Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus

Abstract

Several lines of evidence suggest interleukin-10 gene (IL-10) is a candidate gene in susceptibility to systemic lupus erythematosus (SLE). We investigated the association of IL-10 promoter single-nucleotide polymorphisms (SNPs) (−3575T/A, −2849G/A, −2763C/A, −1082A/G, −819T/C and −592A/C) and microsatellites (IL10.R, IL10.G) with SLE in 554 Hong Kong Chinese patients and 708 ethnically matched controls. Six haplotypes (hts) were identified from the SNPs. The genotype distribution of the ht1 (T-C-A-T-A), which is associated with low IL-10 production, was different in patients and controls (P=0.009). The homozygous genotype of non-ht1 was significantly increased in patients (P=0.009, odds ratio (OR)=1.80, 95% CI: 1.15–2.82). The frequency of IL10.G4 of IL10.G was also significantly increased in patients (P=0.017, OR=2.53, 95% CI: 1.18–5.40). We found that the homozygous non-ht1 combined with short allele (CA repeat number 21) of IL10.G has a dose-dependent effect on SLE susceptibility: non-ht1/non-ht1 with homozygous short allele showed a higher OR (OR=4.11, 95% CI: 1.27–13.2, P=0.018) of association with SLE than the genotype of non-ht1/non-ht1 with heterozygous short/long allele (OR=2.98, 95% CI: 1.26–7.07, P=0.013) and homozygous long allele (OR=1.05, 95% CI: 0.62–1.78, P=0.848). The frequency of non-ht1 was significantly increased in patients with serositis (P<0.0001, OR=2.42, 95% CI: 1.55–3.80). In conclusion, the high expression promoter genotype is associated with SLE in Chinese.

Introduction

Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease characterized by the dysregulation of T and B cells that leads to hyperactivity of B cells and production of autoantibodies.1 Development of SLE involves both environmental and genetic factors. The heritability of SLE is supported by increase in concordance rate in identical twins,2 frequency of SLE in first-degree relatives3 and risk of SLE in siblings of SLE patients.4

Disease development is the result from the accumulation of a series of events that involve the interaction between environmental and genetic factors.5, 6 A number of susceptibility genes, such as HLA, mannose-binding lectin gene, C4A, FcγR, tumor necrosis factor alpha gene (TNF-α) and programmed cell death 1 gene (PDCD1), have been reported to be associated with SLE among various populations.7, 8, 9, 10, 11, 12, 13, 14 In addition, total genome scan has been used in the mapping of chromosomal regions linked with SLE satisfying Lander and Kruglyak's criteria.15, 16, 17, 18, 19, 20, 21, 22

Several lines of evidence indicate that interleukin-10 gene (IL-10) is a strong candidate gene in SLE susceptibility. First, it maps in 1q31–32, which is a susceptibility region for SLE (LOD=3.79).21 It is also homologous to a murine SLE susceptibility region.23 Second, IL-10 is known to be an important immunoregulatory cytokine. It inhibits T cells by suppressing the expression of Th1 cytokines from Th1 cells.24, 25 It also inhibits macrophages by downregulating major histocompatibility complex class II and B7 expression.26 Besides its inhibitory actions, it enhances B-cell survival, proliferation, differentiation and autoantibodies production,27 so IL-10 may be a causal factor for the hyperactivity of B cells in SLE. Third, high IL-10 production has been observed in B cells and macrophages from SLE patients in vitro,28 and elevated serum IL-10 levels were observed in SLE patients and have been shown to be associated with disease activity.29, 30 Fourth, IL-10 plays an important role in murine lupus models. Ishida et al31 reported that continuous administration of anti-IL-10 antibodies in New Zealand black/white (NZB/W) F1 mice, which is a murine lupus model, delayed the onset of autoimmunity and improved the survival rate from 10 to 80%. All these informations suggest that an elevated IL-10 level may play a role in SLE pathogenesis by causing the hyperactivity of B cells and the autoantibody production.

