Masaya Ono

A common polymorphism of uncoupling protein 2 gene is associated with hypertension

Objectives The genes responsible for obesity are also candidate genes for obesity-related conditions, such as hypertension and type 2 diabetes. A functional polymorphism in the uncoupling protein 2 (UCP2) promoter has been reported to be associated with obesity in Caucasians. To clarify the contribution of this polymorphism to obesity and related conditions, we studied the association of the −866 G/A polymorphism of the UCP2 gene with obesity, hypertension and type 2 diabetes mellitus. Methods A total of 632 unrelated Japanese subjects were studied: 342 type 2 diabetic patients (among them, 158 patients complicated with hypertension), 156 hypertensive patients without diabetes mellitus and 134 control subjects. The −866 G/A polymorphism of UCP2 was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Results The frequency of the minor A allele was significantly higher in Japanese than in Caucasians (48.9 versus 37.2%, P = 0.01). In contrast to the significant association with obesity in Caucasians, the polymorphism was not associated with obesity in Japanese. The polymorphism, however, was significantly associated with hypertension in Japanese (frequency of A allele: 51.8% in hypertensives versus 46.6% in normotensives, P < 0.05). No significant difference was observed in body mass index (BMI), fasting insulin level or HOMA-R between patients with different genotypes. Conclusion These data indicate that the polymorphism of the UCP2 gene is associated with hypertension, and suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of hypertension.

Age-related association of MHC class I chain-related gene A (MICA) with type 1 (insulin-dependent) diabetes mellitus

To assess the contribution of the HLA class I region to susceptibility to and heterogeneity of type 1 diabetes, we investigated the association of polymorphism of MHC class I chain-related gene A (MICA) with age-at-onset as well as susceptibility to type 1 diabetes. One hundred one Japanese patients and 110 healthy control subjects were studied. The frequency of A4 allele was significantly higher and that of A6 allele was significantly lower in patients than in control subjects. The frequency of A5.1 allele was highest in early-onset patients (23.0%), intermediate in intermediate-onset patients (9.2%) and lowest in late-onset patients (7.7%) (trend chi-squared test, p = 0.0098). A5. 1 allele was strongly associated with HLA-B7 and Cw7, suggesting that MICA*A5.1-B7-Cw7 haplotype contains a gene responsible for age-at-onset. A4 allele was associated with a susceptible haplotype, DR4-DQB1*0401, and A6 allele was associated with a protective haplotype, DR2-DQB1*0601, suggesting that the association of MICA with type 1 diabetes susceptibility may be due to linkage disequilibrium with class II haplotypes. These data suggest that MICA gene is associated with age-at-onset and that a gene (or genes) responsible for age-at-onset of type 1 diabetes is located in the HLA class I region, probably near the region of MICA-B-C.

Association of plasma fibrinogen level and blood pressure with diabetic retinopathy, and renal complications associated with proliferative diabetic retinopathy, in Type 2 diabetes mellitus

Aim To clarify the association of several clinical parameters, including plasma fibrinogen level, with diabetic retinopathy in patients with Type 2 diabetes mellitus (DM).

Hepatocyte nuclear factor-1a gene and non-insulin-dependent diabetes mellitus in the Japanese population

Abstract Recently, hepatocyte nuclear factor-1α (HNF-1α, which is encoded by the TCF1 gene) mutations were reported in a subset of patients with maturity onset diabetes of the young (MODY3). We studied the contribution of TCF1 to genetic susceptibility to common non-insulin-dependent diabetes mellitus (type 2) in Japanese subjects by investigating allelic association with type 2 diabetes use of three markers. We also studied the frequency of the G191D mutation, the only mutation of TCF1 reported so far in late-onset type 2 diabetes. A total of 356 subjects were studied. There were no significant differences in allele frequency of the three markers between patients with type 2 diabetes and control subjects. A G191D mutation was not found in the subjects studied, giving a frequency of less than 0.4% in common type 2 diabetes. The lack of association of type 2 diabetes with three markers in and near TCF1 suggests that mutations in TCF1 derived from a limited number of founders are not a major cause of common type 2 diabetes even in the genetically homogeneous Japanese population. The data also indicate that the G191D mutation in TCF1 plays little, if any, role in susceptibility to common type 2 diabetes in the Japanese.

Molecular scanning of the gene for thioredoxin, an antioxidative and antiapoptotic protein, and genetic susceptibility to type 1 diabetes.

Oxidative stress has been implicated in the destruction of β cells in type 1 diabetes (T1D). Thioredoxin has been shown to protect cells from oxidative stress and apoptosis. In this study, we screened for sequence variants of the human thioredoxin gene (TXN), and studied the association of the variants in persons with T1D in Japanese. The frequency of the A allele of the G/A SNP in the 3′ flanking region was highest in T1D (8.4%), followed by type 2 diabetes (6.8%), and the lowest in the controls (5.9%), suggesting the contribution of TXN polymorphism to susceptibility to T1D.

Polymorphism in gene for islet autoantigen, IA-2, and type 1 diabetes in Japanese subjects.

Autoantibodies against IA-2 have been detected in up to 86% of newly diagnosed patients with type 1 diabetes and appear to identify a subgroup of prediabetic subjects who rapidly progress to type 1 diabetes. We examined the association of IA-2 gene polymorphism with type 1 diabetes in Japanese subjects. A total of 276 Japanese subjects were studied for disease association and, in addition, another 53 patients were studied for association with the autoantibody status to IA-2. A microsatellite marker D2S1753E, located in the intron of the IA-2 gene, was used as a genetic marker in this study. In Japanese, two alleles (161mu and 165mu) were more frequent, and the 163mu allele was less frequent than in Caucasians (p = 0.0001). There was no significant difference in frequencies of alleles between diabetic patients and control subjects. The frequency of IA-2 gene polymorphism was not significantly different between patients stratified by age-at-onset, or between patients with and without susceptible HLA, DRB1*0405, DRB1*0802 and DRB1*0901. There was no significant difference in allele frequency of the IA-2 gene polymorphism between patients with and without autoantibody to IA-2. In conclusion, IA-2 gene polymorphism is not associated with either susceptibility to, or heterogeneity in type 1 diabetes in Japanese subjects.

Less frequent body weight gain in elderly type 2 diabetic patients treated with glimepiride

Background:  The purpose of the present paper was to study the effect of a new sulfonylurea, glimepiride, which has an extra‐pancreatic action that improves insulin resistance, on glycemic control and body weight gain in elderly patients with type 2 diabetes mellitus (DM).