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Rheumatology 2001; 40: 393-400
© 2001 British Society for Rheumatology

Interleukin-6 promoter polymorphism (-174 G/C) in Caucasian German patients with systemic lupus erythematosus

H. Schotte, B. Schlüter1, S. Rust1,2, G. Assmann1,2, W. Domschke and M. Gaubitz

Medizinische Klinik und Poliklinik B,
1 Institut für Klinische Chemie und Laboratoriumsmedizin and
2 Institut für Arterioskleroseforschung, Westfälische Wilhelms-Universität, Münster, Germany


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. A biallelic polymorphism (-174 G/C) within the interleukin-6 (IL-6) promoter reportedly has functional importance through the modulation of IL-6 expression in vitro and in vivo.

Methods. We performed a population-based case–control study to analyse the association of the -174 G/C polymorphism with disease susceptibility and clinical manifestations in 211 German patients with systemic lupus erythematosus (SLE).

Results. There were no significant differences in allelic and genotypic frequencies between patients and healthy controls. Comparing patients with various disease manifestations, we found an association of the -174 G allele with discoid skin lesions (Pc=0.034) and anti-histone antibodies (Pc=0.009).

Conclusions. The IL-6 promoter polymorphism -174 G/C does not contribute significantly to disease susceptibility, but predisposes to distinct clinical and immunological features. A genetically determined high IL-6 response may have a pathogenic role under these conditions.

KEY WORDS: Anti-histone antibodies, Case–control studies, Cytokines, Discoid skin lesions, Disease susceptibility, Genetics, Caucasian German patients, Interleukin-6, Systemic lupus erythematosus, Promoter polymorphism.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by polyclonal B-cell activation, elevated production of pathogenic autoantibodies, impaired immune complex clearance and inflammatory responses in multiple organs [1–4]. Although the initiating immunological event in SLE remains unknown, it has been shown that an imbalance between depressed TH1 cell cytokines, which promote cell-mediated immunity, and enhanced TH2 cell cytokines, which support humoral immunity, plays a crucial role in the pathophysiological cascade. There is accumulating evidence from experimental and clinical studies to suggest that IL-6 is a central cytokine in this context.

Interleukin-6 (IL-6) is a B-cell differentiation factor that induces the final maturation of IL-4-preactivated B cells into immunoglobulin (Ig)-secreting plasma cells. In vitro, the production of IgG by peripheral blood mononuclear cells (PBMC) from SLE patients can be increased by exogenous IL-6 [5, 6]. Anti-IL-6 antibodies and anti-IL-6 receptor antibodies inhibit the production of Ig by normal and SLE B cells [7, 8]. In vivo, spontaneous and drug-induced animal models of SLE show an association of elevated serum levels of IL-6 with B-cell hyperactivity, polyclonal IgG secretion, production of autoantibodies, and glomerulonephritis [9–13]. In some animal models, inhibition of IL-6 reverses disease symptoms [14, 15]. In SLE patients, high serum levels of IL-6 correlate with disease activity, especially when patients suffer from serositis, but not with polyclonal IgG production, anti-double-stranded (ds) DNA antibodies and parameters of the acute-phase response [5, 16–22]. Increased immunohistochemical staining for IL-6 is detected in biopsies from affected skin or kidneys [23, 24]. In addition, significant amounts of IL-6 are found in the urine of patients with lupus nephritis [21, 25] and in the cerebrospinal fluid of SLE patients with active central nervous system involvement [26–28].

The increased levels of IL-6 in SLE patients may derive from constitutively increased cellular production. Indeed, other than in normal PBMC, IL-6 messenger RNA (mRNA) and protein are detected in freshly isolated SLE PBMC [5, 29]. In addition, PBMC from SLE patients produce significantly more IL-6 upon in vitro stimulation than PBMC from normal controls [8, 30–32]. This raises the question of the regulation of IL-6 expression in SLE patients. It has been shown that production of IL-6 is under genetic control. Analysis of a XbaI restriction fragment length polymorphism (RFLP) in the 3' flanking region of the IL-6 gene revealed an allelic imbalance between SLE patients and unrelated controls. In one family studied, SLE-associated XbaI restriction alleles were associated with higher than normal levels of constitutive IL-6 mRNA [33]. Recently, a G/C polymorphism at position -174 of the IL-6 promoter in the 5' flanking region has been demonstrated [34]. In a luciferase reporter vector assay, a -174 G construct showed significantly higher expression than the corresponding -174 C construct. In addition, the G allele was associated with higher levels of plasma IL-6 in healthy adults.

