Skip Navigation


Rheumatology Advance Access originally published online on February 3, 2006
Rheumatology 2006 45(6):711-717; doi:10.1093/rheumatology/kei262
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary data
Right arrow All Versions of this Article:
45/6/711    most recent
kei262v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hur, J.-W.
Right arrow Articles by Bae, S.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hur, J.-W.
Right arrow Articles by Bae, S.-C.
Related Collections
Right arrow Systemic Lupus Erythematosus and Autoimmunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Poly(ADP-ribose) polymerase (PARP) polymorphisms associated with nephritis and arthritis in systemic lupus erythematosus

J.-W. Hur, Y.-K. Sung, H. D. Shin1, B. L. Park1, H. S. Cheong1 and S.-C. Bae

Department of Internal Medicine, Hospital for Rheumatic Diseases, Hanyang University, Seoul 133-792 and 1 Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul 153–803, Republic of Korea.

Correspondence to: S.-C. Bae, Hospital for Rheumatic Diseases, Hanyang University Medical Center, 17 Haengdang-Dong, Seongdong-Gu, Seoul 133-792, Republic of Korea. E-mail: scbae{at}hanyang.ac.kr


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Supplementary data
 References
 
Objective. The objective of this study was to confirm whether polymorphisms of the poly(ADP-ribose) polymerase gene (PARP) are associated with genetic susceptibility to systemic lupus erythematosus (SLE) and to investigate the possible association of nephritis and arthritis in SLE with PARP polymorphisms.

Methods. Using direct DNA sequencing in 24 individuals, we identified 44 sequence variants within exons and their flanking regions, including the 1.5-kb promoter region of PARP. Six common polymorphic sites were selected for larger-scale genotyping (in 350 Korean SLE patients and 330 healthy controls), which identified six common haplotypes.

Results. Although no statistically significant association with the risk of SLE was observed, we found that two single-nucleotide polymorphisms (SNPs –1963A -> G and +28077G -> A) were significantly associated with an increased risk of nephritis, and one non-synonymous variant [+40329T -> C(V762A)] was also significantly associated with an increased risk of arthritis, while the –1963A -> G SNP showed a protective effect on arthritis in Korean SLE patients.

Conclusion. Our results demonstrate that PARP polymorphisms are not associated with SLE susceptibility, but that –1963A -> G, +28077G -> A and +40329T -> C(V762A) are significantly associated with nephritis and arthritis in Korean SLE patients.

KEY WORDS: Poly(ADP-ribose) polymerases, Single-nucleotide polymorphism, Systemic lupus erythematosus


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Supplementary data
 References
 
Systemic lupus erythematosus (SLE) is characterized by the accelerated apoptosis of lymphocytes and a failure in the clearance of apoptotic cells [1]. It has been postulated that several antinuclear antibodies (Abs) are present [2] and that DNA repair is impaired in patients with SLE [3, 4]. It is widely recognized that several genetic factors, including a gene linkage to human chromosome 1q41-42, contribute to SLE susceptibility [5]. The gene for poly(ADP-ribose) polymerase (PARP) is one of the candidate genes located in this region. The human PARP gene is 43 kb long and split into 23 exons [6].

PARP has been demonstrated to be a nuclear enzyme that catalyses the synthesis of poly(ADP-ribose) using NAD+ as a substrate. This process is induced by DNA strand breaks that are generated directly or indirectly by genotoxic agents and enzymatic function, and it plays a pivotal role in DNA repair, proliferation, transcription regulation, apoptosis, genomic stability and malignancy [7, 8]. Several studies have suggested that levels of PARP activity and mRNA are subnormal in lupus patients (and intermediate in unaffected relatives of lupus patients), which consequently decreases poly(ADP-ribose) synthesis [9, 10]. These data implicate PARP in susceptibility to SLE.

