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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 6 2358-2362
Copyright © 2007 by The Endocrine Society

Association of Small Ubiquitin-Like Modifier 4 (SUMO4) Variant, Located in IDDM5 Locus, with Type 2 Diabetes in the Japanese Population

Shinsuke Noso, Tomomi Fujisawa, Yumiko Kawabata, Katsuaki Asano, Yoshihisa Hiromine, Aya Fukai, Toshio Ogihara and Hiroshi Ikegami

Department of Endocrinology, Metabolism, and Diabetes (S.N., Y.K., Y.H., H.I.), Kinki University School of Medicine, Osaka 589-8511, Japan; and Department of Geriatric Medicine (S.N., H.I., T.F., Y.K., K.A., Y.H., A.F., T.O.), Osaka University Graduate School of Medicine, Osaka, Japan

Address all correspondence and requests for reprints to: Hiroshi Ikegami, M.D., Ph.D., Department of Endocrinology, Metabolism, and Diabetes, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan. E-mail: ikegami{at}med.kindai.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Despite distinct differences in the pathogenesis, epidemiological data have indicated familial clustering of type 1 and type 2 diabetes, suggesting a common genetic basis between these two types of diabetes. Few shared susceptibility genes, however, have been reported to date.

Objective: Small ubiquitin-like modifier 4 (SUMO4) has been identified as a candidate gene for the IDDM5 locus and suggested to have possible involvement in immune responses, such as autoimmunity and inflammation. Recent reports demonstrated that a polymorphism with an amino acid substitution (Met55Val) in SUMO4 was associated with type 1 diabetes in Asian populations, although no association was reproduced in subjects of Caucasian descent. The present study aimed to clarify the contribution of SUMO4 to type 2 diabetes susceptibility in the Japanese population.

Subjects: The 753 subjects included 355 cases and 398 control subjects.

Methods: The SUMO4 Met55Val (rs237025) and 001Msp (rs577001) polymorphisms were genotyped.

Results: Strong linkage disequilibrium (D': 1.0 in each pair of single-nucleotide polymorphisms) across the MAP3K7IP2/SUMO4 region was shown in the Japanese population. The frequency of genotypes with the G allele of the SUMO4 Met55Val polymorphism was significantly higher in patients with type 2 diabetes [odds ratio, 1.46; 95% confidence interval (CI), 1.08–1.93; P = 0.01, {chi}2 test]. The association was concentrated in patients without insulin therapy (odds ratio, 1.56; 95% CI, 1.13–2.15; P = 0.0072), but not in those with insulin (odds ratio, 1.24; 95% CI, 0.81–1.89; not significant).

Conclusions: These data, together with previous reports, suggest the contribution of the SUMO4 Met55Val polymorphism to both type 1 and type 2 diabetes susceptibility in the Japanese population.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DIABETES MELLITUS IS a chronic disorder characterized by hyperglycemia due to relative or absolute deficiency of circulating insulin, consisting of two major forms with distinct pathogenesis, type 1 and type 2 diabetes. Type 1 diabetes is caused by autoimmune destruction of insulin-producing ß-cells of the pancreas, leading to absolute loss of endogenous insulin. In contrast, type 2 diabetes is a more heterogeneous disease caused by impaired insulin secretion and/or insulin sensitivity to various degrees in each individual. Both type 1 and type 2 diabetes are multifactorial diseases in which genetic factors consisting of multiple susceptibility genes and environmental factors contribute to the disease development (1). Despite the clear differences in their disease pathogenesis, epidemiological data have indicated familial clustering of type 1 and type 2 diabetes (2, 3), which suggests a common genetic basis between the two types of diabetes. Only a few possible shared susceptibility genes, however, have been reported to date. The HLA region (IDDM1), the major susceptibility locus for type 1 diabetes, is associated with type 2 diabetes (4, 5). Moreover, a 5' variable number of tandem repeat locus of INS (INS-VNTR, IDDM2) has been associated with both types of diabetes, but with predisposition determined by opposite alleles (6). More recently, an analysis of type 2 diabetes-associated single-nucleotide polymorphisms (SNPs) showed a significant association of the PPARG2 Pro12Ala variant with type 1 diabetes (7).