In view of these findings, we hypothesized that the IL-6 promoter polymorphism -174 G/C may constitute a genetic susceptibility factor for SLE and/or its manifestations. To test this hypothesis, we performed a population-based association study in German patients with SLE.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
SLE patients and healthy controls
The study protocol was approved by the local independent ethics committee. Blood samples were collected from Caucasian German SLE patients from the out-patient clinic for rheumatology at the Department of Medicine B, Münster, Germany. The patients satisfied at least four of the 1982 revised American College of Rheumatology (ACR) criteria for SLE [35]. The patients' medical histories were reviewed from the onset of disease until admission to the study. Clinical features of the disease, as defined by the ACR criteria, were recorded in standardized questionnaires. Where there were renal biopsies, World Health Organization (WHO) criteria were used to classify the histopathological findings. Central nervous system (CNS) disease included the following manifestations: aseptic meningitis, cerebrovascular disease, demyelinating syndrome, myelopathy, seizure disorders, cognitive dysfunction, psychosis and mood disorders [36]. To investigate autoantibody status, antinuclear antibodies were demonstrated by indirect immunofluorescence on HEp 2 cells [37]. Anti-dsDNA antibodies were assessed by radioimmunoassay (Biermann, Bad Nauheim, Germany). Other antibodies were tested by enzyme-linked immunoassay (ELIAS, Freiburg, Germany). Anti-histone and ß2-glycoprotein-1 antibody testing was restricted to sera from patients admitted in 1999 when these tests became available in the study centre.

As healthy controls, volunteers from the regional German population presenting for routine medical check-up were enrolled into the study unless excluded because of significant cardiovascular, pulmonary, metabolic, rheumatic and renal disease. The control population consisted of unrelated individuals matched for ethnicity, age and sex.

IL-6 -174 G/C genotyping
DNA was extracted from blood anticoagulated with EDTA (ethylene diamine tetraacetic acid) according to standard protocols [38]. Genotyping of the IL-6 promoter polymorphism -174 G/C was performed with the mutagenically separated polymerase chain reaction (MS-PCR), which was developed by one of the authors (SR) [39]. Briefly, allele-specific primer sets of different lengths (IL-6 G, 5'-GCACTTTTCCCCCTAGTTGTGTCTTACG-3'; IL-6 C, 5'-ATGACGACCTAAGCTTTACTTTTCCCCCTAGTTGTGTCTTGAC-3'), together with a non-specific complementary strand primer (IL-6 GSP: 5'-ATAAATCTTTGTTGGAGGGTGAGG-3'), were used in a single-tube reaction assay. At least one PCR product was found in a single reaction, thus avoiding false-negative results. Additional base substitutions at different mutagenic positions were introduced into the allele-specific primers (Fig. 1Go), as described elsewhere [39]. This allowed clear separation between the two alleles during the subsequent amplification steps by the reduction of cross-reactions. The specificity of MS-PCR for the different genotypes was confirmed by direct sequencing of genomic DNA (data not shown).



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  		FIG. 1. Primers used in MS-PCR for the detection of the IL-6 promoter polymorphism -174 G/C in the 5' flanking region of the gene. Primers and their relative positions along the sequence axis (horizontal double line) are drawn to scale. Allelic and mutagenic positions are indicated by open and filled triangles respectively. For primer sequences, see text.