It has been suggested that a microsatellite polymorphism—the CA dinucleotide repeat in the promoter region of PARP—affects transcription, because it is located close to the transcription factor Yin Yang 1 [11]. Family-based association studies have revealed that a polymorphic CA dinucleotide repeat in the promoter region of PARP is transmitted to affected offspring. An 85-bp PARP allele was found to be significantly associated with SLE, whereas a 97-bp PARP allele was protective in a multiethnic group comprising Caucasians, Hispanics, Asians and African Americans [5]. However, another study involving a similar cohort produced contradictory results [12], and case–control studies have shown no significant association in French and German Caucasians [13, 14].

Additionally, the human chromosome 1q31-42 region corresponds to the telomeric end of mouse chromosome 1, which is the region involving specific manifestations of murine lupus, including glomerulonephritis and IgG antichromatin Ab [15, 16]. Interestingly, it has been shown that PARP is overactivated in neighbouring cells by the massive synthesis of nitric oxide, which could lead to DNA breaks, and consequently necrosis triggered by depletion of NAD+ cellular stores results in inflammatory injury [17]. Thus, PARP has been suggested to regulate the transcription of genes related to inflammation. The lineage of marker D1S235 to chromosome 1q41-43 has been demonstrated in genome-wide screening in multiplex rheumatoid arthritis families [18]. Furthermore, it was recently reported that one PARP haplotype including the 97-bp CA repeat was associated with rheumatoid arthritis in a Spanish population [19]. However, there is no reported evidence of an association of PARP with nephritis and arthritis in SLE.

In an effort to confirm whether PARP polymorphisms are associated with genetic susceptibility to SLE and investigate the possible association of nephritis and arthritis in SLE with PARP polymorphisms, we explored sequence variations of PARP in a Korean population, examined the genetic associations of single-nucleotide polymorphisms (SNPs) with SLE, and analysed the association of PARP polymorphisms with nephritis and arthritis among SLE patients. The study cohort consisted of 350 patients with SLE and 330 ethnically matched controls. Written informed consent was obtained from each subject. The study was approved by the Institutional Review Board of Hanyang University Medical Center.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Supplementary data
 References
 
Patients and controls
A total of 350 Korean SLE patients who fulfilled the 1997 American College of Rheumatology (ACR) criteria of SLE [20] were consecutively enrolled between September 1998 and February 2002 from the Hospital for Rheumatic Diseases, Hanyang University, Seoul, Republic of Korea. The ethnicity of all patients and controls was Korean, and the following clinical and laboratory data were obtained: sex, age, ages at first symptom onset and clinical diagnosis, ACR diagnosis, and SLICC/ACR (Systemic Lupus International Collaborating Clinics/ACR) damage index [21]. Renal disorder was defined as persistent proteinuria greater than 0.5 g per day or greater than 3+ if quantitation was not performed or cellular casts were present. Arthritis was defined as non-erosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion according to ACR criteria [20]. As a control group, we included 330 healthy ethnically matched subjects in our examination of the genetic association of polymorphisms with susceptibility to SLE and related phenotypes. The mean age of the SLE patients was 35.6 yr (range 10.5–72.7 yr), and they comprised 15 males and 335 females. Antinuclear Abs were detected by indirect immunofluorescence using IT-1 cells and anti-double-stranded DNA (dsDNA) Abs in a Crithidia luciliae assay. Of these patients, 36.2% had renal disorders and 64.1% had non-erosive arthritis during any interval of observation.

PARP sequencing
We used the ABI Prism 3730 DNA analyser (Applied Biosystems, Foster City, CA, USA) to sequence exons and their flanking regions, including the promoter region (1.5 kb) of PARP in order to discover variants in 24 Korean unregulated individual DNA samples. Twenty-eight primer sets for the amplification and sequencing analysis were designed based on GenBank sequences (reference genome sequence for PARP: NT_004559 [GenBank] .12, released in August 2004). The primer sets for amplification are listed in Supplementary Table 1. Sequence variants were verified in chromatograms.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Logistic analysis of PARP polymorphisms with SLE using age and sex as covariates in a Korean population

