Werner's syndrome (WS) is an inherited disease with clinical symptoms resembling premature aging. Early susceptibility to a number of major age-related diseases is a key feature of this disorder. The gene responsible for WS (known as WRN) was identified by positional cloning. The predicted protein is 1432 amino acids in length and shows significant similarity to DNA helicases. Four mutations in WS patients were identified. Two of the mutations are splice-junction mutations, with the predicted result being the exclusion of exons from the final messenger RNA. One of the these mutations, which results in a frameshift and a predicted truncated protein, was found in the homozygous state in 60 percent of Japanese WS patients examined. The other two mutations are nonsense mutations. The identification of a mutated putative helicase as the gene product of the WS gene suggests that defective DNA metabolism is involved in the complex process of aging in WS patients.

OBJECTIVE -Resistin, secreted from adipocytes, causes insulin resistance in rodents. We previously reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at Ϫ420 increases type 2 diabetes susceptibility by enhancing promoter activity. We report here on the relation between plasma resistin and either SNP Ϫ420 genotype or factors related to insulin resistance. RESEARCH DESIGN AND METHODS-We cross-sectionally analyzed 2,078 community-dwelling Japanese subjects attending a yearly medical checkup. The SNP Ϫ420 genotype was determined by TaqMan analysis. Fasting plasma resistin was measured using an enzyme-linked immunosorbent assay kit.RESULTS -Plasma resistin was associated with the SNP Ϫ420 genotype (P Ͻ 0.0001), which was highest in G/G followed by C/G and C/C. Plasma resistin was higher in elderly individuals, female subjects, nondrinkers, and subjects with high blood pressure (P Ͻ 0.001, 0.003, Ͻ0.001, and 0.001, respectively). Simple regression analysis revealed that age, female sex, homeostasis model assessment of insulin resistance (HOMA-IR) index, systolic blood pressure, low HDL cholesterol, and high-sensitivity C-reactive protein (hs-CRP) were positively correlated with plasma resistin (P Ͻ 0.001, 0.003, Ͻ0.001, 0.004, Ͻ0.001, and 0.003, respectively). Multiple regression analysis adjusted for age, sex, and BMI revealed that plasma resistin was an independent factor for HOMA-IR, low HDL cholesterol, and hs-CRP (P ϭ 0.001, Ͻ0.001, and 0.006, respectively).CONCLUSIONS -Plasma resistin was associated with SNP Ϫ420 and was correlated with insulin resistance, low serum HDL cholesterol, and high hs-CRP in the Japanese general population.

Recent observations have suggested that the pathological mutations in human P-450(C21) deficiency are generated through gene conversion-like events between the functional gene [P-450(21)B] and the pseudogene [P-450(C21)A]. To address this point more extensively, we investigated the effects of the base changes in the A pseudogene on the P-450(21) activity by using the COS cell expression system. In addition to the defective mutations found previously in the pseudogene, four single base changes with amino acid substitutions of Pro(30), Ile(172), Val(282), or Arg(356) were further identified as causing complete [Arg(356)] or partial [Pro(30), Ile(172), and Val(282)] inactivation of P-450(C21). Blot hybridization analysis of patient DNAs using oligonucleotide probes specific for these mutations revealed that the splicing mutation in the 2nd intron was distributed most frequently in both simple-virilizing and salt-wasting forms. The mutation Ile(172) seemed to be frequent in patients with the less severe simple-virilizing form, whereas the mutation Arg(356), together with other most serious mutations reported previously, was preferentially associated with salt-wasting, the most severe form of the disease. In combination with the present results of the effects of various mutations on the P-50(C21) activity, a survey of the distribution of the various mutations in the patient genomes so far reported suggests that the heterogeneous clinical symptoms of this genetic disease are somehow related to the degree of attenuation of the activities of the mutated gene products.

Abstract-Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced by endothelial and smooth muscle cells.Many lines of biological evidence suggest that the ET-1 gene is a candidate gene for hypertension. Moreover, recent association studies suggested that a G/T polymorphism with an amino acid substitution (Lys/Asn) at codon 198 in exon 5 of the ET-1 gene interacts with body mass index (BMI) in association with blood pressure. They suggested that T carriers are more sensitive to weight gain than GG homozygotes in association with blood pressure. However, association studies are often irreproducible, and the first study often suggests a stronger genetic effect than is found by subsequent studies. We therefore assessed the interaction in 2 large Japanese populations. The present study showed a nonsignificant but similar trend to the results of previous reports. Moreover, in line with previous reports, this study revealed a significant interaction between the ET-1 K198N (G/T) polymorphism and BMI in association with hypertension in our populations (Pϭ0.027). The interaction was significant, even after adjustment for gender and age (Pϭ0.045) and for all confounding factors (Pϭ0.044). T carriers were more sensitive to weight gain than GG homozygotes in association with hypertension. Considering the combined impact of obesity and hypertension on the development of cardiovascular and cerebrovascular disorders, T allele carriers might represent elective targets for therapy to lower their body weight. Key Words: endothelin Ⅲ hypertension, essential Ⅲ genetics Ⅲ polymorphism Ⅲ body mass index E ndothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced by vascular endothelial cells. 1 Some patients with moderate-to-severe essential hypertension, similar to some experimental rat models with severe blood pressure elevation, exhibit enhanced endothelial expression of the ET-1 gene. 2 Plasma ET-1 concentration is elevated in hypertensive patients. 3-6 An endothelin-receptor antagonist significantly lowered blood pressure in patients with essential hypertension. 7 Given these lines of biological evidence, the ET-1 gene is a candidate responsible for hypertension.Hypertension is a common, complex phenotype and has been intensively studied to identify susceptibility loci in humans. Nonetheless, there is no known genotypic polymorphism consistently associated with hypertension in humans, thus far. Moreover, albeit that the development of hypertension is considered to be due at least partly to gene-gene and gene-environmental interactions, fewer interaction analyses have been conducted than simple association analyses. In this regard, the ET-1 gene is an attractive candidate because, in addition to its biological function, this gene has been shown to interact with body mass index (BMI) in association with blood pressure in 3 large populations. 8,9 However, association studies are often irreproducible, and the first study often suggests a stronger genetic effect than is found by subsequent studies. 10 We therefore a...