Genetic Heterogeneity in Association of the SUMO4 M55V Variant With Susceptibility to Type 1 Diabetes

Abstract

Association studies are a potentially powerful approach to identifying susceptibility variants for common multifactorial diseases such as type 1 diabetes, but the results are not always consistently reproducible. The IDDM5 locus has recently been narrowed to an ϳ200-kb interval on chromosome 6q25 by two independent groups. These studies demonstrated that alleles at markers in the mitogen-activating protein kinase 7 interacting protein 2 (MAP3K7IP2)/ SUMO4 region were associated with susceptibility to type 1 diabetes. Subsequent studies, however, showed inconsistency in the association of the SUMO4 gene with type 1 diabetes. To clarify the contribution of the M55V polymorphism of the SUMO4 gene to type 1 diabetes susceptibility, 541 type 1 diabetic patients and 768 control subjects were studied in Asian populations. T ype 1 diabetes is a common multifactorial disease caused by the autoimmune destruction of insulin-producing ␤-cells of the pancreas. Previous studies have suggested that Ͼ20 genetic intervals are associated with susceptibility to type 1 diabetes (1,2). Of these, four loci have been identified and replicated as disease susceptibility genes by genetic association studies: the HLA class II genes (IDDM1) (3), INS gene (IDDM2) (4), CTLA4 gene (IDDM12) (5), and PTPN22 gene (6). Recently, the IDDM5 locus has been narrowed down to an ϳ200-kb interval on chromosome 6q25 by two independent groups (7,8). Several single nucleotide polymorphisms (SNPs) that were in linkage disequilibrium in the SUMO4/mitogen-activating protein kinase 7 interacting protein 2 (MAP3K7IP2) region were found to be associated with susceptibility to type 1 diabetes (7,9). The SUMO4 gene, encoding small ubiquitin-like modifier 4, is a posttranslational modifier, which has recently been identified as a novel member of the SUMO family and is suggested to modify immune response through the putative substrate, inhibitor of nuclear factor-B␣, a suppressor of nuclear factor-B (NF-B) (7). SUMO4 is located entirely within the sixth intron of the MAP3K7IP2 gene (Fig. 1), whose product indirectly regulates the activation of NF-B in response to interleukin-1 stimulation (10,11).Among the disease-associated SNPs in the SUMO4/ MAP3K7IP2 gene, a common nonsynonymous SNP (rs237025) encoding a methionine-to-valine substitution at codon 55 (M55V) of SUMO4 was proposed as the causative variant of IDDM5 by two groups but with alleles with opposite risk (7,9). The original report by Guo et al. (7) with subjects from diverse ethnic groups and the subsequent study by Park et al. (12) in Korean subjects showed that possession of the G allele was significantly associated with increased risk for type 1 diabetes, whereas studies in Caucasian subjects of European descent showed no association (13-15) or even an association of the A allele with the disease (9).Of note is the positive association in studies with subjects from Asian populations (7,12) in contrast to the lack of association in subjects of European descent (13,14) and a tendency for an opposite assoc...

SUMO4 M55V Variant Is Associated With Diabetic Nephropathy in Type 2 Diabetes

“…Some investigators indicate the NF-B pathway is related to the development of type 1 diabetes (19), and other studies (13,20,21) have found a significant association of SUMO4 M55V gene variant with type 1 diabetes in Asian populations. In contrast, several studies have found no such association in European subjects (22,23), and even an opposite association in British individuals was reported (14).…”

“…The reasons for these discrepancies could be genetic heterogeneity and gene-environment interaction in different ethic populations. In studies from Asian populations, the frequencies of SUMO4 AA, GA, and GG have been reported to be 49, 41, and 10% in control subjects and 39, 49, and 12%, respectively, in patients with type 1 diabetes (13,20,21). In this study, the frequencies of SUMO4 AA, GA, and GG in our type 2 diabetic patients were 48, 44, and 8%, respectively, similar to the above-mentioned studies in Asia (13,20,21) but different from Caucasian studies (13,22).…”

Genetic Basis of Type 1 Diabetes: Similarities and Differences between East and West

“…To clarify the contribution of SUMO4 to susceptibility to type 1 diabetes, we re-sequenced a >2000bp interval of chromosome 6q25, including the whole SUMO4 gene, in a Japanese sample and the identified polymorphisms were subjected to association studies in both Japanese and Korean populations [43]. The M55V variant was significantly associated with type 1 diabetes in the Japanese and Korean populations, and metaanalysis of published studies as well as our own data confirmed a significant association of the M55V variant with type 1 diabetes in Asian (summary odds ratio: 1.29, p = 7.0×10 -6 ), but not Caucasian populations [43], suggesting heterogeneity in the genetic effect of SUMO4 on type 1 diabetes among diverse ethnic groups.…”

Association of SUMO4 Met55Val variation with increased insulin resistance in newly diagnosed type 2 diabetes in a Chinese population

“…A study by Zou et al showed that SUMO4 Met55Val polymorphism was implicated in some diseases which are closely related to inflammation process [2] . This variant was also revealed to be associated with type 1 diabetes, an autoimmune related disease, in Asian populations [3][4][5] .Recently, the relationship between SUMO4 Met55Val polymorphism and type 2 diabetes has been a subject of interest in the endocrinological community. Studies by Noso [6] and Shimada [7] reported the contribution of the SUMO4 Met55Val polymorphism to type 2 diabetes susceptibility in a Japanese population.…”