 
PARP polymorphism genotyping
Genotyping was read blinded to clinical outcomes on the whole process. Polymorphic sites were genotyped using amplifying primers and probes designed for TaqMan [22]. Primer Express (Applied Biosystems) was used to design both the polymerase chain reaction (PCR) primers and the MGB TaqMan probes. One allelic probe was labelled with FAMTM dye and the other with the fluorescent VIC® dye. PCRs were run in the TaqMan Universal Master mix without UNG (Applied Biosystems), with PCR primer at a concentration of 900 nM and TaqMan MGB probe at a concentration 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. The TaqMan assay plates were transferred to a real-time PCR system (Prism 7900HT, Applied Biosystems) that read the fluorescence intensity in each well of the plate. Fluorescence data files from each plate were analysed using automated software (SDS 2.1; Applied Biosystems). The primers sequences are provided in Supplementary Table 2.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Logistic analysis of PARP polymorphisms with nephritis in SLE

 
Statistical analysis
The {chi}2 test was used to quantify the distribution of PARP alleles in SLE patients. We examined the linkage disequilibrium (LD), expressed as Lewontin's D' (|D'|), where D' = D/|Dmax|, and the LD coefficient r2 between all pairs of biallelic loci [23, 24]. The haplotypes of each individual were inferred using the PHASE algorithm developed by Stephens et al. [25], which uses a Bayesian approach incorporating a priori expectations of haplotypic structure based on population genetics and coalescence theory. Genetic effects of inferred haplotypes were analysed in the same way as polymorphisms. The genotype distributions of PARP polymorphisms and haplotypes were compared between the SLE patients and healthy controls with multiple logistic regression models, while controlling for age (continuous variable), sex (male = 0, female = 1), and/or disease duration (continuous variable) as covariates. The common alleles were used as the reference genotype to the heterozygote and homozygote of the minor allele. P values of codominant, dominant and recessive models were also calculated.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Supplementary data
 References
 
Polymorphisms and haplotypes
Direct sequencing identified 44 SNPs: five in the 5' flanking region, six exonic SNPs (including four non-synonymous) and 33 intronic SNPs. Pairwise comparisons between SNPs revealed five sets of absolute LDs (|D'| = 1 and r2 = 1) (Fig. 1A). Several complete LDs (|D'| = 1 and r2 != 1) were also found (Fig. 1B). Six SNPs (–1963A -> G, –759C -> T, +28077G -> A, +39794C -> T, +40329T -> C and +46133C -> T) were selected for larger-scale (n = 680) genotyping based on LDs and frequencies (frequency >0.05). The genotype distributions and frequencies of these six SNPs are listed in Supplementary Table 3. Three variants (+28077G -> A, +39794C -> T and +46133C -> T) were newly identified in this study, and the others (–1963A -> G, –759C -> T and +40329T -> C) have been reported previously [26, 27]. Six haplotypes (ht1 to ht6) inferred using the algorithm developed by Stephens et al. [25] were observed at frequencies higher than 5% (Fig. 1C). Because the three haplotypes ht2, ht5 and ht6 were almost equivalent to +28077G -> A, +39794C -> T and +46133C -> T, respectively, they were excluded from further statistical analyses.


Figure 1
View larger version (20K):
[in this window]
[in a new window]
  		FIG. 1. Gene map and haplotypes of PARP. 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. *indicate polymorphisms genotyped in a larger population (N = 680). The frequencies of polymorphisms not subjected to larger-scale genotyping were based on sequence data (n = 24). (A) Polymorphisms identified in PARP on chromosome 1q41-42 (reference genome sequence: NT_004559.12). (B) Linkage disequilibrium co-efficients (|D'| and r2) among PARP polymorphisms. (C) Haplotypes of PARP. Only those with frequencies of at least 0.05 are shown. Others contain rare haplotypes: ACGCTC, GCGCCC and ATGCCC. Only two individuals (0.03%) showed haplotype probabilities lower than 95% in our study by PHASE.