Positional cloning approaches have recently narrowed the IDDM5 locus to an approximately 200-kb interval on chromosome 6q25 (8, 9). The newly identified IDDM5 locus contains two genes, small ubiquitin-like modifier 4 (SUMO4) and MAPK kinase kinase 7 interacting protein 2 (MAP3K7IP2). SUMO4 is located entirely within the sixth intron of MAP3K7IP2 and is suggested to be possibly involved in immune responses including autoimmunity and inflammation through regulation of nuclear factor-{kappa}B (NF{kappa}B) and heat shock transcriptional factor activation (8, 9, 10). Another candidate gene, MAP3K7IP2, also known as TAB2, is well characterized and indicated to act as a regulator of NF{kappa}B activation (11). Recent reports showed that SNPs including amino acid substitutions in SUMO4 (Met55Val) located in the SUMO4/MAP3K7IP2 region were associated with susceptibility to type 1 diabetes in diverse ethnic groups (8, 9). Although subsequent analyses (12, 13) in Caucasian populations showed inconsistency of the association with initial reports (8, 9), the association has been reproduced in Eastern Asian populations (14, 15). Our meta-analysis showed significant genetic heterogeneity of the association across ethnicities, in clear contrast to the strong, homogeneous association with type 1 diabetes in subjects of Eastern Asian descent (14).

Several linkage studies have indicated that the SUMO4/MAP3K7IP region of chromosome 6 also harbors susceptibility loci for type 2 diabetes in multiple ethnic groups (16, 17, 18, 19), suggesting a shared susceptibility locus for both types of diabetes in the region.

Given the possible functional as well as genetic evidence for SUMO4/MAP3K7IP2 as a candidate gene for type 2 diabetes, we studied the contribution of the SUMO4/MAP3K7IP locus to susceptibility to type 2 diabetes.


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

A total of 753 Japanese subjects [355 patients with type 2 diabetes (171 women and 184 men) and 398 healthy control subjects (132 women and 266 men)] were recruited from the western area of Japan. Type 2 diabetes was diagnosed according to the criteria of the American Diabetes Association (20). The clinical characteristics of type 2 diabetic patients were age at onset, 46.0 ± 12.6 yr (mean ± SD); body mass index (BMI), 22.7 ± 3.6 kg/m2; and number of patients for each mode of treatment, insulin/oral hypoglycemic agent/diet = 109/182/62. Control subjects had no clinical diabetes and no family history of diabetes. Insulin levels were measured to evaluate endogenous insulin secretion during a 75-g oral glucose tolerance test (n = 55). Insulin sensitivity was evaluated by fasting insulin level, homeostasis model assessment for insulin resistance (HOMA-IR) and the ratio of the area under the curve (AUC) of serum insulin divided by AUC of plasma glucose levels during the 75-g oral glucose tolerance test (insulin AUC/glucose AUC).

All DNA samples were collected after approval from the relevant research ethics committees, and informed consent was obtained from the participants.

Genotyping

Genotyping of M55V (rs237025) of SUMO4 was undertaken using TaqMan (Applied Biosystems, Tokyo, Japan) with the probes and primers described in a previous report (13). To avoid genotyping error, all genotyping 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 Biolab, Beverly, MA), and 16 genotypes were confirmed by direct sequencing using an ABI 3100 capillary sequencer. No discrepancy was observed between the three methods.

Genotyping of 001Msp (rs577001) was undertaken using TaqMan with the probes and primers described in a previous report (13).

Isolation of peripheral blood mononuclear cells (PBMC) and measurement of TNF{alpha} concentration

PBMC from healthy control subjects were isolated with LSM lymphocyte separation medium by the standard method (ICN, Cappel Research Reagents, Costa Mesa, CA) for each genotype (n = 3, respectively). Then, 5 x 105 PBMC in RPMI 1640 were seeded in a 96-well culture plate with 10 ng/ml lipopolysaccharide and cultured at 37 C for 24 h. The culture supernatant was harvested, and TNF{alpha} concentration was measured using a human TNF{alpha} ELISA kit, Quantikine (R&D Systems, Minneapolis, MN).

