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Rheumatology 2001; 40: 662-667
© 2001 British Society for Rheumatology

Original Papers

Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population

S. Ahmed, K. Ihara, S. Kanemitsu, H. Nakashima1, T. Otsuka1, K. Tsuzaka2, T. Takeuchi2 and T. Hara

Departments of Pediatrics and
1 Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, and
2 Department of Internal Medicine II, Saitama Medical Center, Saitama, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. Systemic lupus erythematosus (SLE) in a multisystem autoimmune disorder characterized by multiorgan pathology and autoantibodies against a variety of autoantigens. The CD28 and CTLA-4 genes might be candidate genes for SLE, because costimulation signals from CD80/CD86 to CD28/CTLA-4 have been suggested to play an important role in the activation or inactivation of T lymphocytes.

Methods. We investigated three polymorphic regions within the CTLA-4 gene, a C/T base exchange in the promoter region -318 (CTLA-4 -318C/T), an A/G substitution in the exon 1 position 49 (CTLA-4 49A/G), an (AT)n repeat polymorphism in the 3' untranslated region of exon 4 [CTLA-4 3' (AT)n], and a CD28 gene polymorphism, a T/C substitution in the intron 3 position +17 (CD28 IVS3+17T/C), in SLE patients and controls.

Results. SLE patients had significantly higher frequencies of the CTLA-4 49G allele (P=0.003) and of the CTLA-4 (AT)n 106 bp allele (P=0.0008) than controls. We also found a strong linkage disequilibrium between the A allele of CTLA-4 49A/G and the 86 bp allele of CTLA-4 3' (AT)n. On the contrary, no association was found between SLE and CTLA-4 -318C/T or CD28 IVS3 +17T/C.

Conclusion. We conclude that the CTLA-4 gene appears to play a significant role in the development of SLE in the Japanese population.

KEY WORDS: CTLA-4 gene, CD28 gene, Polymorphism, Systemic lupus erythematosus.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE) is an autoimmune multisystem disorder characterized by the production of immunoglobulin G autoantibodies. Inappropriate T-cell-dependent expansion of autoreactive B cells is considered to play a role in the production of pathogenic autoantibodies against nuclear, cytoplasmic and cell-surface autoantigens [1].

T-cell activation requires two discrete signals: a signal delivered by the T-cell receptor and an accessory signal that occurs when costimulatory receptors interact with their ligands. CD28, a major costimulatory molecule, binds to CD80/CD86 on antigen-presenting cells and delivers a potent costimulatory signal to T cells [2]. CTLA-4, a related receptor of CD28, also binds to CD80/CD86 on antigen-presenting cells but delivers negative signals to T cells, depending on both the T-cell activation state and the strength of the T-cell receptor signal [3]. Thus, CD28 and CTLA-4 molecules regulate the immune responses to self and foreign antigens by controlling antigen-specific T-cell activation [4].

The chromosome 2q33 region, where the CTLA-4 and CD28 genes are located [5], is one of the potential susceptibility loci for human SLE [6, 7]. Manipulation of CD28/CTLA-4 in animal models of autoimmunity has shown that CD28 as well as CTLA-4 plays a role in the development of autoimmune disorders [8–10]. In fact, association studies have revealed that CTLA-4 gene polymorphism is genetically linked to several autoimmune diseases [11–16]. However, there have been conflicting results as to the association between the CTLA-4 gene and SLE by the examination of a single polymorphism and there are no data on the association between the CD28 gene and SLE.

The purpose of this study was to determine which of the two T-cell costimulatory molecule genes at 2q33 is linked to the development of SLE by the analysis of all the known polymorphisms of the CTLA-4 and CD28 genes.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients and controls
The study population comprised 113 SLE patients. All these patients fulfilled the American College of Rheumatology 1982 revised criteria for SLE. The mean (S.D.) age at onset of SLE was 31 (13) yr. Two hundred normal individuals (104 males and 96 females) in the northern Kyushu area of Japan were recruited for the control population. Informed consent was obtained from subjects and/or their parents.