 

View this table:
[in this window]
[in a new window]
  		TABLE 3. Logistic analysis of PARP polymorphisms with arthritis in SLE

 
PARP polymorphisms and SLE susceptibility
These six SNPs and three haplotypes (ht1, ht3 and ht4) were used in the subsequent association study. A multiple logistic regression analysis controlling for age and sex as covariates revealed that none of the PARP polymorphisms was associated with SLE (Table 1).

PARP polymorphisms and nephritis in SLE
We next tested the effect of PARP polymorphisms on renal manifestations using age, disease duration and sex as covariables in lupus patients. Two SNPs (–1963A -> G and +28077G -> A) were significantly associated with an increased risk of lupus glomerulonephritis among SLE patients (Table 2). The minor allele of –1963A -> G and +28077G -> A showed a strong susceptibility to lupus glomerulonephritis among SLE patients, in that the frequencies of the G-allele-containing genotypes of –1963A -> G and the A allele of +28077G -> A were significantly higher among SLE patients who were positive for renal disorder than among those who were negative [P = 0.03, odds ratio (OR) = 1.76 and P = 0.0008, OR = 2.49, respectively] (Table 2).

PARP polymorphisms and arthritis in SLE
We also investigated the genetic association with arthritis. Two SNPs (–1963A -> G and +40329T -> C[V762A]) and two common haplotypes (ht1 and ht3) were significantly associated with arthritis in SLE patients (Table 3). Variants –1963A -> G and ht4 showed a strong protective effect in a gene-dose-dependent manner on arthritis in SLE patients (P = 0.002–0.03, OR = 0.56–0.31 and P = 0.004–0.01, OR = 0.51–0.22, respectively) (Table 3). On the other hand, +40329T -> C(V762A) and ht1 had opposite effects on arthritis in SLE patients (P = 0.02–0.12, OR = 1.77–1.55 and P = 0.006–0.05, OR = 2.72–1.79, respectively) (Table 3). It was likely that the significant associations of ht1 (ACGCCC) depended on +40329T -> C(V762A), because ht1 was almost tagged (frequency >0.90) by +40329T -> C(V762A), which showed a positive association (Fig. 1B).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Supplementary data
 References
 
Several studies have suggested that interactions of multiple genes and environmental factors result in susceptibility to SLE. Linkage analyses have shown that chromosome 1q41-42, which contains PARP, is one of the loci with a significant linkage to SLE [28, 29]. A case–control study involving Japanese subjects identified five PARP polymorphisms, including a CA-repeat polymorphism [30], and detected complete LD between C1362T and the (CA)11 allele corresponding to the 85-bp allele [26]. Two SNPs identified in our study (–759C -> T and –449G -> A, which was linked with –1963A -> G by absolute LD) correspond to C1362T and G1672A. Even though the –759C -> T SNP is not considered to be linked to the (CA)11 allele by absolute LD, our results show that –759C -> T is not associated with an increased risk of SLE in Koreans and that its allele frequency (21.4%) is low, as in Japanese subjects (19.3–20.4%), compared with Caucasians (54%) [26].

PARP has been demonstrated to be a nuclear protein binding to DNA via two zinc-finger motifs, and to play a key role in DNA repair, which has led to the suggestion that PARP is crucial in the processing of DNA lesions by triggering the base-excision repair pathway; it has also been shown that PARP-deficient mice are hypersensitive to genotoxic agents [31, 32]. Furthermore, the significant delay in cell death in an experimental model with a non-cleavable variant of the enzyme during apoptosis led to the suggestion that loss of PARP function is required for the efficient completion of apoptosis [33]. Thus, it is likely that dysregulation of apoptosis by decreased PARP activity contributes to the development of SLE. However, a recent study implicated translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus in the initiation of apoptosis, and showed that PARP activation is necessary for the translocation of AIF [34]. Therefore, further investigations are needed to clarify the role of PARP during apoptosis in SLE.

