Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet

UK Medical Research Council (MRC) Epidemiology Unit, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
Nature Genetics (Impact Factor: 29.35). 09/2007; 39(8):951-3. DOI: 10.1038/ng2067
Source: PubMed


We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.

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Available from: Colin N A Palmer, Sep 16, 2014
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    • "The E23K variant in this gene demonstrated a robust association with T2D using the candidate gene approach [9]. WFS1 and HNF1B were also uncovered as established genes associated with T2D [11, 12]. WFS1 encodes wolframin, a membrane glycoprotein that maintains calcium homeostasis of the endoplasmic reticulum. "
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    ABSTRACT: With rapidly increasing prevalence, diabetes has become one of the major causes of mortality worldwide. According to the latest studies, genetic information makes substantial contributions towards the prediction of diabetes risk and individualized antidiabetic treatment. To date, approximately 70 susceptibility genes have been identified as being associated with type 2 diabetes (T2D) at a genome-wide significant level (P < 5 × 10(-8)). However, all the genetic loci identified so far account for only about 10% of the overall heritability of T2D. In addition, how these novel susceptibility loci correlate with the pathophysiology of the disease remains largely unknown. This review covers the major genetic studies on the risk of T2D based on ethnicity and briefly discusses the potential mechanisms and clinical utility of the genetic information underlying T2D.
    BioMed Research International 04/2014; 2014:926713. DOI:10.1155/2014/926713 · 1.58 Impact Factor
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    • "With the high-throughput genotyping technologies, genome-wide association studies (GWAS) not only confirmed the candidate genes such as PPARG [5], KCNJ11 [6], TCF7L2 [7] and WFS1 [8], but also identified more than 70 novel loci for T2D risk [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. The majority of these variants conferred T2D risk through pancreatic beta-cell dysfunction [17], [21], [22], while only a few like PPARG, FTO and IRS1 affected fat metabolism [12], [17], [22]. "
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    ABSTRACT: Recent genome-wide association studies (GWAS) identified more than 70 novel loci for type 2 diabetes (T2D), some of which have been widely replicated in Asian populations. In this study, we investigated their individual and combined effects on T2D in a Chinese population. We selected 14 single nucleotide polymorphisms (SNPs) in T2D genes relating to beta-cell function validated in Asian populations and genotyped them in 5882 Chinese T2D patients and 2569 healthy controls. A combined genetic score (CGS) was calculated by summing up the number of risk alleles or weighted by the effect size for each SNP under an additive genetic model. We tested for associations by either logistic or linear regression analysis for T2D and quantitative traits, respectively. The contribution of the CGS for predicting T2D risk was evaluated by receiver operating characteristic (ROC) analysis and net reclassification improvement (NRI). We observed consistent and significant associations of IGF2BP2, WFS1, CDKAL1, SLC30A8, CDKN2A/B, HHEX, TCF7L2 and KCNQ1 (8.5×10(-18)<P<8.5×10(-3)), as well as nominal associations of NOTCH2, JAZF1, KCNJ11 and HNF1B (0.05<P<0.1) with T2D risk, which yielded odds ratios ranging from 1.07 to 2.09. The 8 significant SNPs exhibited joint effect on increasing T2D risk, fasting plasma glucose and use of insulin therapy as well as reducing HOMA-β, BMI, waist circumference and younger age of diagnosis of T2D. The addition of CGS marginally increased AUC (2%) but significantly improved the predictive ability on T2D risk by 11.2% and 11.3% for unweighted and weighted CGS, respectively using the NRI approach (P<0.001). In a Chinese population, the use of a CGS of 8 SNPs modestly but significantly improved its discriminative ability to predict T2D above and beyond that attributed to clinical risk factors (sex, age and BMI).
    PLoS ONE 12/2013; 8(12):e83093. DOI:10.1371/journal.pone.0083093 · 3.23 Impact Factor
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    • "The WFS1 gene is one of the genes repeatedly shown to be associated with Type 2 diabetes [29-32], indicating that WFS may be an unusual example of a Type 2-like diabetes mellitus of monogenic cause. This characteristic may present an opportunity for testing diabetes therapies in a monogenic setting or further delineating the mechanism of disease in Type 2 diabetes. "
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    ABSTRACT: Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. Eighteen subjects (ages 5.9--25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 +/- 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 +/- 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression.
    Orphanet Journal of Rare Diseases 04/2013; 8(1):64. DOI:10.1186/1750-1172-8-64 · 3.36 Impact Factor
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