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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 8 3138-3143
Copyright © 2006 by The Endocrine Society

Evidence for the Role of Small Ubiquitin-Like Modifier 4 as a General Autoimmunity Locus in the Japanese Population

Masako Tsurumaru, Eiji Kawasaki, Hiroaki Ida, Kiyoshi Migita, Akie Moriuchi, Keiko Fukushima, Tetsuya Fukushima, Norio Abiru, Hironori Yamasaki, Shinsuke Noso, Hiroshi Ikegami, Takuya Awata, Hitoshi Sasaki and Katsumi Eguchi

Clinical Research and Trial Center (M.T., H.S.), Department of Metabolism/Diabetes and Clinical Nutrition (E.K., A.M., K.F.), Nagasaki University Hospital of Medicine and Dentistry, Nagasaki 852-8501, Japan; First Department of Internal Medicine (H.Id., T.F., N.A., H.Y., K.E.), Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan; Clinical Research Center (K.M.), National Hospital Organization Nagasaki Medical Center, Nagasaki 856-8562, Japan; Department of Geriatric Medicine (S.N., H.Ik.), Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; and Division of Endocrinology and Diabetes (T.A.), Department of Medicine, Saitama Medical School, Saitama 350-0495, Japan

Address all correspondence and requests for reprints to: Eiji Kawasaki, M.D., Ph.D., Department of Metabolism/Diabetes and Clinical Nutrition, Nagasaki University Hospital of Medicine and Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. E-mail: eijikawa{at}net.nagasaki-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Recently, an association of a single nucleotide polymorphism, 163A>G encoding M55V, in the gene SUMO4, which has been shown to be a negative feedback regulator for nuclear factor {kappa}B, has been reported in type 1 diabetes.

Objective: To establish whether SUMO4 locus contributes to the genetic susceptibility to other autoimmune disorders, a case-control analysis was carried out using genomic DNA from type 1 diabetes, autoimmune thyroid disease (AITD), rheumatoid arthritis (RA), and primary Sjögren’s syndrome.

Subjects: A total of 1480 samples, including 929 cases (411 patients with type 1 diabetes, 292 AITD, 172 RA, and 54 primary Sjögren’s syndrome) and 551 healthy control subjects of Japanese origin participated in the study.

Methods: The 163A>G (rs237025, M55V) polymorphism of SUMO4 was genotyped.

Results: SUMO4 M55V variant was associated not only with type 1 diabetes [odds ratio (OR), 1.42; 95% confidence interval (CI), 1.09–1.84; P = 0.0072], but also with increased risk of other autoimmune diseases, AITD (OR, 1.52; 95% CI, 1.14–2.03; P = 0.0041) and RA without amyloidosis (OR, 1.53; 95% CI, 1.65–2.24; P = 0.027), but not primary Sjögren’s syndrome. Furthermore, the association of SUMO4 M55V variant was stronger in type 1 diabetic patients complicated with AITD (OR, 1.62; 95% CI, 1.06–2.47; P = 0.023) and in patients who have neither type 1 diabetes-susceptible class II HLA, DRB1*0405 nor DRB1*0901 (OR, 2.28; 95% CI, 1.34–3.87; P = 0.0018).

Conclusions: These results indicate that the SUMO4 is a more common autoimmune disease gene and a supplementary risk factor to type 1 diabetes in conjunction with class II HLA.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TYPE 1 DIABETES IS a multigenic autoimmune disease with four loci identified so far, i.e. the major histocompatibility complex on chromosome 6q21 (1), the insulin gene on chromosome 11p15 (2), the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) locus on chromosome 2q33 (3), and the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) locus on chromosome 1p13 (4). Besides major histocompatibility complex, the CTLA4 and PTPN22 have been implicated in multiple autoimmune disorders including autoimmune thyroid disease (AITD), rheumatoid arthritis (RA), systemic lupus erythematosus, and Addison’s disease (3, 5, 6, 7, 8, 9, 10, 11, 12). Recently, linkage and single nucleotide polymorphism (SNP)-based fine mapping studies of type 1 diabetes cohorts narrowed the interval for the IDDM5 locus on chromosome 6q25 to an approximately 200-kb region containing only two genes, SUMO4 and TAB2 (also known as MAP3K7IP2) (13, 14). Subsequently, a missense polymorphism (rs237025, 163A>G) that results in a nonconserved substitution of methionine to valine (M55V) within the CUE domain of SUMO4 was proposed as the causative variant of IDDM5 that associated with type 1 diabetes (13, 14). Functional studies revealed that SUMO4 sumoylates I{kappa}B{alpha}, acting as a negative feedback regulator for nuclear factor {kappa}B (NF-{kappa}B) activity which has a central role in the immune response (14, 15). The M55V substitution of SUMO4 results in a significant reduction of its sumoylation capacity (14, 16), leading to higher NF-{kappa}B activity and enhanced IL-12p40 secretion (14).