DNA extraction
Genomic DNA was obtained from peripheral blood lymphocytes using the QIAamp DNA extraction kit (Qiagen, Tokyo, Japan).

Restriction fragment length polymorphism (RFLP) analysis of CTLA-4 promoter polymorphism
To amplify the region containing the C/T polymorphism at position -318, the following primer pairs were used: forward 5'-AATGAATTGGACTGGATGG-3' and reverse 5'-TTACGAGAAAGGAAGCCGTG-3'. The polymerase chain reaction (PCR) was carried out in a volume of 50 µl containing 40 ng of genomic DNA, 25 pmol of each primer, 1.25 U of Taq polymerase (Promega, Madison, WI, USA) and 0.2 mM of each deoxynucleoside triphosphate. The PCR profile was as follows: initial denaturation at 94°C for 2 min, followed by 40 cycles of 94°C for 30 s, 60°C for 30 s and 72°C for 30 s, with final extension at 72°C for 7 min. The reaction products were analysed on 3% agarose gels. To screen these substitutions, the products were incubated with MseI restriction enzyme at 37°C for 3 h, separated on 3.0% agarose gels and visualized by ethidium bromide staining (Fig. 1Go).



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  		FIG. 1. Genotyping of the CTLA-4 gene promoter -318C/T polymorphism by MseI RFLP. M, DNA size marker (100-bp ladder). PCR fragments containing -318 C are digested into two fragments (226, 21 bp), whereas PCR fragments containing -318 T are digested into three fragments (21, 96, 130 bp). The 21-bp fragments are not visible on the agarose gel.

 

Single-strand conformation polymorphism analysis of CTLA-4 exon 1 49 A/G polymorphism
To amplify the region containing the exon 1 49A/G polymorphism, the following primer pairs were used: forward 5'-GTTCAAACACATTTCAAAGCTTC-3' and reverse 5'-AAATGACTGCCCTTGACTGC-3'. The PCR profile was identical to that described above except for the annealing temperature of 55°C and genomic DNA quantity of 20 ng. For genotype screening, single-strand conformation polymorphism (SSCP) analysis was carried out with GeneGel Excel 12.5/24 (Amersham Pharmacia Biotech, Uppsala, Sweden) with 25 mA at 20°C, according to the manufacturer's instructions. Single-strand DNA fragments in the gel were visualized by subsequent silver staining (Fig. 2Go). The results of SSCP analysis were confirmed by the direct sequencing of 20 randomly chosen samples.



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  		FIG. 2. Genotyping of CTLA-4 gene exon 1 49A/G polymorphism by SSCP analysis. Alleles with G and A polymorphisms at nucleotide position 49 show different mobility in the gels. Lane 1, G/G genotype; lane 2, A/G genotype; lane 3, A/A genotype.

 

CTLA-4 3' (AT)n genotype using PCR and a fluorescence-based technique
The CTLA-4 3' untranslated region (UTR) containing the (AT)n repeat was amplified with the following primer pairs: forward 5'-GCCAGTGATGCTAAAGGTTG-3' and reverse 5'-AACATACGTGGCTCTATGCA-3'. The 5' end of the forward primer was labelled with 6-carboxyfluorescein dye. PCR was employed in a volume of 25 µl containing 20 ng of genomic DNA, 10 pmol of each primer, 0.625 U of Taq DNA polymerase and 0.2 mM of each deoxynucleoside triphosphate. The PCR conditions were the same as described above except for the cycles of 30, the annealing temperature of 55°C and the extension time of 15 s. Genotyping was performed in a mixture of amplified products with an internal size standard (Gene Scan -350) by an ABI Prism 310 genetic analyser (Perkin-Elmer, Foster City, CA, USA).