Statistical analysis

Allele frequencies were estimated by direct counting. Hardy-Weinberg equilibrium was tested using {chi}2 analysis. Observed and expected genotypes for each SNP were compared using the Hardy-Weinberg equation, and no significant deviation from equilibrium was observed in this study. The overall genotype call rate was 97.9% (rs237025) and 95.5% (rs577001). Linkage disequilibrium between markers was assessed by D'. Haplotypes were estimated by the expectation-maximization algorithm (Haploview version 3.2). Haplotype blocks were constructed based on D' in 16 control subjects, with D' at least 0.95 for pairs of markers representing a haplotype block. Haplotype tag SNPs were selected based on Paul de Bakker’s Tagger using Haploview version 3.2 software. The significance of the difference in distribution of alleles between patients with type 2 diabetes and healthy control subjects was determined by the {chi}2 method. The significance of differences in BMI, fasting plasma glucose, fasting insulin concentration, HOMA-IR, and AUC insulin/AUC glucose was determined by ANOVA. Statistical significance was defined as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Strong linkage disequilibrium across SUMO4/MAP3K7IP2 region in Japanese population

A novel SNP in the promoter region of SUMO4 (–504A->G), as well as M55V (rs237025) and 438C->T in the 3'-untranslated region (rs237024), has been previously identified by direct sequencing of the whole SUMO4 gene in 32 Japanese samples. In addition, another novel SNP in the promoter region (–804G->A) was newly identified in the present study by resequencing the upstream region. We identified a single haplotype block consisting of these four SNPs in SUMO4 and one SNP (001Msp) in MAP3K7IP2 (Fig. 1AGo), which was reported to be associated with type 1 diabetes, with strong linkage disequilibrium (D' for each pair of SNPs was 1.0). Three haplotypes were defined in this region (Fig. 1BGo), and 001Msp and SUMO4-M55V were selected as haplotype tag SNPs for further analysis of the association of this locus with type 2 diabetes (001Msp vs. –504A->G and SUMO4-M55V vs. 438C->T; r2 = 1.0, respectively).


Figure 1
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  		FIG. 1. A, Localization of SNPs of SUMO4/MAP3K7IP2 region in IDDM5 locus; B, haplotype block consisting of five SNPs in SUMO4/MAP3K7IP2 region. Three haplotypes were defined by expectation-maximization algorithm (Haploview version 3.2).

 
Association of Met55Val variant of SUMO4 with type 2 diabetes

There was a significant difference in the distribution of genotypes between patients with type 2 diabetes and control subjects (P = 0.04, {chi}2 test, 2 degrees of freedom). The frequency of the G allele was significantly higher in patients with type 2 diabetes than in control subjects (Table 1Go; odds ratio, 1.29; 95% confidence interval (CI), 1.04–1.60; P = 0.02, Fisher’s exact probability test). The frequency of genotypes with the G allele was significantly higher in patients with type 2 diabetes than in control subjects (Table 1Go, odds ratio, 1.46; 95% CI, 1.08–1.93; P = 0.01). 001Msp was not associated with susceptibility to type 2 diabetes (supplemental table, published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org).


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  		TABLE 1. Association of M55V variant with type 2 diabetes

 
Stratified analysis by clinical characteristics of patients

The association was emphasized when cases were limited to patients treated with oral hypoglycemic agents or diet therapy only, in that the frequency of genotypes with the G allele was much higher in patients than in controls (Table 1Go, 61 vs. 50%; odds ratio, 1.56; 95% CI, 1.13–2.15; P = 0.0072). The difference in genotype frequencies of the G allele between the two subsets of type 2 diabetes did not reach statistical significance, possibly due to insufficient sample size. In contrast, no significant difference was observed between patients with insulin therapy and control subjects [55 vs. 50%, odds ratio, 1.24; 95% CI, 0.81–1.89, not significant (NS)]. When the cases were divided into tertiles according to BMI so that approximately equal numbers of patients were included in each group (BMI: lean, 16.1 ± 1.6; intermediate, 22.5 ± 0.8; obese, 26.7 ± 2.6 kg/m2), no difference was observed in the frequency of alleles or genotypes. Stratification by genotypes with the disease-associated G allele showed no difference in various clinical characteristics in patients except for glycosylated hemoglobin (8.5 ± 2.3 vs. 8.0 ± 2.2%, P < 0.05). Type 2 diabetic patients with the G allele showed a tendency for a lower frequency of insulin therapy and an older age at onset than those without the G allele (28.8 vs. 33.8%, 47.0 ± 12.1 vs. 44.6 ± 13.2 yr, respectively). Healthy control subjects were also stratified by genotypes and analyzed for insulin resistance-related phenotypes. There was no difference in BMI (22.4 ± 2.8 vs. 22.4 ± 2.5 kg/m2). Fasting serum insulin concentration (9.4 ± 15.9 vs. 6.8 ± 5.2 µg/dl), HOMA-IR (2.0 ± 3.4 vs. 1.5 ± 1.2), insulin AUC/BMI (0.89 ± 1.53 vs. 0.29 ± 0.22 µg·min·kg/dl·m2), and insulin AUC/glucose AUC (0.34 ± 0.76 vs. 0.19 ± 0.09 µg·mg) tended to be higher in subjects with the G allele than in those without. Stratification by sex and family history of diabetes showed no difference in genotype distribution.