IL-10 production is under strong genetic influence.32 Six single-nucleotide polymorphisms (SNPs) were reported in IL-10 promoter that have a potential association with IL-10 production.33, 34, 35, 36 They are located at positions −3575 (T/A), −2849 (G/A), −2763 (C/A), −1082 (A/G), −819 (T/C) and −592 (A/C) from the transcription start site. The −3575 SNP lies within a putative Pit-1-binding site and −2763 SNP lies within putative lymphocyte-specific factor- and myeloid zinc-finger-binding sites.36 SNP at position −1082 is lying within a putative ETS-like transcription factor-binding site.37 For −592, it is lying at a region exerting negative regulatory function37 and −819 may affect an estrogen receptor element.38 Several studies showed that −1082, −819 and −592 combined to form three haplotypes (hts): G-C-C, A-C-C and A-T-A that linked with different IL-10 expression levels.33, 39, 40 Gibson et al36 reported that the haplotype of −3575T and −2763C is associated with high IL-10 expression levels in African-American. Two microsatellites, IL10.R and IL10.G, have also been found at position −4.0 and −1.1 kb of IL-10 promoter region, which could alter IL-10 expression level, respectively.41, 42, 43

We hypothesized that IL-10 promoter haplotypes may predispose to the disease development and different clinical features of SLE through their effect on IL-10 expression level. In this study, we aimed to seek for the association of these six SNPs (−3575, −2849, −2763, −1082, −819 and −592) and the two microsatellites, IL10.R and IL10.G, at IL-10 promoter region with SLE in Hong Kong Chinese. We found that the homozygous genotype of high IL-10 production haplotypes was significantly increased in SLE patients.

Results

Gene frequencies of IL-10 promoter polymorphisms

The genotypes of the six SNPs were determined by TaqMan and restriction enzyme fragment length polymorphism (RFLP) in Hong Kong Chinese SLE patients and controls with corresponding primers and probes (Table 1). SNP −2849 G/A was found to be nonpolymorphic in 120 healthy controls, that is, only allele G was identified. Out of 73 patients, 72 were homozygous G carriers and only one heterozygous was found. Thus, this SNP was not included in our analysis due to its low frequency. The genotype frequencies of the other five SNPs were shown in Table 2. The genotype distributions were consistent with the existence of Hardy–Weinberg equilibrium. The allele frequencies of the SNPs were not statistically different in the patients and controls, after adjusting with age as a covariable by logistic regression. The genotype frequencies of −592 SNP were found to have different distribution in patients and controls (P=0.009; 3 × 2 χ2 analysis) (Table 2). The homozygous of −592C was significantly increased from 0.066 in the controls to 0.116 in the patients (P=0.009, odds ratio (OR)=1.80, 95% CI: 1.15–2.82) (Table 2).

Table 1 Primers and probes that were used in genotyping of IL-10 promoter polymorphisms
Table 2 SNP genotype frequencies of IL-10 promotera

Frequencies of IL-10 promoter haplotype

Linkage disequilibrium (LD) analysis was preformed and the results were shown in Table 3. Haplotypes were identified by nonambiguous phasing and directing counting due to the absolute linkage between −592 and −892 (ie absolute value of Lewontin's D prime, D=1, r2=1)33, 44 and complete linkage among SNPs (D=1, r2≠1) (Table 3) and their frequencies were also shown in Table 4. These six haplotypes were identical with those predicted from E–M algorithm (SAS/Genetics, SAS Institute Inc., NC, USA)45 with similar frequencies (Table 4). The haplotype frequencies have no difference between SLE patients and controls (P=0.79)

Table 3 Analysis of LD among SNPsa
Table 4 Haplotype frequencies of IL-10 promotera

Frequencies of microsatellite IL10.R. and IL10.G

For IL10.R, only IL10R.2 was found in 60 patients and 144 controls. Therefore, this microsatellite was nonpolymorphic in our population and it was not included in the analysis. The distribution of alleles at the IL10.G in Hong Kong Chinese SLE patients and controls was shown in Table 5. A total of 15 alleles of IL10.G with different CA repeat numbers were found in our study. They ranged from IL10.G3 (CA repeat number=15) to IL10.G17 (CA repeat number=29). The distribution of alleles at the IL10.G in patients and controls differ significantly (P=0.003; overall χ2 analysis). Among the 15 alleles, the frequency of IL10.G4 was significantly increased in the patients when compared with the controls (IL10.G4: P=0.017, OR=2.53, 95% CI: 1.18–5.40).

