ht2 are tagged by the A allele (Gln) of +2373A>G(Gln244Arg) (>94%) and the G allele of +2035C>G (>96%), respectively (Fig. 1B). Similarly, the positive signals of the nearby intronic SNP, +2035C>G, might be tracking the effect of nearby non-synonymous SNP, +2373A>G(Gln244Arg), in exon 8 due to the strong LD (|D'|=1) (Fig. 1C). The genetic effect of +2373A>G(Gln244Arg) was therefore analyzed further.


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  		Table 1. Logistic analysis of DNase I polymorphisms with the risk of SLE while controlling for age and sex as covariates among SLE patients and normal controls
 

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  		Table 2. Frequencies of minor alleles of DNase I polymorphisms and logistic analysis of allelic distributions with the production of three common auto-Abs (anti-Ro, -RNP and -dsDNA Abs) detected among SLE patients controlling for age, disease duration and sex as covariates among SLE patients
 
The higher risk and stronger association of the homozygotes for minor allele (Arg/Arg) of +2373A>G(Gln244Arg) (OR=1.77, P=0.002) than those of heterozygotes (Gln/Arg) (OR=1.21, P=0.54) in reference analyses indicate that it is more likely that this allele has a recessive effect on the production of the anti-RNP Abs. A similar association with anti-dsDNA Ab production was also detected (data not shown), which was a weaker signal than the anti-RNP Ab. The frequency of the homozygous minor allele (Arg/Arg) was much higher in patients who had the anti-RNP Ab (31.3%) than in patients who did not have the anti-RNP Ab (14.4%) (P=0.0006, OR=2.86) (Table 3).


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  		Table 3. Logistic analysis of genotype distributions of DNase I +2373A>G(Gln244Arg) according to the status of anti-RNP Ab, while controlling for age, disease duration and sex as covariates among SLE patients
 
The effects of +2373A>G(Gln244Arg) on the production of both anti-dsDNA Ab and anti-RNP Ab were also analyzed. The allele frequencies among patients carrying both auto-Abs (n=58), only one auto-Ab (n=203) and no auto-Abs (n=64) are shown in Figure 2, which clearly indicates that the allele frequencies increased with susceptibility to auto-Ab production (P=0.00004).



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  		Figure 2. The allele frequencies of +2373A>G(Gln244Arg) among SLE patients bearing both auto-Abs (n=58), only one auto-Ab (n=203) and none (n=64).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
Like other autoimmune diseases, SLE shows a strong genetic predisposition. This disease shows a high concordance in identical twins and occurs with increased frequency among first-degree relatives of patients. An analysis of multiplex families suggested that the genetic component of disease susceptibility involves a set of unlinked genes that operate in concert to induce either SLE or other autoimmune diseases (8).

The present results show that the SNPs in DNase I are not associated with the risk of SLE, but one non-synonymous SNP in exon 8, +2373A>G(Gln244Arg), is significantly associated with an increased production of anti-RNP and anti-dsDNA Abs among SLE patients. In addition, neither SLE patients (n=350) nor controls (n=330) carried any A/T mutation in exon 2 of DNase I, which has been reported in two Japanese SLE patients (3). The absence of this mutation in our Korean population, combined with the results of previous reports (4,5), strongly suggests that the mutation reported previously in Japanese SLE patients is not present in the three major ethnic groups.

A large array of auto-Abs are found in the serum of SLE patients, including Abs to single- and double-stranded DNA, histone, DNA–histone complex, some nuclear RNA proteins (Sm, nRNP) and cytoplasmic antigens (Ro, La). However, the existence of these auto-Abs is not sufficient to evoke an autoimmune disease. Anti-dsDNA Abs are intimately associated with SLE, and their presence has both diagnostic and prognostic significance. Chromatin and nucleosomes have been proposed as the antigens initiating the formation of Abs that are potentially pathogenic to DNA. In addition to this central role of chromatin and nucleosomes, nucleosome-activated T lymphocytes from patients with SLE can help B lymphocytes produce IgG Abs to DNA. The ability to make Abs to chromatin, nucleosomes and DNA may depend in part on genetic susceptibility.

Auto-Abs directed against the snRNP (small nuclear RNP) autoantigens, referred to as RNPs, were originally detected in the sera of SLE patients and are present in about one-third of patients with SLE (9). The snRNPs are a group of nuclear particles comprising several polypeptides associated with a small nuclear RNA molecule. The most abundant snRNPs are involved in pre-mRNA splicing. RNP auto-Abs are able to precipitate one particular type, referred to as U1 snRNA. Anti-RNP Abs react with the U1-snRNP-specific polypeptides.

