Missense Variations of the Gene Responsible for Wolfram Syndrome (WFS1/wolframin) in Japanese: Possible Contribution of the Arg456His Mutation to Type 1 Diabetes as a Nonautoimmune Genetic Basis

Awata, Takuya; Inoue, Kazuaki; Kurihara, Susumu; Ohkubo, Tomoko; Inoue, Ituro; Abe, Takahiro; Takino, Hirofumi; Kanazawa, Yasunori; Katayama, Shigehiro

doi:10.1006/bbrc.2000.2169

Cited by 47 publications

(41 citation statements)

References 19 publications

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“…In this animal model, beta cell death occurred by an accelerated process of apoptosis; similarly, increased levels of markers reflecting ER stress were also demonstrated [7][8][9]. In line with the outcome of studies in mice, previous and statistically undersized human studies have indicated that variation in WFS1 may be associated with type 1 diabetes mellitus [10], type 2 diabetes mellitus [11] and a combination of diabetes mellitus and deafness [12,13]. Moreover, two patients with the Wolfram syndrome were reported to be without insulin-producing beta cells [14].…”

supporting

confidence: 78%

Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

et al. 2008

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Aim/hypothesis Recently, variants in WFS1 have been shown to be associated with type 2 diabetes. We aimed to examine metabolic risk phenotypes of WFS1 variants in glucosetolerant people and in individuals with abnormal glucose regulation. Methods The type 2 diabetes-associated WFS1 variant rs734312 (His611Arg) was studied in the population-based Inter99 cohort involving 4,568 glucose-tolerant individuals and 1,471 individuals with treatment-naive abnormal glucose regulation, and in an additional 3,733 treated type 2 diabetes patients. ResultsThe WFS1 rs734312 showed a borderline significant association with type 2 diabetes with directions and relative risks consistent with previous reports. In individuals with abnormal glucose regulation, the diabetogenic risk A allele of rs734312 was associated in an allele-dependent manner with a decrease in insulinogenic index (p=0.025) and decreased 30-min serum insulin levels (p=0.047) after an oral glucose load. In glucose-tolerant individuals the same allele was associated with increased fasting serum insulin concentration (p=0.019) and homeostasis model assessment of insulin resistance (HOMA-IR; p=0.026). To study the complex interaction of WFS1 rs734312 on insulin release Diabetologia (2008) and insulin resistance we introduced Hotelling's T 2 test. Assuming bivariate normal distribution, we constructed standard error ellipses of the insulinogenic index and HOMA-IR when stratified according to glucose tolerance status around the means of each WFS1 rs734312 genotype level. The interaction term between individuals with normal glucose tolerance and abnormal glucose regulation on the insulinogenic index and HOMA-IR was significantly associated with the traits (p=0.0017). Conclusions/interpretation Type 2 diabetes-associated risk alleles of WFS1 are associated with estimates of a decreased pancreatic beta cell function among middle-aged individuals with abnormal glucose regulation.

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supporting

confidence: 78%

Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

et al. 2008

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“…Previous works described the polymorphisms R456H, H611R and I720V in WFS1 gene, related with non-autoimmune type 1 diabetes mellitus. 12 We have observed significant statistical differences in the allelic and genotypic distribution in H611R change in patients with type 2 diabetes mellitus, when compared with the control group. This suggest a possible contribution of this variant with diabetes mellitus.…”

Section: Discussionmentioning

confidence: 70%

“…By studying the frequencies of alleles and genotypes of the WFS1 polymorphisms in the four groups of individuals analysed, we have found significant statistical differences in the distribution of substitutions 1185T4C, 1832A4G, previously related with type 1 diabetes mellitus, 12 and in the distribution of the changes 2433G4A and 2565A4G, in the diabetic groups (DM and/or DM+F) ( Table 1). Previous works described the polymorphisms R456H, H611R and I720V in WFS1 gene, related with non-autoimmune type 1 diabetes mellitus.…”

Section: Discussionmentioning

confidence: 87%

WFS1 mutations in Spanish patients with diabetes mellitus and deafness

2002

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Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterised by early onset diabetes mellitus and progressive optic atrophy, as well as other clinical features such as deafness, diabetes insipida, renal tract abnormalities and diverse psychiatric illnesses. A gene responsible for WS was identified in 4p16.1 (WFS1). It encodes a putative 890 amino acid transmembrane protein expressed in a wide spectrum of tissues. Recently, a new locus for WS has been located on 4q22-24, providing additional evidence for the genetic heterogeneity of this syndrome. We have studied the presence of WFS1 variants in three groups of individuals: patients with diabetes mellitus, patients with deafness and patients with both conditions. A fourth group of healthy subjects was used as control. We have identified a total of 18 nucleotide changes in the WFS1 gene: three mutations and 15 polymorphisms. Six of these changes were previously undescribed. Four of the 15 polymorphisms studied among the patients group present statistical differences in the allelic and genotypic distribution when comparing affected vs control groups.

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“…5,90 For example, it has been shown in a Japanese study that the WFS1 allele variants R456H, H611R and I720V significantly correlate with type 1 diabetes. 91 There is also a link between Wolfram syndrome and type 2 diabetes. In type 2 diabetes, peripheral resistance to insulin action leads to hyperinsulinemia.…”

Section: Type 1 and Type 2 Diabetes And The Er Stress Connectionmentioning

confidence: 99%