Table 5 Distribution of alleles at the IL-10.G microsatellites in Hong Kong Chinese SLE patients and controlsa

As described previously,46 we divided all these 15 alleles into two subgroups: ‘long allele’ and ‘short allele’ as defined by long allele with CA repeat number greater than 21 (IL10G.9) and short allele with CA repeat number equal to or smaller than 21 (IL10G.9), because IL10G.9 has the median number of repeats and it is the most dominant allele (around 50% in both SLE patients and controls). In further genetic analysis, the frequency distribution of ht1 genotype together with the short and long alleles was significantly different between patients and controls (overall χ2 test, P=0.01) (Table 6). We found that the genotype of non-ht1/non-ht1 with homozygous short allele showed a higher OR (OR=4.11, P=0.018) than the genotype of non-ht1/non-ht1 with heterozygous short and long allele (OR=2.98, P=0.013) and homozygous long allele (OR=1.05, P=0.848) (Table 6). This indicated that the short allele of IL10.G with the non-ht1/non-ht1 genotype has a dose-dependent effect on the susceptibility of SLE.

Table 6 Frequencies of IL-10 genotypes with IL10.G long and short allelesa

IL-10 promoter polymorphisms and clinical features of SLE

The association between the clinical features and antibody profiles of 298 SLE patients with various haplotypes and genotypes were analyzed and the result was shown in Table 7. The frequency of non-ht1 was significantly increased in patients with serositis (P<0.0001, OR=2.42, 95% CI: 1.55–3.80) and hematological disorder (P<0.05, OR=1.45, 95% CI: 1.02–2.05). The IL-10 promoter genotype frequency was significantly different in patients in the presence of antinuclear ribonucleoproteins (anti-nRNP). The homozygous genotype non-ht1/non-ht1 associated with anti-nRNP (P<0.05, OR=2.64, 95% CI: 1.14–6.07). After correction by Bonferroni method, only the association of non-ht1 with serositis remained to be significant (P<0.003).

Table 7 Frequencies of IL-10 promoter haplotypes and genotypes of SLE patients with various clinical features and autoantibody profilesa

Discussion

Many studies have been undertaken to investigate the association of different IL-10 promoter polymorphisms with SLE, using a relatively small number of patients (summarized in Table 8). However, they could only report a marginal association,36 and association to several clinical features but not directly to the disease;37, 44 only the microsatellite, IL10.G, showed a consistent significant association with SLE in various populations.46, 47, 48, 49 As discussed elsewhere,50, 51 a large sample size should be used in association study to maintain statistical power to detect a significant association. Here, we have recruited over 1000 subjects (554 SLE patients and 708 healthy controls) and demonstrated the significant association between SLE and IL-10 promoter genotypes.

Table 8 Summary of association studies of IL-10 promoter polymorphisms with SLE

Several studies showed functional data that related IL-10 production level to IL-10 promoter haplotypes.33, 34, 36, 39, 40, 43, 52 Many studies reported that decreased production of IL-10 by peripheral-blood mononuclear cells or whole blood is associated with the −592A allele or its associated haplotype, A-T-A (−1082/−819/−592),33, 39, 40 although observation of increased production of IL-10 by peripheral-blood mononuclear cells has been associated with −592A allele has also been reported.52 Crawley et al40 performed transient transfection studies to further confirm that the A-T-A haplotype was associated with lower transcriptional activity. Eskdale et al34, 43 performed several functional studies of IL-10 promoter SNPs and the two microsatellites, IL10.R and IL10.G. They showed that with IL10R.2 allele, which was the only allele present in our population, the A-T-A haplotype was associated with the lowest IL-10 production when compared with G-C-C and A-C-C.34 All these studies suggested that the −592A allele or A-T-A haplotype is associated with decreased production of IL-10.