Allele-specific PCR and RFLP analysis of the polymorphism at position IVS3+17 of the CD28 gene
We have recently reported a CD28 gene T/C polymorphism in the intron 3 position +17 (CD28 IVS3 +17T/C) [17]. The polymorphism was determined by allele-specific PCR (ASPCR) using an allele-specific primer for C or T at position IVS3+17 in the CD28 gene. The primers used to detect T and C alleles were 5'-CTGGGTAAGAGAAGCAGCAAT-3' (T primer) and 5'-CTGGGTAAGAGAAGCAGCAAC-3' (C primer) respectively and the common primer 5'-CTCAATGCCTTCTGGAAATC-3' (Cm primer). A single-base mismatch was introduced at position 2 from the 3' end of both allele-specific primers (shown by the underline). Each primer combination detected only the primer-specific allele (Fig. 3aGo). To confirm the accuracy of ASPCR, 91 samples were analysed by restriction fragment length polymorphism (RFLP). To amplify the region containing the CD28 IVS3+17T/C polymorphism, the following primer pairs were used for the PCR reaction: forward 5'-TTTTCTGGGTAAGAGAAGCAGCGC-3' and reverse 5'-GAACCTACTCAAGCATGGGG-3'. The PCR products were then incubated with the Eco47III restriction enzyme at 37°C overnight, separated on 3.0% agarose gels and visualized by ethidium bromide staining (Fig. 3bGo).



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  		FIG. 3. Genotype analysis of CD28 IVS3 +17T/C. (a) ASPCR analysis of CD28 IVS3 +17T/C genotype. Lanes 1 and 2, TT, T/T genotype; lanes 3 and 4, TC, T/C genotype; Lanes 5 and 6, CC, C/C genotype. (b) RFLP analysis by Eco47III of the CD28 IVS3 +17 T/C genotype. PCR fragments containing T are digested into two fragments (126 and 22 bp), whereas PCR fragments with the C/C genotype are undigested. The 22-bp fragments are not visible on the agarose gel.

 

Statistical analysis
Differences between allele or genotype frequencies of groups were evaluated by {chi}2 analysis with 2x2 and 2x3 contingency tables with Stat View J-5.0 (software for Apple Macintosh). When at least one cell number was not more than 5, Yates’ correction was applied to the {chi}2 value. A P value <0.05 was considered to be statistically significant for the CTLA-4 gene -318C/T, 49A/G and CD28 gene I VS3 +17T/C analyses. Because of the multiple comparisons for the microsatellite allele frequencies, a Bonferroni multiple adjustment was made to the level of significance in the 3'-UTR of the CTLA-4 gene, which was set at P<0.0045 (0.05/11). The sample size was sufficient to detect an odds ratio (OR) of 1.7 or greater with 80% power at the 5% level of significance, assuming a frequency of about 50% for the G allele of the CTLA-4 49A/G polymorphism in the control population.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Allele and genotype frequencies of CTLA-4 49A/G, 3' (AT)n and -318C/T
With respect to CTLA-4 gene 49A/G polymorphism, the frequency of the G allele was significantly higher in SLE patients than in control subjects (69.5 vs 57.2%, P=0.003) because of a significant increase in the frequency of the GG genotype in SLE patients (48.7 vs 31.0%) (Table 1Go). Regarding the CTLA-4 3' (AT)n polymorphism, 15 discrete alleles were identified in the Japanese population with sizes ranging from 86 to 132 base pairs (bp), of which the 86-bp allele was the most frequent in the control subjects. Compared with the frequency of the 86-bp allele, the frequency of the 106-bp allele was significantly higher in SLE patients than in controls (OR 3.19, P=0.0008) (Table 2Go). There was significant linkage disequilibrium between the 86-bp allele of the 3' microsatellite polymorphism and the A allele of the 49A/G polymorphism in exon 1 of the CTLA-4 gene (Table 3Go). On the other hand, there were no significant differences in the allele and genotype frequencies of the -318C/T polymorphism between SLE patients and controls (Table 1Go).