 
Amplification was performed on a Perkin-Elmer thermocycler in a 20-µl reaction mixture containing 1 µl of genomic DNA solution, GeneAmp PCR Gold buffer (15 mM Tris–HCl, pH 8.05, 50 mM KCl; PE Applied Biosystems, Weiterstadt, Germany), 1 mM MgCl2, 50 µM each of dGTP, dATP, dTTP and dCTP (Pharmacia, Erlangen, Germany), 0.6 U AmpliTaq Gold polymerase (PE Applied Biosystems, Weiterstadt, Germany), and primers in the following concentrations: 0.075 µM IL-6 G; 0.4 µM IL-6 C; 0.2 µM IL-6 complementary strand primer. The cycling conditions were as follows: hot start at 95°C for 10 min; 40 cycles of 94°C for 30 s, 61°C for 45 s, 72°C for 45 s; final extension at 72°C for 7 min. Aliquots (8 µl) of the PCR products were separated by size on 4% agarose gels. After staining of the gels with ethidium bromide, PCR products were visualized under ultraviolet light. PCR products that were 121 base pairs (bp) (G allele) and 136 bp (C allele) in length could be distinguished readily. A Polaroid photograph of a representative agarose gel is shown in Fig. 2Go.



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  		FIG. 2. Representative agarose gel showing alleles of the IL-6 promoter polymorphism -174 G/C. The C allele gave rise to a 136-bp PCR product and the G allele to a 121-bp PCR product. Genotype assignments: homozygous -174 GG, lanes 3–5, 8, 11; heterozygous -174 G/C, lanes 10, 12, 15, 18, 21, 22; homozygous -174 CC, lanes 6, 7, 9, 13, 14, 16, 17, 19, 20, 23. Lane 1 is a DNA length marker; lane 2 is the negative PCR control.

 

Statistical analysis
Genotype and allele frequencies in SLE patients and healthy controls were compared by 3x2 or 2x2 {chi}2 analysis, respectively. A P value of <0.05 was taken as significant. The same tests were also adopted for the study of the association of the various genotypes and alleles with clinical manifestations and autoantibodies in SLE patients. As multiple comparisons between feature-positive and feature-negative patients were performed, corrected P values (Pc) were calculated by multiplying the P value of an individual test by the number of features tested. The risk of clinical manifestations due to the presence of an individual allele was calculated as the odds ratio (OR), and is given with the 95% confidence interval (CI). The Kruskal–Wallis test for independent samples was used to compare non-parametric data. All statistical calculations were performed with a personal computer using SPSS software (version 9.0.1 for Windows 95/NT).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
IL-6 promoter polymorphism -174 G/C in SLE patients and controls
Between 1997 and 1999, 211 SLE patients (191 female, 20 male) and 158 sex-matched healthy German controls (142 female, 16 male) entered the study. Mean age at onset of SLE (30.4±13.2 yr) and mean age of the control group (33.1±9.2 yr) were similar. At study entry, the mean duration of SLE was 11.5±7.0 yr. The genotype distribution and the G allele frequencies for the IL-6 promoter polymorphism -174 G/C in German SLE patients, in German controls and in a population of 383 healthy Caucasians from the UK [described in Reference 34] are shown in Table 1Go. No significant differences could be demonstrated by the {chi}2 test between the SLE patients, the German controls and the healthy UK Caucasians. The OR for the -174 G allele in the SLE patients compared with the German controls was 1.26 (95% CI 0.94–1.69).


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  		TABLE 1. IL-6 promoter polymorphism -174 G/C: genotype distribution and allele frequencies in German SLE patients, German controls and healthy UK Caucasians

 

IL-6 promoter polymorphism -174 G/C and clinical manifestations of SLE
The genotype distribution and G allele frequencies of the IL-6 promoter polymorphism -174 G/C in SLE patients with different clinical manifestations and autoantibody profiles are shown in Table 2Go. Patients with different genotypes had a similar sex distribution, age at disease onset and duration of disease, as shown by the Kruskal–Wallis test. Using the {chi}2 test, significant differences in genotype distribution could be demonstrated for patients with anti-histone antibodies compared with the respective antibody-negative patients. Significant associations of the G allele were shown with discoid skin lesions (OR 3.11, 95% CI 1.46–6.63; Pc=0.034) and with anti-histone antibodies (OR 3.20, 95% CI 1.71–6.00; Pc=0.0085). In a small subgroup of patients without joint involvement (6.6% of the total patient population) we found an increased frequency of the G allele (OR 0.30, 95% CI 0.11–0.80; P=0.011). However, this difference did not reach the significance level after correction for multiple comparisons (Pc=0.187). No other significant differences in genotype distribution and allele frequencies were found. Odds ratios for the G allele in the subsets of patients with different clinical disease manifestations and autoantibodies are shown in Fig. 3Go.