Many recent studies have implicated an important role for cell-death processes in mediating the bypass of tolerance to autoantigens such as chromatin, nucleosome, DNA and snRNPs, although the underlying mechanisms are poorly understood. A previous study revealed that lymphocytes from SLE patients showed a higher rate of apoptosis compared with lymphocytes from rheumatoid arthritis patients or normal donors (10). It has also been shown that autoantigens targeted in SLE become concentrated in two discrete populations of surface structures on apoptotic cells, namely, apoptotic bodies and apoptotic surface blebs. This increased rate of apoptosis could lead to overloading on the phagocytic system with apoptotic cell material, resulting in an increased amount of intracellular components in the serum of these patients. This intracellular material would be recognized as non-self-antigens by immunocompetent cells, leading to the formation of auto-Abs against intracellular particles. Therefore, several events (e.g., dysregulated apoptosis and phagocytosis) might contribute to the development of SLE and/or production of auto-Abs to intracellular components.

DNase I, which is present in serum, urine and secreta, encodes a nuclease that has the potential to remove DNA and to preferentially attack double-stranded DNA and produces 5' phosphoryl oligonucleotides at sites of high cell turnover. Mice deficient of this enzyme show SLE-like features (11). A hallmark of apoptosis is the cleavage of chromatin by caspase-activated DNase (12). This fragmentation occurs at the internucleosomal level and leads to the formation of DNA ladders classically associated with apoptosis (13). The dysregulation of DNA fragmentation due to defective DNase I might be directly linked to the production of Abs to dsDNA or nucleosomes in concert with increased apoptosis and impaired phagocytosis in patients with SLE.

The present study suggests that the substitution of Gln (an uncharged R group) to Arg (a positively charged R group) in the +2373A>G(Gln244Arg) SNP of DNase I could cause conformational changes in the expressed protein, and subsequently could influence enzyme activity and result in the high production of anti-RNP and anti-dsDNA Abs in the sera of SLE patients.

The correction of P values obtained from multiple tests of SNPs in a single gene (or a single LD block) with related phenotypes would be complicate issue when considering the following factors: (1) generally, most markers in single genes are in strong LDs and are not independent (and not completely dependent either), (2) haplotypes constructed by combinations of SNPs are not independent of SNPs and (3) alternative analyses (e.g., the referent, codominant, dominant and recessive models in the present study) might be performed with closely related phenotypes (auto-Abs in this study). In the case of DNase I, DNase I +2035G>C and +2373A>G(Gln244Arg) for anti-RNP auto-Abs (Table 2) would retain significance after Bonferroni correction, whereas a weak association with anti-dsDNA auto-Abs would disappear. Therefore, further biological and/or functional evidence is needed to confirm the association of DNase I polymorphisms with auto-Abs shown in this study.

In conclusion, (1) 15 SNPs were identified, including three known and four non-synonymous ones, (2) one non-synonymous SNP in exon 8, +2373A>G(Gln244Arg), was significantly associated with an increased risk of the production of anti-RNP and anti-dsDNA Abs among Korean SLE patients and (3) the A/T nonsense mutation in exon 2 of DNase I reported by Yasutomo et al. (3) was not found in either SLE patients or controls in a Korean population.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
Patients
A total of 350 Korean patients who fulfilled the 1997 ACR (American College of Rheumatology) criteria for SLE (14) were consecutively enrolled from the Hospital for Rheumatic Diseases, Hanyang University, Seoul, South Korea. Antinuclear Abs were tested by indirect immunofluorescence using IT-1 cells: anti-dsDNA Abs by Crithidia luciliae assay; and anti-Sm, -SSA (Ro), -SSB (La) and -RNP Abs by double immunodiffusion. As a control group, we included 330 healthy ethnically matched subjects in order to examine the genetic association with susceptibility to SLE and related phenotypes. Written informed consent was obtained from each subject. The clinical parameters are summarized in Table 4.


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  		Table 4. Clinical profiles of the study subjects
 
Sequencing analysis of the human DNase I gene
We have sequenced exons and their boundaries of the DNase I gene, including the promoter region (~1500 bp), to discover genetic variants in 12 SLE patients and 12 healthy subjects using a DNA analyzer (ABI PRISM 3700, Applied Biosystems, Foster City, CA, USA). Information regarding primers is available on our website (http://www.snp-genetics.com/user/news_content.asp?board_idx=175). Sequence variants were verified using chromatograms.

Genotyping with fluorescence polarization detection
For genotyping of six polymorphic sites [–2125A>C, +273C>T, +1649C>G(Pro154Ala), +2035C>G, +2120C>T and +2373A>G(Gln244Arg)], amplifying primers and probes were designed for TaqMan (15). Primer Express (Applied Biosystems) was used to design both the PCR primers and the MGB TaqMan probes. One allelic probe was labeled with the FAM dye and the other with the fluorescent VIC dye. PCRs were run in a TaqMan Universal Master mix without UNG (Applied Biosystems) with PCR primer concentrations of 900 nM and TaqMan MGB-probe concentrations of 200 nM. Reactions were performed in a 384-well format in a total reaction volume of 5 µl using 20 ng of genomic DNA. The plates were then placed in a thermal cycler (PE 9700, Applied Biosystems) and heated at 50°C for 2 min and 95°C for 10 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min, with a final soak at 25°C. The TaqMan assay plates were transferred to a Prism 7900HT instrument (Applied Biosystems) where the fluorescence intensity in each well of the plate was read. Fluorescence data files from each plate were analyzed by automated allele-calling software (SDS 2.1). Information regarding the probes is available on our website (http://www.snp-genetics.com/user/news_content.asp?board_idx=175).