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  		TABLE 1. Comparison of genotype distributions and allelic frequencies between SLE patients and controls

 

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  		TABLE 2. Allele frequencies of respective repeat number polymorphism at the 3' UTR of the CTLA-4 gene in SLE patients and controls

 

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  		TABLE 3. Linkage disequilibrium between the CTLA-4 49A/G and CTLA-4 3' (AT)n polymorphisms

 

Allele and genotype frequencies of CD28 IVS3 +17T/C
No significant differences were observed in the allele and genotype frequencies of this polymorphism between SLE patients and control subjects (Table 1Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Multiple genetic and environmental factors are involved in the pathogenesis of SLE [18]. The genetic factors of SLE include major histocompatibility complex (MHC) class II genes [19–23] and non-MHC genes, including genes for complement components, Fc receptor II/III, the T-cell receptor, apoptosis (Fas, Fas-ligand, bcl-2) and cytokines [24–30]. A recent genome-wide search for potential susceptibility loci for human SLE revealed numerous loci, including 2q33, depending on racial origin [7].

The CTLA-4 and CD28 molecules encoded at 2q33 perform critical roles in the regulation of the antigen-specific immune response [31]. In the present study, CTLA-4 but not CD28 gene polymorphisms were associated with the development of SLE, suggesting that the genetic factors of SLE are distinct from those of insulin-dependent diabetes mellitus (IDDM), to which CD28 gene polymorphism has also been marginally linked [K. Ihara et al., submitted for publication]. It is worthy of note that neither CTLA-4 nor CD28 gene polymorphisms were associated with atopic asthma, in a population with the same genetic background [17]. With respect to the CTLA-4 gene, lack of association with SLE has been reported in Mexican American, British, Italian and Japanese populations [30, 32–34], while there has been one association reported in the Slovak population [35]. The studies described above were done by the analysis of either the 49A/G or the 3' (AT)n polymorphism of the CTLA-4 gene. To increase the reliability of the analysis, we examined all three polymorphic sites, 49A/G, 3' (AT)n and the -318 promoter region, and found that the former two polymorphisms were significantly associated with SLE. Possible reasons for the conflicting results might include the differences in the ethnic groups and the age at onset of the disease in the Mexican American, British and Italian populations and a smaller sample size, as well as a minor difference in the genetic background in the Japanese population. As has been found for IDDM, Graves disease, Hashimoto's thyroiditis, multiple sclerosis and rheumatoid arthritis [11–15, 36, 37], the G allele of the CTLA-4 49A/G polymorphism was associated with SLE in recent studies [35] and the present work. The 106-bp allele of the CTLA-4 3' (AT)n polymorphism showed a significant association with SLE, consistent with results from other autoimmune disorders such as IDDM, Graves disease, Addison's disease and Wegener's granulomatosis [12, 13, 16, 38].

The CTLA-4 49A/G and 3' (AT)n polymorphisms are unlikely to affect the function of the gene because 49A/G and 3' (AT)n are located on the peptide leader and the 3' untranscribed region respectively. However, it is possible that either or both of the CTLA-4 gene polymorphisms affects CTLA-4 mRNA stability and subsequent CTLA-4 expression [11]. CTLA-4-deficient mice develop a lethal lymphoproliferative disease by massive uncontrolled T cells [8, 9]. CTLA-4 not only counterbalances CD28 signals but also inhibits T-cell responses independently of CD28. Recent studies have suggested that CTLA-4 interacts with the CD3{zeta} chain of the T-cell receptor complex and interferes with very early T-cell receptor signalling events [39]. Thus, CTLA-4 might induce autoimmunity by the inhibiting CD3{zeta} signal because a decrease in CD3{zeta} expression was associated with SLE in a proportion of cases [40].

In conclusion, the CTLA-4 gene appears to play a significant role in the development of SLE in Japanese population. Further study will be necessary to elucidate the mechanisms of the association between CTLA-4 gene polymorphisms and SLE.


   Acknowledgments
 
We extend special thanks to Yoko Katafuchi, Tamami Tanaka and Kanako Uchida for technical assistance. This work was supported by Grant-in-Aid for Scientific Research (B) from the Ministry of Health and Welfare and Ministry of Education, Science, and Culture of Japan.


   Notes
 
Correspondence to: K. Ihara, Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Back


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 5 April 2000; Accepted 14 December 2000


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