Tendency for higher TNF{alpha} production from PBMC with susceptible genotype

An in vitro assay using lipopolysaccharide-stimulated PBMC was performed to examine the possible function of the SUMO4 variant in the production of inflammatory cytokines. A tendency for a higher TNF{alpha} concentration in the culture supernatant of PBMC with the Met55Val GG genotype than in those with the GA and AA genotypes (3965 ± 1783 vs. 2275 ± 860 pg/ml, NS) was observed.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study showed that SNPs in the SUMO4/MAP3K7IP2 region on chromosome 6q25 are positively associated with susceptibility to type 2 diabetes in the Japanese population. Despite the significant association of SUMO4 Met55Val with type 2 diabetes and strong linkage disequilibrium between SNPs in the SUMO4/MAP3K7IP2 region, no association with 001Msp in MAP3K7IP2 was observed. This was possibly due to the low r2 between 001Msp and Met55Val (r2 = 0.53) and suggests that SUMO4, rather than MAP3K7IP2, is likely to be responsible for type 2 diabetes susceptibility. The association was concentrated in patients without insulin therapy, and type 2 diabetic patients with the disease-associated G allele showed a lower frequency of insulin treatment. There are two possibilities to explain these results. First, this locus might be related to the pathogenesis of a relatively mild form of type 2 diabetes, in which insulin is not required for glycemic control. Second, patients who do not need exogenous insulin may mainly exhibit insulin resistance rather than insufficiency of insulin secretion because of greater endogenous insulin secretion. The tendency for a higher fasting insulin concentration, higher HOMA-IR, and higher AUC insulin/AUC glucose in healthy control subjects with the G allele also suggests that the association of SUMO4 with type 2 diabetes may be related to insulin resistance. An in vitro assay using lipopolysaccharide-stimulated PBMC showed a tendency for a higher TNF{alpha} concentration in the culture supernatant of patients with the Met55Val GG genotype, suggesting a possible role of this variant in the regulation of proinflammatory cytokines. Additional analysis is required to validate the role of the SUMO4/MAP3K7IP2 region in the regulation of proinflammatory cytokine production. Although ß-cell failure or vulnerability has often been considered to be a possible common mechanisms for both types of diabetes (21, 22, 23), we could not find any evidence or even any tendency to suggest impairment of endogenous insulin secretion by stratification of the subjects by clinical characteristics.

Recent studies, which unveiled an important mechanism involved in insulin resistance, have provided a novel insight into the common etiology between type 1 diabetes and insulin resistance. Low-grade inflammation mediated by the I{kappa}B kinase ß NF{kappa}B pathway has been implicated in the pathogenesis of insulin resistance and type 2 diabetes (24, 25). Therefore, inflammation induced by the NF{kappa}B activation pathway in immune cells could play an important role in the development of insulin resistance (26) as well as autoimmune insulitis in type 1 diabetes. Although its detailed function is still controversial, the SUMO4 protein is considered to be involved in immune reaction. Guo et al. (9) reported that SUMO4 is a posttranscriptional modifier that inhibits degradation of I{kappa}B{alpha}, leading to activation of NF{kappa}B. On the other hand, the MAP3K7IP2 protein was indicated to be involved in the activation of NF{kappa}B via inhibitor of {kappa}B{alpha} phosphorylation. These data suggest the possibility of a contribution of the SUMO4/MAP3K7IP2 region to regulation of the immune response, including low-grade inflammation, leading to insulin resistance.

Slowly progressive insulin-dependent diabetes (SPIDDM), with positivity for islet-related autoantibodies, is often misdiagnosed as type 2 diabetes. However, patients with SPIDDM, who are positive for GAD65 autoantibodies, showed a comparable frequency of GG+GA genotypes to that in controls (0.48 vs. 0.50, NS), rather than type 1 diabetes (0.58) (14) or type 2 diabetes patients (0.59) in the Japanese population (unpublished data). We could not find any association of SUMO4 Met55Val with susceptibility to SPIDDM, suggesting less contribution of SUMO4 to the development of SPIDDM and the significance of our observation on the association with type 2 diabetes.