Because a study investigating the shared autoimmunity gene hypothesis has demonstrated linkage and association of the IDDM5 locus with RA (17) and the NF-{kappa}B regulates a wide variety of immune responses, the SUMO4 could be an important determinant of multiple autoimmune disorders. This prompted us to study the association of the M55V variant in SUMO4 with other autoimmune diseases, including AITD, RA, and primary Sjögren’s syndrome, in addition to type 1 diabetes. We also examined the putative correlation between the SUMO4 genotype and the clinically or genetically defined subset of type 1 diabetes.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A case-control study was performed to assess associations of the SUMO4 M55V SNP (rs237025, 163A>G) with type 1 diabetes, AITD, RA, and primary Sjögren’s syndrome. A total of 1480 subjects of Japanese origin, including 929 cases and 551 control subjects, were studied. Cases consisted of 411 patients with type 1 diabetes, 292 AITD, 172 RA, and 54 primary Sjögren’s syndrome. The DNA samples from patients with type 1 diabetes and control subjects were obtained from three of four centers (Osaka, Saitama, and Nagasaki) in the previous study (18), and more than 90% of samples were overlapped. The remaining cases were recruited from the Saitama and Nagasaki area. The clinical characteristics of the subjects are shown in Table 1Go. The clinical data on AITD were available in 281 patients with type 1 diabetes.


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  		TABLE 1. Clinical characteristics of cases and controls

 
The diagnosis of type 1 diabetes was made by endocrinologists according to the criteria of National Diabetes Data Group (19). Among the patients with type 1 diabetes, 110 patients (26.7%) were complicated with AITD. AITD consisted of Graves’ disease and Hashimoto’s thyroiditis and was diagnosed based on the finding of palpable goiter or the presence of chronic thyroiditis with ultrasonography examination in the absence of goiter, abnormal levels of thyroid hormones, and positivity for autoantibodies to thyroid peroxidase (TPO), thyroglobulin (TG), and/or TSH receptor.

Cases with RA and primary Sjögren’s syndrome were assessed by a rheumatologist and fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association) classification criteria for the respective diseases (20). All patients with primary Sjögren’s syndrome, including those without anti-SSA/Ro or anti-SSB/La antibodies, had positive results on lip biopsies, with Daniels’ focus scores of more than 2. Amyloidosis was diagnosed based on the presence of Congo red staining and greenish birefringence on polarizing light microscopy of tissue biopsy samples (either sc fat aspiration biopsy, rectal biopsy, gingival/tongue biopsy, or renal biopsy).

The healthy control subjects had no clinical diabetes and no family history of autoimmune diseases. All cases and control subjects were informed of the purpose of the study, and their consent was obtained. The ethics committee from each institute approved the study.

Genotyping and sequencing

Genotyping of SUMO4 M55V was undertaken using TaqMan (Applied Biosystems, Tokyo, Japan) with probes and primers described in previous reports (18, 21). The assay validity was reproduced by PCR-restriction fragment length polymorphism methods with a second nonpolymorphic cutting site in the same PCR products using restriction enzyme TspRI (New England Biolabs, Ipswich, MA) that cleaved the PCR product in the presence of the Valine encoding allele, and a part of them was confirmed by direct sequencing using an ABI 3100 capillary sequencer. No discrepancy was observed between the three methods. Furthermore, no deviations from Hardy-Weinberg equilibrium were observed for SUMO4 M55V A>G genotypes in control subjects.

The interaction analyses used HLA-DRB1 and two SNPs in the CTLA4, +6230G>A (CT60, rs3087243) and +49G>A (rs231775), which were also genotyped as reported previously (22). The data on HLA-DRB1, CTLA4 +6230G>A, and CTLA4 +49G>A polymorphism were available in 400, 409, and 405 patients with type 1 diabetes, respectively.

Autoantibody determinations

Antiislet autoantibodies, including anti-GAD antibody and ICA512/IA-2 antibody, were determined using RIA as described previously (23, 24). Autoantibodies to TPO and TG were measured using a commercial RIA kit, following the instructions provided by the manufacturer (RSR Limited, Cardiff, UK). The cutoff level for TPO antibodies and TG antibodies was 0.2 and 0.3 U/ml, respectively. TSH receptor autoantibody status was determined by a radioactive inhibition method (RSR Limited). Rheumatoid factor was detected by a latex immunoturbidimetric assay with cutoff value of 14 IU/ml (Dade-Behring, Tokyo, Japan). Anti-SSA/Ro and anti-SSB/La antibodies of IgG isotype were measured by an ELISA using a cutoff value of 20 IU/ml or less as suggested by the manufacturer (MBL, Nagoya, Japan).