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  		TABLE 2. Association of clinical features and autoantibody profiles in SLE patients with IL-6 -174 G/C genotypes and G allele frequencies

 


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  		FIG. 3. OR and 95% CI for the G-allele of the IL-6 promoter polymorphism -174 G/C in SLE patients with different clinical manifestations and autoantibodies. Significant ORs were seen for discoid skin lesions, joint involvement, and anti-histone antibodies (95% CI!=1). ANA, antinuclear antibodies.

 

IL-6 promoter polymorphism -174 G/C and renal disease
Sixty-four of our SLE patients had renal disease as defined by the ACR criteria. Table 3Go shows the relationship between the IL-6 genotypes and the histological WHO classes of lupus nephritis in 26 patients who had undergone a renal biopsy. Interestingly, none of the patients with diffuse proliferative nephritis (class IV), which has the worst prognostic outcome, revealed -174 CC homozygosity. However, due to the small number of biopsies performed we were unable to demonstrate significant differences in the distribution of genotype or allele frequencies between patients with class IV nephritis and those without (class II, III or V). The OR for the G allele in patients with class IV nephritis was 2.68 (95% CI 0.73–9.92).


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  		TABLE 3. Genotype distribution of the IL-6 promoter polymorphism -174 G/C and allele frequencies in SLE patients with and without diffuse proliferative nephritis (WHO class IV)

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Recent immunogenetic studies demonstrated that polymorphisms at several loci, including the major histocompatibility complex, complement proteins, immunoglobulin receptors, cytokines and other as yet unmapped genes, are associated with SLE, implying that the gene products of these loci are involved in the pathogenesis of SLE [40]. In addition, clinical and experimental data suggest the IL-6 locus to be a further candidate gene for SLE. Thus, IL-6 has been shown to promote many immunopathological features typical of SLE, such as polyclonal B-cell hyperactivity and the production of autoantibodies. Moreover, IL-6 can be detected in compartments involved in active disease. One recent study demonstrated a functionally relevant biallelic polymorphism within the human IL-6 promoter region (-174 G/C). We performed our case–control study in German SLE patients, hypothesizing that this genetic polymorphism may contribute to the susceptibility to SLE or its diverse clinical and immunological manifestations.

The German SLE patient population under study can be regarded as a representative one as far as the diversity of clinical manifestations and autoantibody profiles is concerned [35]. The genotypic and allelic frequencies of the IL-6 promoter polymorphism were similar in healthy UK Caucasians [34], which were genotyped by RFLP analysis, and in our German controls. In addition, genotyping results obtained by MS-PCR were completely confirmed by direct sequencing of genomic DNA in selected cases. Thus, our allele-specific recently established PCR method is a reliable method for genotyping the IL-6 promoter polymorphism -174 G/C. The polymorphism has been shown to influence IL-6 transcription and circulating IL-6 levels, at least in healthy persons. However, in our study we did not measure systemic IL-6 concentrations because we felt that it was difficult to correlate the IL-6 level at any single time point to the patients' IL-6 genotypes because of the long duration of disease (in most cases) and multiple interfering factors, such as the natural course of the disease and therapeutic interventions.

The genotypic and allelic frequencies of the IL-6 promoter polymorphism were not significantly different between German SLE patients and healthy controls. This means that either this polymorphism plays no role in disease susceptibility, as suggested by recent data on Caucasian American SLE patients [41], or that SLE patients display heterogeneity of their genetic background that masks its effect. The role of the promoter polymorphism may be evident only in certain extended IL-6 haplotypes comprising the AT-rich minisatellite in the 3'-flanking region [41], or when it is examined in the context of interaction with other polymorphic genes [42]. There are some hints that overexpression of IL-6 in SLE may be due, at least in part, to the kinetics and availability of regulatory cytokines [43].