Animal models of both type 1 and type 2 diabetes are often derived from the same closed colony (27). The nonobese diabetic (NOD) mouse is a well-known inbred animal model of autoimmune type 1 diabetes derived from a closed colony of Jcl:ICR (28). The Nagoya-Shibata-Yasuda (NSY) mouse, in contrast, has been established as an inbred animal model of type 2 diabetes by selective breeding for glucose intolerance from Jcl:ICR mice, the same closed colony from which the NOD mouse was established (29). As in the case of the mouse model, animal models for both type 1 and type 2 diabetes exist in sister strains of rat: the Long-Evans Tokushima lean (LETL) rat, a type 1 diabetes model, and the Otsuka Long-Evans Tokushima fatty (OLETF) rat, a type 2 diabetes model, derived from same closed-colony Long-Evans rats (30, 31). It is possible that inbred sister strains share some genetic intervals derived from the original outbred colony, and such shared genes might be involved in susceptibility to both types of diabetes. Consistent with these data in animal models, epidemiological data indicate intrafamilial clustering of type 1 and type 2 diabetes in humans (2, 3). More recently, genome-wide scans for type 2 diabetes revealed linkage of type 2 diabetes at chromosome 6q, where a susceptibility gene for type 1 diabetes (IDDM5) was mapped, in African-American (18), Chinese (17), and Finnish populations (16). Duggirala et al. (19) also reported that chromosome 6q22–26 harbored major gene(s) with a strong effect on fasting serum insulin concentration. Taken together, these findings indicate that chromosome 6q may harbor susceptibility gene(s) for not only type 1 diabetes but also type 2 diabetes, suggesting the possibility of shared susceptibility gene(s) for both types of diabetes.

In the Caucasian populations, weak association of SUMO4 with type 1 diabetes (12, 13, 32, 33) and no association with systemic lupus erythematosus (34), rheumatoid arthritis (35), or Graves’ disease (36) has been reported, in clear contrast to a strong association with type 1 diabetes in Asian populations (14, 15) and with rheumatoid arthritis and autoimmune thyroid disease (Graves’ disease and Hashimoto disease) in the Japanese population (37). These reports, including a meta-analysis of type 1 diabetes (14), indicate genetic heterogeneity in the associations across diverse ethnicities and a contribution of SUMO4 to more common autoimmune susceptibility rather than to specifically type 1 diabetes, at least in the Japanese population, suggesting a possible role of SUMO4 in a common mechanism underlying immune response, such as autoimmunity and inflammation. These findings warrant additional studies on the associations with type 2 diabetes in different ethnic groups.

In conclusion, these data together with previous studies on the association of the SUMO4 variant with type 1 diabetes in the Asian population suggest the possibility of a contribution of the SUMO4/MAP3K7IP2 region to both type 1 and type 2 diabetes susceptibility in the Japanese population.


   Acknowledgments
 
We thank M. Moritani and Y. Tsukamoto for their skillful technical assistance.


   Footnotes
 
This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (to H.I.), Grants-in-Aid for Scientific Research (to H.I. and T.F.), and a Grant-in-Aid for Exploratory Research (to H.I.) from the Ministry of Education, Science, Sports, Culture, and Technology of Japan.

Disclosure Statement: The authors (S.N., T.F., Y.K., K.A., Y.H., A.F., T.O., and H.I.) have nothing to declare.

First Published Online March 20, 2007

Abbreviations: AUC, Area under the curve; BMI, body mass index; CI, confidence interval; HOMA-IR, homeostasis model assessment for insulin resistance; MAP3K7IP2, MAPK kinase kinase 7 interacting protein 2; NF{kappa}B, nuclear factor-{kappa}B; NS, not significant; PBMC, peripheral blood mononuclear cells; SNP, single-nucleotide polymorphism; SPIDDM, slowly progressive insulin-dependent diabetes; SUMO4, small ubiquitin-like modifier 4.

Received January 8, 2007.

Accepted March 14, 2007.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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S.-J. Shin, H.-Y. Lin, C.-L. Wang, P.-J. Hsiao, and K.-D. Lin
Response to Comment on: Lin et al. (2007) SUMO4 M55V Variant Is Associated With Diabetic Nephropathy in Type 2 Diabetes: Diabetes 56:1177 1180
Diabetes, August 1, 2007; 56(8): e12 - e13.
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