Statistical analysis

Data are given as mean ± SD. Allelic and genotypic frequencies of all the genetic variants were obtained by direct counting. Deviations from Hardy-Weinberg equilibrium were tested by comparison of observed and expected genotype frequencies. The significance of differences in the distribution of alleles and genotypes between cases and healthy control subjects was determined by {chi}2 method with 2 x 2 contingency tables. Odds ratio (OR) and its 95% confidence interval (95% CI) were also calculated. Statistical heterogeneity between subpopulations was evaluated with the I2 statistic (25). Statistical tests were considered significant at P value less than 0.05 or, in case of k independent tests, at P value less than 0.05/k (Bonferroni correction).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
SUMO4 M55V variant and type 1 diabetes

The patients with type 1 diabetes and healthy control subjects were recruited from three geographical areas in Japan: Osaka, Saitama, and Nagasaki. Similar allele and genotype frequencies were observed in each geographical area and no heterogeneity was found (I2 = 0.0%). As shown in Tables 2Go and 3Go, the frequency of subjects with the G allele (encoding Val55) was significantly higher in patients with type 1 diabetes than that in healthy controls [GG+GA: 58.6 vs. 49.9%, OR: 1.42 (95% CI 1.09–1.84), P = 0.0072]. We then further analyzed the contributions of SUMO4 M55V variant with the clinical characteristics of type 1 diabetes, and found that the association of SUMO4 polymorphism was stronger in patients complicated with AITD [GG+GA: 61.8 vs. 49.9%, OR: 1.62 (95% CI 1.06–2.47), P = 0.023], and less so with type 1 diabetes alone compared with healthy controls (Table 2Go). However, we failed to detect any association between SUMO4 M55V variant and sex, age at disease onset, or presence of antiislet autoantibodies (data not shown).


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  		TABLE 2. Genotype frequencies of the SUMO4 M55V variant in type 1 diabetes vs. controls

 

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  		TABLE 3. Allele frequencies of the SUMO4 M55V variant in type 1 diabetes vs. controls

 
Because of the well-known contribution of IDDM1 in the HLA region and IDDM12 to susceptibility to type 1 diabetes, associations between SUMO4 M55V variant and HLA-DRB1 and CTLA4 were examined. In the Japanese population, HLA-DRB1*0405 and DRB1*0901 confer genetic susceptibility to type 1 diabetes. The frequency of SUMO4 GG+GA genotype was significantly higher in patients who have neither DRB1*0405 nor DRB1*0901 than that in control subjects [69.4 vs. 49.9%, OR: 2.28 (95% CI 1.34–3.87), P = 0.0018] or in patients carrying either DRB1 allele [69.4 vs. 56.4%, OR: 1.76 (95% CI 1.02–3.04), P = 0.042; Table 2Go]. Stratification of patients by high-risk (GG) and low-risk (GA+AA) genotypes of CTLA4 +6230G>A or +49G>A showed no difference in the association of SUMO4 GG+GA genotypes with type 1 diabetes (58.4 vs. 59.6%, OR: 1.05 for +6230G>A; 57.8 vs. 59.9%, OR: 1.10 for +49G>A; Table 2Go).

SUMO4 M55V variant and AITD, RA, or primary Sjögren’s syndrome

As autoimmune disorders share a number of characteristics and constitute a tendency toward familial aggregation, it is likely that common underlying genes and alleles are involved in some disorders, as demonstrated at CTLA4 or PTPN22. Owing to the accumulating lines of evidence that indicate involvement of the NF-{kappa}B pathway in the development of autoimmune disorders in humans and mice (26), the SUMO4 M55V variant could be a shared determinant among different autoimmune diseases. Hence, we investigated whether this locus is also associated with AITD, RA, or primary Sjögren’s syndrome. As shown in Tables 4Go and 5Go, patients with AITD showed significant difference in their genotype distribution [60.3 vs. 49.9%, OR: 1.52 (95% CI 1.14–2.03), P = 0.0041], particularly, patients with Graves’ disease showed more significant association with SUMO4 G allele [62.8 vs. 49.9%, OR: 1.69 (95% CI 1.19–2.40), P = 0.0031]. Furthermore, we also found evidence for an association of SUMO4 M55V with RA patients without amyloidosis [60.4 vs. 49.9%, OR: 1.53 (95% CI 1.65–2.24), P = 0.027], but not patients with amyloidosis (OR: 0.84, P = 0.62). However, the SUMO4 genotype distribution was similar between the two subgroups stratified by rheumatoid factor positivity among RA patients without amyloidosis (OR: 0.97, P = 0.95). No statistically significant differences were observed in the distribution of the SUMO4 genotypes between patients with primary Sjögren’s syndrome and healthy controls. Similarly, no association was detected when patients were stratified according to anti-SSA/Ro and/or anti-SSB/La status (data not shown).