Tissue injury results from immune complex deposition, with a high level of autoantibodies directed to nuclear antigens in SLE. In particular, renal disorder with severe proteinuria and renal failure is a major complication of lupus. Although anti-dsDNA Abs have been shown to be strongly associated with renal involvement through deposition of these Abs directly on the glomerular basement membrane [35, 36], lupus glomerulonephritis can occur in the absence of anti-dsDNA Abs and breaking tolerance to nuclear antigens [37, 38]. Recently it was shown that breaking tolerance to dsDNA, nucleosomes and other nuclear antigens was not required for the development of lupus nephritis [39]. An immune response involving both T cells and B cells to kidney antigens is implicated in the pathogenesis of lupus nephritis [39]. On the other hand, increased IgG Abs reacting to PARP were observed in patients with SLE and autoimmune bowel diseases [40, 41]. These autoantibodies prevent caspase-3-mediated PARP cleavage during early apoptosis, which, if not regulated, can lead to prolonged autoimmune stimulation by increasing autoimmune cell survival [42]. These findings support the hypothesis that the PARP –1963A -> G and +28077G -> A SNPs identified in the present study can influence enzyme activity and subsequently result in an increased risk of lupus nephritis. Moreover, the common (frequency 0.313) promoter SNP, –1963A -> G, was analysed for a putative transcription-factor-binding site using TFSEARCH software (Searching Transcription Factor Binding Sites, V1.3; putative score >0.90), which revealed that it is located in the consensus sequence of ADR1 and NIT2 (zinc-finger transcription factor) binding sites. Thus, a nucleotide change from A to G could disrupt the binding site of these transcription factors. The present study also suggests that +40329T -> C(V762A) is consistently associated with an increased risk of arthritis, while the –1963A -> G SNP is associated with protection from arthritis. The location of the associated non-synonymous +40329T -> C(V762A) SNP in exon 17 (frequency = 0.440) in the regulatory domain of PARP suggests its possible involvement in functional differences mediated by alternative amino acids.

Genetic associations with SLE manifestations have been reported, but only the association between polymorphism of low-binding Fc{gamma} receptor genes and lupus nephritis has been replicated [43]. Therefore our results need to be replicated in larger studies because there may be a problem of replication validity in this genetic association study. In addition, future studies should investigate the relationship between amino acid substitutions and the activity of this gene.


   Supplementary data
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary data
References
 
Formula Supplementary data are available at Rheumatology Online.


   Acknowledgments
 
We thank Young-Hi Lee and Eun-Kyoung Ju for data collection and analysis, and Jung-Ah Kim for DNA preparation. This work was partially supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (no. 01-PJ3-PG6-01GN11-0002).

