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...

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.

No abstract

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with openlabel eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population.