In the present study, −592A has been shown to be the specific marker for ht1 (Table 4). Since −592A is associated with low IL-10 production, ht1 was considered as low IL-10 production haplotype and non-ht1 was high production haplotype. We observed that the homozygous non-ht1 genotype (−592CC) was associated with SLE predisposition (P=0.009, OR=1.80, 95% CI: 1.15–2.82). This may partially explain the high serum IL-10 level and production capacity that were observed in SLE patients.28, 29, 30 This also agrees with the hypothesis that a high IL-10 level predisposes to SLE disease development, because IL-10 activates B cells and promotes autoantibody production.27 Although the association of −592CC with SLE susceptibility was clearly stated in this study, no association of −592 allele or genotype were reported previously.36, 37, 46, 44 This may be due to the difference in allele frequencies of IL-10 promoter SNPs in different ethnic groups. For example, −592C is the rare allele in Hong Kong Chinese (29.4% in our study) but is the common allele in Western population (70%).35, 46, 44 Also, we included more than 1000 subjects to investigate the association of IL-10 promoter polymorphisms with SLE in Hong Kong Chinese, which should provide a stronger statistical power when compared with other similar studies.

The microsatellite, IL10.G, has been shown to be associated with SLE in various populations (Table 8). However, different alleles of IL10.G have been reported. Frequency of IL10.G9 was significantly decreased in British,47 Mexican-American48 and Italian46, 49 SLE patients; IL10.G10, IL10.G11 and IL10.G13 were significantly increased in Mexican-American,48 Italian46, 49 and British47 SLE patients, respectively. In our study, we found that the frequency of IL10.G4 was significantly increased in SLE (IL10.G4: P=0.017, OR=2.53, 95% CI: 1.18–5.40). Together with our data, five different alleles were shown to be associated with SLE. It seems that IL10.G is not directly linked to disease and may be a marker in LD with other variations.

However, D'Alfonso et al46 divided the IL10.G alleles into two groups: ‘long allele’ (CA repeat number greater than 21) and ‘short allele’ (CA repeat number smaller or equal to 21) and found a significant increase in long allele in Caucasians with SLE. We therefore divided the IL10.G alleles in our subjects into these two groups similarly, and the association of the long allele with SLE susceptibility still holds after combining our data with theirs (P=0.003, OR=1.17, 95% CI: 1.06–1.31; 2 × 2 χ2 test).46 In our study, we found that with the genotype of non-ht1/non-ht1 (shown to be a risk factor in SLE in our study), the short allele of IL10.G has a dose-dependent effect in SLE susceptibility. There is an increasing trend of the susceptibility to disease from the homozygous long allele (LL), heterozygous (SL) and homozygous short allele (SS) with non-ht1/non-ht1 genotype (OR=1.05, 2.98, 4.11, respectively). Our observation is different from that of D'Alfonso et al46 as they claimed that none of the polymorphisms in IL-10 plays a role in SLE susceptibility, except the long allele as a risk factor. However, we have shown that the frequency of genotype non-ht1/non-ht1 was significantly increased in our SLE patients and the short allele showed a dose-dependent effect on SLE susceptibility with this genotype. One of the explanations for this is that we are looking at the genotype level and they focused on the haplotype level. Also, different ethnic groups could also account for this difference. Previous studies have already shown that the frequencies of IL-10 promoter polymorphisms as well as other polymorphisms in different cytokine genes such as tumor necrosis factor receptor 1 gene (TNFR1) and transforming growth factor-beta1 gene (TGFB) are significantly different in Caucasians as compared to Chinese.44, 53 However, the dose-dependent effect on SLE susceptibility is based on the analysis of a smaller subset of individuals (64 patients and 46 controls). Thus, further independent association studies are needed to confirm this observation. Future studies should also be conducted to investigate the association between the length of IL10.G and IL-10 production level.