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary data
 References
 

  1. Emlen W, Niebur J, Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol 1994;152:3685–92.[Abstract]
  2. Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol 1989;44:93–151.[Web of Science][Medline]
  3. Golan TD, Foltyn V, Roueff A. Increased susceptibility to in vitro ultraviolet B radiation in fibroblasts and lymphocytes cultured from systemic lupus erythematosus patients. Clin Immunol Immunopathol 1991;58:289–304.[CrossRef][Web of Science][Medline]
  4. Rosenstein BS, Rosenstein RB, Zamansky GB. Repair of DNA damage induced in systemic lupus erythematosus skin fibroblasts by simulated sunlight. J Invest Dermatol 1992;98:469–74.[CrossRef][Web of Science][Medline]
  5. Tsao BP, Cantor RM, Grossman JM et al. PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus. J Clin Invest 1999;103:1135–40.[Web of Science][Medline]
  6. Auer B, Nagl U, Herzog H, Schneider R, Schweiger M. Human nuclear NAD+ ADP-ribosyltransferase (polymerizing): organization of the gene. DNA 1989;8:575–80.[Web of Science][Medline]
  7. Oliver FJ, Menissier-de Murcia J, de Murcia G. Poly(ADP-ribose) polymerase in the cellular response to DNA damage, apoptosis, and disease. Am J Hum Genet 1999;64:1282–8.[CrossRef][Web of Science][Medline]
  8. D’Amours D, Desnoyers S, D'Silva I, Poirier GG. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 1999;342:249–68.[CrossRef][Web of Science][Medline]
  9. Sibley JT, Haug BL, Lee JS. Altered metabolism of poly(ADP-ribose) in the peripheral blood lymphocytes of patients with systemic lupus erythematosus. Arthritis Rheum 1989;32:1045–9.[Web of Science][Medline]
  10. Haug BL, Lee JS, Sibley JT. Altered poly(ADP-ribose) metabolism in family members of patients with systemic lupus erythematosus. J Rheumatol 1994;21:851–6.[Web of Science][Medline]
  11. Oei SL, Shi Y. Transcription factor Yin Yang 1 stimulates poly(ADP-ribosyl)ation and DNA repair. Biochem Biophys Res Commun 2001;284:450–4.[CrossRef][Web of Science][Medline]
  12. Criswell LA, Moser KL, Gaffney PM et al. PARP alleles and SLE: failure to confirm association with disease susceptibility. J Clin Invest 2000;105:1501–2.[Web of Science][Medline]
  13. Delrieu O, Michel M, Frances C et al. Poly(ADP-ribose) polymerase alleles in French Caucasians are associated neither with lupus nor with primary antiphospholipid syndrome. GRAID Research Group. Group for Research on Auto-Immune Disorders. Arthritis Rheum 1999;42:2194–7.[CrossRef][Web of Science][Medline]
  14. Boorboor P, Drescher BE, Hartung K et al. Poly(ADP-ribose) polymerase polymorphisms are not a genetic risk factor for systemic lupus erythematosus in German Caucasians. J Rheumatol 2000;27: 2061.[Web of Science][Medline]
  15. Kono DH, Burlingame RW, Owens DG et al. Lupus susceptibility loci in New Zealand mice. Proc Natl Acad Sci USA 1994;91:10168–72.[Abstract/Free Full Text]
  16. Drake CG, Rozzo SJ, Hirschfeld HF, Smarnworawong NP, Palmer E, Kotzin BL. Analysis of the New Zealand Black contribution to lupus-like renal disease. Multiple genes that operate in a threshold manner. J Immunol 1995;154:2441–7.[Abstract]
  17. Szabo C, Dawson VL. Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 1998;19:287–98.[CrossRef][Medline]
  18. Jawaheer D, Seldin MF, Amos CI et al. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am J Hum Genet 2001;68:927–36.[CrossRef][Web of Science][Medline]
  19. Pascual M, Lopez-Nevot MA, Caliz R et al. A poly(ADP-ribose) polymerase haplotype spanning the promoter region confers susceptibility to rheumatoid arthritis. Arthritis Rheum 2003;48:638–41.[CrossRef][Web of Science][Medline]
  20. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.[Web of Science][Medline]
  21. Gladman D, Ginzler E, Goldsmith C et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 1996;39:363–9.[Web of Science][Medline]
  22. Livak KJ. Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet Anal 1999;14:143–9.[Medline]
  23. Hedrick PW. Gametic disequilibrium measures: proceed with caution. Genetics 1987;117:331–41.[Abstract/Free Full Text]
  24. Hedrick P, Kumar S. Mutation and linkage disequilibrium in human mtDNA. Eur J Hum Genet 2001;9:969–72.[CrossRef][Web of Science][Medline]