Although IL-6 has been found in cerebrospinal fluid of SLE patients with active CNS disease and in kidney biopsies and urine samples of patients with lupus nephritis, we did not find an association of the IL-6 promoter polymorphism -174 G/C with neuropsychiatric lupus, with lupus nephritis or its severity. This may have been due to other, more potent genetic regulatory elements or the non-specific production of IL-6 under inflammatory conditions. Furthermore, modulation of IL-6 production by other endogenous or exogenous factors, such as hormones, other cytokines and immunomodulating therapy, may be even more important. Although our data do not support the significance of IL-6 in the pathophysiology of neuropsychiatric lupus or lupus nephritis, they do not rule it out.

We found a significant association of the IL-6 high-responder allele -174 G with discoid skin lesions but not with other forms of dermatitis. In a previous study, however, the increased immunohistochemical staining for IL-6 in lesional skin of SLE patients was not restricted to discoid lesions [23]. This may have been due to the small number of skin biopsies examined in the study or to cofactors that influence the development of dermatitis, such as proinflammatory cytokines. Nevertheless, our finding supports the notion of IL-6 as a contributing pathogenic factor in the development of discoid skin lesions.

Interestingly, our study revealed an increased frequency of the IL-6 high-responder allele -174 G in SLE patients without joint involvement. However, this finding was not significant after correction for multiple testing, and thus needs to be confirmed in further studies including even larger numbers of patients. At first sight, it seems difficult to account for the fact that a genetically determined high level of expression of IL-6, which is generally considered to be a proinflammatory cytokine, should protect from arthritis. However, IL-6 has been shown to have potent anti-inflammatory properties by inhibiting the production of tumour necrosis factor {alpha} (TNF-{alpha}) and IL-1 as well as by stimulating synthesis of the TNF soluble receptor type I and the IL-1 receptor antagonist [44–47]. Indeed, local production of TNF-{alpha} within the synovial compartment is a well-documented central process in the development of arthritis, especially in the pathophysiology of rheumatoid arthritis [48]. Thus, the lack of inhibition by IL-6 may promote the inflammatory process within the synovium.

We found a highly significant association of the IL-6 high-responder allele -174 G with the presence of anti-histone antibodies. Apart from SLE, these antibodies can be found in patients with drug-induced lupus and are associated with elevated IL-6 levels [49, 50]. In vitro data suggest that increased cellular secretion of IL-6 contributes to the development of drug-induced lupus [51]. The -174 G allele of the IL-6 promoter may be a predisposing factor in this clinical setting; further trials are needed to test this possibility.

A typical feature of SLE is the production of antibodies directed against dsDNA. Earlier clinical studies revealed that, except in animal models, IL-6 levels in SLE patients are not related to the production of anti-dsDNA and polyclonal IgG. These findings are consistent with our results showing a lack of association of the promoter polymorphism with the presence of anti-dsDNA antibodies.

In summary, our data demonstrate that the IL-6 promoter polymorphism -174 G/C does not contribute significantly to susceptibility to SLE, but predisposes to discoid skin lesions and the production of anti-histone antibodies. The increased prevalence of the high-response allele, -174 G, suggests that a genetically determined high IL-6 response may have a pathogenic role under these conditions. After we had completed our study, Terry et al. [52] demonstrated that additional variations in the IL-6 promoter region together with the -174 G/C polymorphism define different haplotypes that show different levels of expression in reporter gene assays. Analysis of these haplotypes may even strengthen our results and may clarify the significance of the weaker associations described in our paper.


   Acknowledgments
 
We thank Dr H. Schulte of the Institut für Arterioskleroseforschung, Münster, for expert statistical analysis of our data. The work reported in this paper has received no financial support or other benefits from commercial sources.


   Notes
 
Correspondence to: H. Schotte, Department of Medicine B, University of Münster, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany Back


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 4 February 2000; revised version accepted 25 October 2000.
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