For clinical features analysis, we found that the high IL-10 production level haplotype, non-ht1, associated with serositis (P<0.0001, OR=2.422, 95% CI: 1.55–3.80) after Bonferroni method for multiple significance tests (P<0.003). Although no significant association was established, an increase of high production haplotype/genotype was found in some other clinical features such as arthritis, hematological disorder, SM antibodies and anti-nRNP. This showed that SLE patients with high IL-10 production genetic background may have a more severe disease. In other studies, several associations with clinical features were also reported (Table 8), for example, Mok et al44 showed that A-T-A haplotype was significantly increased in Chinese SLE patients with glomerulonephritis. Our data supported them in showing a trend in the increase of A-T-A haplotype in SLE patients with renal disorder (Table 7). This suggested that high IL-10 production may be protective against glomerulonephritis in SLE, despite high IL-10 production being a susceptibility factor in developing SLE.

We have also genotyped two more polymorphisms at IL-10 promoter, one SNP at position −2849 in 120 controls and 73 patients and a microsatellite IL10.R at −4.0 kb in 144 controls and 60 patients, respectively. All of the tested samples were homozygous G at −2849 except one heterozygous that was observed in patients. In the case of IL10.G, only IL-10.R2 was present in all of the tested samples. Thus, we concluded that these two common polymorphisms, which were previously reported in various populations,36, 42, 54 were in a very low frequency (−2849 SNP) or not observed (IL10.R) in our Hong Kong Chinese population. A comparison of these two polymorphisms in Hong Kong Chinese (our control) and Caucasian36, 42, 54 was shown in Table 9, which revealed significant difference in frequencies for all the polymorphisms between these two populations.

Table 9 Frequencies of IL10 promoter polymorphisms in Hong Kong Chinese and UK Caucasian

In conclusion, we have shown that the homozygous −592C, which links to non-ht1/non-ht1 genotype resulting in high IL-10 production, was a risk factor in SLE susceptibility. The short allele of IL10.G showed dose-dependent effect with non-ht1/non-ht1 genotype in SLE susceptibility.

Patients and methods

Patients and controls

In all, 554 Hong Kong Chinese patients with SLE from the Queen Marry Hospital were studied. Their mean age was 39±12 years, with 89% female. All SLE patients met the revised American College of Rheumatology criteria for systemic lupus.55 The study was approved by the Ethics Committee of the Faculty of Medicine, The University of Hong Kong, and all patients gave informed consent. Clinical and serological data and autoantibody profile were carefully recorded at the time that they were diagnosed with SLE. Renal disease was defined as proteinuria of >0.5 gm/day or biopsy-proven lupus nephritis. Neurological disorder included psychosis, seizure, organic brain syndrome, aseptic meningitis, depression, and cognitive dysfunction. Hematologic disorder included hemolytic anemia, leukopenia, lymphopenia or thrombocytopenia. DNA samples from 708 Hong Kong Chinese healthy blood donors from Red Cross served as controls. Their mean age was 25±10 years with 47% female.

DNA extraction

Genomic DNA was extracted from EDTA whole blood using a Qiagen DNA Blood Mini kit (Qiagen, CA, USA) according to the manufacturer's instructions. The DNA samples were then stored at 4°C until used.

Genotyping

IL-10 promoter polymorphisms at positions −3575, −1082 and −592 were genotyped by TaqMan system (Applied Biosystems, Foster City, CA, USA). In brief, the samples were amplified in a 20 μl reaction mixture, containing sample DNA, 10 μl of TaqMan Universal Master Mix (Applied Biosystems), 0.9 μM of each primer and 0.25 μM of each probe. The sequences of the primers and probes were listed in Table 1. The real-time polymerase chain reaction (PCR) was performed in ABI7700 machine (Applied Biosystems) as follows: 2 min at 50°C for decontamination via UNG, 10 min at 95°C for AmpliTaq Gold preactivation and 40 cycles of 15 s at 95°C and 1 min at 60°C. The T and C alleles at position −819 have been shown to be linked with the A and C alleles at position −592 respectively;33, 44 thus, the genotypes of −819 were deduced according to the genotypes of −592.