  25. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001;68:978–89.[CrossRef][Web of Science][Medline]
  26. Kato N, Morita H, Sugiyama T et al. Evaluation of the poly(ADP-ribose) polymerase gene in human stroke. Atherosclerosis 2000;148:345–52.[CrossRef][Web of Science][Medline]
  27. Cottet F, Blanche H, Verasdonck P et al. New polymorphisms in the human poly(ADP-ribose) polymerase-1 coding sequence: lack of association with longevity or with increased cellular poly(ADP-ribosyl)ation capacity. J Mol Med 2000;78:431–40.[CrossRef][Web of Science][Medline]
  28. Gaffney PM, Kearns GM, Shark KB et al. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci USA 1998;95:14875–9.[Abstract/Free Full Text]
  29. Moser KL, Neas BR, Salmon JE et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci USA 1998;95:14869–74.[Abstract/Free Full Text]
  30. Fougerousse F, Meloni R, Roudaut C, Beckmann JS. Dinucleotide repeat polymorphism at the human poly (ADP-ribose) polymerase gene (PPOL). Nucleic Acids Res 1992;20:1166.[Free Full Text]
  31. Wang ZQ, Stingl L, Morrison C et al. PARP is important for genomic stability but dispensable in apoptosis. Genes Dev 1997;11:2347–58.[Abstract/Free Full Text]
  32. Masutani M, Suzuki H, Kamada N et al. Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes. Proc Natl Acad Sci USA 1999;96:2301–4.[Abstract/Free Full Text]
  33. Oliver FJ, de la Rubia G, Rolli V, Ruiz-Ruiz MC, de Murcia G, Murcia JM. Importance of poly(ADP-ribose) polymerase and its cleavage in apoptosis. Lesson from an uncleavable mutant. J Biol Chem 1998;273:33533–9.[Abstract/Free Full Text]
  34. Yu SW, Wang H, Poitras MF et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 2002;297:259–63.[Abstract/Free Full Text]
  35. Suzuki N, Mihara S, Sakane T. Development of pathogenic anti-DNA antibodies in patients with systemic lupus erythematosus. Faseb J 1997;11:1033–8.[Abstract]
  36. Ravirajan CT, Rahman MA, Papadaki L et al. Genetic, structural and functional properties of an IgG DNA-binding monoclonal antibody from a lupus patient with nephritis. Eur J Immunol 1998;28:339–50.[CrossRef][Web of Science][Medline]
  37. Morel L, Rudofsky UH, Longmate JA, Schiffenbauer J, Wakeland EK. Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1994;1:219–29.[CrossRef][Web of Science][Medline]
  38. Mohan C, Alas E, Morel L, Yang P, Wakeland EK. Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes. J Clin Invest 1998;101:1362–72.[Web of Science][Medline]
  39. Waters ST, McDuffie M, Bagavant H et al. Breaking tolerance to double stranded DNA, nucleosome, and other nuclear antigens is not required for the pathogenesis of lupus glomerulonephritis. J Exp Med 2004;199:255–64.[Abstract/Free Full Text]
  40. Decker P, Briand JP, de Murcia G, Pero RW, Isenberg DA, Muller S. Zinc is an essential cofactor for recognition of the DNA binding domain of poly(ADP-ribose) polymerase by antibodies in autoimmune rheumatic and bowel diseases. Arthritis Rheum 1998;41:918–26.[CrossRef][Web of Science][Medline]
  41. Reumaux D, Meziere C, Colombel JF, Duthilleul P, Mueller S. Distinct production of autoantibodies to nuclear components in ulcerative colitis and in Crohn's disease. Clin Immunol Immunopathol 1995;77:349–57.[CrossRef][Web of Science][Medline]
  42. Decker P, Isenberg D, Muller S. Inhibition of caspase-3-mediated poly(ADP-ribose) polymerase (PARP) apoptotic cleavage by human PARP autoantibodies and effect on cells undergoing apoptosis. J Biol Chem 2000;275:9043–6.[Abstract/Free Full Text]
  43. Karassa FB, Trikalinos TA, Ioannidis JP. The Fc gamma RIIIA-F158 allele is a risk factor for the development of lupus nephritis: a meta-analysis. Kidney Int 2003;63:1475–82.[CrossRef][Web of Science][Medline]
Submitted 5 July 2005; revised version accepted 18 November 2005.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary data
Right arrow All Versions of this Article:
45/6/711    most recent
kei262v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hur, J.-W.
Right arrow Articles by Bae, S.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hur, J.-W.
Right arrow Articles by Bae, S.-C.
Related Collections
Right arrow Systemic Lupus Erythematosus and Autoimmunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?