Statistics
We examined Lewontin's D' (|D'|) and the LD coefficient r2 between all pairs of biallelic loci (16,17). Haplotype associations were estimated using Haplo.Score (http://www.biostat.wustl.edu/genetics/geneticssoft/), which imputes score statistics to test associations between haplotypes and a wide variety of traits, including binary, ordinal, quantitative and Poisson (18). This software provides several haplotype-specific tests for association, as well as adjustment for non-genetic covariates and computation of simulation P-values, using the assumption that all subjects are unrelated and that haplotypes are ambiguous owing to unknown linkage phases of the genetic markers. Genotype distributions of DNase I SNPs among SLE patients and normal subjects were analyzed with logistic regression models while controlling for age, sex and disease duration as covariates.


   ACKNOWLEDGEMENT
 
This work was supported in part by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of South Korea (no. 01-PJ3-PG6-01GN11-0002). In addition, we greatly appreciate Mrs Mun-Ja Nam's for personal fund support.


   FOOTNOTES
 
* To whom correspondence should be addressed at: The Hospital for Rheumatic Diseases, Hanyang University Medical Center, 17 Haengdang-Dong, Seongdong-Gu, Seoul 133-792, South Korea. Tel: +82 222909203; Fax: +82 222988231; Email: scbae{at}hanyang.ac.kr


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 

  1. Wakeland, E.K., Liu, K., Graham, R.R. and Behrens, T.W. (2001) Delineating the genetic basis of systemic lupus erythematosus. Immunity, 15, 397–408.[CrossRef][Web of Science][Medline]

  2. Tew, M.B., Johnson, R.W., Reveille, J.D. and Tan, F.K. (2001) A molecular analysis of the low serum deoxyribonuclease activity in lupus patients. Arthritis Rheum., 44, 2446–2447.[Medline]

  3. Yasutomo, K., Horiuchi, T., Kagami, S., Tsukamoto, H., Hashimura, C., Urushihara, M. and Kuroda, Y. (2001) Mutation of DNASE1 in people with systemic lupus erythematosus. Nat. Genet., 28, 313–314.[CrossRef][Web of Science][Medline]

  4. Simmonds, M.J., Heward, J.M., Kelly, M.A., Allahabadia, A., Foxall, H., Gordon, C., Franklyn, J.A. and Gough, S.C. (2002) A nonsense mutation in exon 2 of the DNase I gene is not present in UK subjects with systemic lupus erythematosus and Graves' disease: comment on the article by Rood et al. Arthritis Rheum., 46, 3109–3110.[Medline]

  5. Chakraborty, P., Kacem, H.H., Makni-Karray, K., Jarraya, F., Hachicha, J. and Ayadi, H. (2003) The A/T mutation in exon 2 of the DNase I gene is not present in Tunisian patients with systemic lupus erythematosus or in healthy subjects. Arthritis Rheum., 48, 3297–3298.[Medline]

  6. Normile, D. (1999) Genetic clues revise view of Japanese roots. Science, 283, 1426–1427.[Free Full Text]

  7. Stephens, M., Smith, N.J. and Donnelly, P. (2001) A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet., 68, 978–89.[CrossRef][Web of Science][Medline]

  8. Pisetsky, D.S. (1998) Antibody responses to DNA in normal immunity and aberrant immunity. Clin. Diagn. Lab. Immunol., 5, 1–6.[Medline]

  9. Mattioli, M. and Reichlin, M. (1971) Characterization of a soluble nuclear ribonucleoprotein antigen reactive with SLE sera. J. Immunol., 107, 1281–1290.[Abstract/Free Full Text]

  10. Emlen, W., Niebur, J. and Kadera, R. (1994) Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J. Immunol., 152, 3685–3692.[Abstract]

  11. Napirei, M., Karsunky, H., Zevnik, B., Stephan, H., Mannherz, H.G. and Moroy, T. (2000) Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat. Genet., 25, 177–181.[CrossRef][Web of Science][Medline]

  12. Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A. and Nagata, S. (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature, 391, 43–50.[CrossRef][Medline]

  13. Wyllie, A.H. (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature, 284, 555–556.[CrossRef][Medline]

  14. Hochberg, M.C. (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum., 40, 1725.[Web of Science][Medline]

  15. Livak, K.J. (1999) Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet. Anal., 14, 143–149.[Medline]

  16. Hedrick, P.W. (1987) Gametic disequilibrium measures: proceed with caution. Genetics, 117, 331–341.[Abstract/Free Full Text]

  17. Hedrick, P. and Kumar, S. (2001) Mutation and linkage disequilibrium in human mtDNA. Eur. J. Hum. Genet., 9, 969–972.[CrossRef][Web of Science][Medline]

  18. Schaid, D.J., Rowland, C.M., Tines, D.E., Jacobson, R.M. and Poland, G.A. (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am. J. Hum. Genet., 70, 425–434.[CrossRef][Web of Science][Medline]


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