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  		TABLE 4. Genotype frequencies of the SUMO4 M55V variant in AITD, RA, primary Sjögren’s syndrome vs. controls

 

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  		TABLE 5. Allele frequencies of the SUMO4 M55V variant in AITD, RA, primary Sjögren’s syndrome vs. controls

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The transcription factor NF-{kappa}B plays a central regulatory role in the immune system, namely, 1) inhibition of immune cell apoptosis, 2) the development of immune cells, 3) the maintenance of immune homeostasis and control of lymphoid architecture, and 4) the regulation of innate and adaptive immune system (27). NF-{kappa}B is expressed in the cytoplasm of various cell types including lymphocyte, dendritic cells, monocytes/macrophages, granulocytes, and is involved in the development of autoimmune disorders, including type 1 diabetes and RA (28, 29). NF-{kappa}B activity is negatively regulated by the I{kappa}B proteins, one of the substrates for SUMO4 sumoylation (15). Therefore, sumoylation is considered to be a novel negative regulatory mechanism for the control of NF-{kappa}B transcription activity.

In the present study, we found evidence that type 1 diabetes-associated SUMO4 G allele at position 163 was also associated with an increased risk of AITD and RA, indicating that this locus may have a general effect on predisposition to autoimmunity. Because the involvement of SUMO4 on the regulation of immune function is not limited to the specific organs (30), the current observation showing the much stronger association between SUMO4 M55V variant and type 1 diabetes with AITD is consistent with this hypothesis. Recently, no evidence of association of the SUMO4 M55V SNP with susceptibility to RA, Addison’s disease, and Graves’ disease was reported in Caucasian populations of European descent (31, 32). Such discrepant associations have also been reported for type 1 diabetes (14, 18, 21, 33, 34, 35), suggesting that the discrepancies may be caused by genetic heterogeneity or population differences in gene-gene and gene-environmental interactions.

Because genetic interactions between HLA and non-HLA loci have been described in susceptibility for type 1 diabetes and other autoimmune diseases (36, 37, 38), we compared genotype distributions for M55V variant among type 1 diabetes stratified by the presence of high-risk HLA-DRB1 alleles, DRB1*0405 or DRB1*0901, or CTLA4 +6230GG or +49GG genotype. The SUMO4 M55V was associated with type 1 diabetic patients without high-risk HLA-DRB1. This suggests that the SUMO4 M55V might be a supplementary risk factor to type 1 diabetes in patients without susceptible class II HLA haplotypes. However, polymorphisms in the CTLA4, which is also a negative regulator of NF-{kappa}B activity (39), did not alter the association of SUMO4 with type 1 diabetes, suggesting that SUMO4 M55V and CTLA4 polymorphisms independently contribute to pathogenesis of type 1 diabetes.

In conclusion, the present study indicated that SUMO4 locus within the IDDM5 region contributes to susceptibility to AITD and RA, in addition to type 1 diabetes, and therefore, may be a general autoimmunity gene. It will be interesting to test in future experiments whether M55V is the only autoimmune disease-associated variant in the gene and in this chromosome region.


   Acknowledgments
 
We thank Ms. Miho Uga and Ms. Miyuki Moritani for their technical assistance.


   Footnotes
 
This work was supported by a Grant-in-Aid for Scientific Research (Category B, No. 30128160) from the Ministry of Education, Culture, Science, Sports and Technology of Japan.

All authors have nothing to declare.

First Published Online May 30, 2006

Abbreviations: AITD, Autoimmune thyroid disease; CI, confidence interval; CTLA4, cytotoxic T lymphocyte-associated antigen 4; NF-{kappa}B, nuclear factor {kappa}B; OR, odds ratio; PTPN22, protein tyrosine phosphatase nonreceptor type 22; RA, rheumatoid arthritis; SNP, single nucleotide polymorphism; TG, thyroglobulin; TPO, thyroid peroxidase.

Received January 30, 2006.

Accepted May 23, 2006.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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S. Noso, T. Fujisawa, Y. Kawabata, K. Asano, Y. Hiromine, A. Fukai, T. Ogihara, and H. Ikegami
Association of Small Ubiquitin-Like Modifier 4 (SUMO4) Variant, Located in IDDM5 Locus, with Type 2 Diabetes in the Japanese Population
J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2358 - 2362.
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