IL-10 promoter polymorphisms at position −2849 and −2763 were analyzed by the PCR-RFLP. Briefly, a 308-bp fragment containing the polymorphism was amplified by PCR in a 25 μl reaction mixture in the presence of 1.5 mM MgCl2, 0.2 mM of each of the dNTPs, 1.0 μM of each primer and 0.5 U of Taq DNA polymerase (Amsersham Biosciencies, Piscataway, NJ, USA). The primer sequences were shown in Table 1. The amplification was performed in ABI2700 PCR machines (Applied Biosystems) and the condition was 5 min at 94°C, 40 cycles of 30 s at 94°C, 40 s at 60°C and 40 s at 72°C, with a final extension at 72°C for 7 min. For −2849, the PCR product was subjected to digestion with 1 U of AlwI (New England Biolabs Inc., Beverly, MA, USA) in 37°C water bath or incubator for 3 h. If the allele G is present, the PCR product will be cleaved into two fragments with 124 and 184 bp. If the allele A is present, the PCR product will remain uncut with 308 bp. For −2763, the PCR product was digested with 1.5 U of DdeI (New England Biolabs) at 37°C for 3 h. If the allele C is present, the PCR product will be cleaved into four fragments (48, 49, 92 and 114 bp). If the allele A is present, the PCR product will be cleaved into three fragments (48, 92 and 163 bp). The genotype of these two SNPs could be determined by separation of the fragments on 4% agarose gel.

For genotyping of the IL-10.R and IL-10.G microsatellites, PCR amplification was performed in a 25 μl reaction mixture in the presence of 1.5 mM MgCl2, 0.2 mM of each of the dNTPs, 1.0 μM of each primer (forward primer was labeled by 6-FAM) and 0.5 U of Taq DNA polymerase (Amsersham Biosciencies), and followed by the cycle condition: 35 cycles of 30 s at 94°C, 40 s at 60°C and 40 s at 72°C, with an initial denaturing step of 5 min at 94°C and a final extension step of 7 min at 72°C. The primers were listed in Table 1. The labeled PCR products were then electrophoresed on an ABI 377 sequencer (Applied Biosystems) and fluorescent signals were analyzed by GeneScan version 3.1.

Statistical analysis

LD among SNPs was calculated by SAS/Genetics (SAS Institute Inc., NC, USA). Haplotypes were identified simply by eye due to the LD among SNPs. Sex has no effect on the genotype frequencies; thus, female and male were grouped together for analysis. The frequencies of IL-10 promoter genotypes were compared between patients with controls by an overall χ2 test. In case of significance, logistic regression was used for calculating odds ratios (95% confidential interval) and corresponding P-values of different genotype frequencies between control and SLE patients by controlling age as a covariable. In all statistical analysis, a P-value of less than 0.05 was used to reject the null hypothesis. Bonferroni method was used for multiple testing in clinical feature and IL-10 promoter polymorphisms analysis. Since all clinical features were recorded at the time of diagnosis, disease duration was not included as a covariable for statistical analysis in clinical feature and IL-10 promoter polymorphisms analysis.

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Acknowledgements

The study was partially supported by the Edward Sai-Kim Hotung Pediatric Education and Research Fund (#38) and Outstanding Researcher Award (YLL) of The University of Hong Kong.

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Correspondence to Y L Lau.

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The present study was approved by the Ethics Committee of the Faculty of Medicine, The University of Hong Kong.

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Chong, W., Ip, W., Wong, W. et al. Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus. Genes Immun 5, 484–492 (2004). https://doi.org/10.1038/sj.gene.6364119

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Keywords

  • systemic lupus erythematosus
  • interleukin 10
  • polymorphism
  • haplotype

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