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 glucose-tolerant 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. RESULTS: The 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 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.
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 glucose-tolerant 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 diabetespatients. RESULTS: The WFS1rs734312 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 WFS1rs734312 on insulin release 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 WFS1rs734312 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.
Authors: H Inoue; Y Tanizawa; J Wasson; P Behn; K Kalidas; E Bernal-Mizrachi; M Mueckler; H Marshall; H Donis-Keller; P Crock; D Rogers; M Mikuni; H Kumashiro; K Higashi; G Sobue; Y Oka; M A Permutt Journal: Nat Genet Date: 1998-10 Impact factor: 38.330
Authors: Jayne A L Minton; Andrew T Hattersley; Katharine Owen; Mark I McCarthy; Mark Walker; Farida Latif; Timothy Barrett; Timothy M Frayling Journal: Diabetes Date: 2002-04 Impact factor: 9.461
Authors: A C Riggs; E Bernal-Mizrachi; M Ohsugi; J Wasson; S Fatrai; C Welling; J Murray; R E Schmidt; P L Herrera; M A Permutt Journal: Diabetologia Date: 2005-10-08 Impact factor: 10.122
Authors: Richa Saxena; Benjamin F Voight; Valeriya Lyssenko; Noël P Burtt; Paul I W de Bakker; Hong Chen; Jeffrey J Roix; Sekar Kathiresan; Joel N Hirschhorn; Mark J Daly; Thomas E Hughes; Leif Groop; David Altshuler; Peter Almgren; Jose C Florez; Joanne Meyer; Kristin Ardlie; Kristina Bengtsson Boström; Bo Isomaa; Guillaume Lettre; Ulf Lindblad; Helen N Lyon; Olle Melander; Christopher Newton-Cheh; Peter Nilsson; Marju Orho-Melander; Lennart Råstam; Elizabeth K Speliotes; Marja-Riitta Taskinen; Tiinamaija Tuomi; Candace Guiducci; Anna Berglund; Joyce Carlson; Lauren Gianniny; Rachel Hackett; Liselotte Hall; Johan Holmkvist; Esa Laurila; Marketa Sjögren; Maria Sterner; Aarti Surti; Margareta Svensson; Malin Svensson; Ryan Tewhey; Brendan Blumenstiel; Melissa Parkin; Matthew Defelice; Rachel Barry; Wendy Brodeur; Jody Camarata; Nancy Chia; Mary Fava; John Gibbons; Bob Handsaker; Claire Healy; Kieu Nguyen; Casey Gates; Carrie Sougnez; Diane Gage; Marcia Nizzari; Stacey B Gabriel; Gung-Wei Chirn; Qicheng Ma; Hemang Parikh; Delwood Richardson; Darrell Ricke; Shaun Purcell Journal: Science Date: 2007-04-26 Impact factor: 47.728
Authors: T M Strom; K Hörtnagel; S Hofmann; F Gekeler; C Scharfe; W Rabl; K D Gerbitz; T Meitinger Journal: Hum Mol Genet Date: 1998-12 Impact factor: 6.150
Authors: P W Franks; O Rolandsson; S L Debenham; K A Fawcett; F Payne; C Dina; P Froguel; K L Mohlke; C Willer; T Olsson; N J Wareham; G Hallmans; I Barroso; M S Sandhu Journal: Diabetologia Date: 2007-11-27 Impact factor: 10.122
Authors: N Cheurfa; G M Brenner; A F Reis; D Dubois-Laforgue; R Roussel; J Tichet; O Lantieri; B Balkau; F Fumeron; J Timsit; M Marre; G Velho Journal: Diabetologia Date: 2010-12-03 Impact factor: 10.122
Authors: Dimitry A Chistiakov; Dmitry S Khodyrev; Svetlana A Smetanina; Larisa N Bel'chikova; Lyudmila A Suplotova; Valery V Nosikov Journal: Rev Diabet Stud Date: 2011-02-10
Authors: T Sparsø; N Grarup; C Andreasen; A Albrechtsen; J Holmkvist; G Andersen; T Jørgensen; K Borch-Johnsen; A Sandbaek; T Lauritzen; S Madsbad; T Hansen; O Pedersen Journal: Diabetologia Date: 2009-04-29 Impact factor: 10.122
Authors: Annemarie M Simonis-Bik; Giel Nijpels; Timon W van Haeften; Jeanine J Houwing-Duistermaat; Dorret I Boomsma; Erwin Reiling; Els C van Hove; Michaela Diamant; Mark H H Kramer; Robert J Heine; J Antonie Maassen; P Eline Slagboom; Gonneke Willemsen; Jacqueline M Dekker; Elisabeth M Eekhoff; Eco J de Geus; Leen M 't Hart Journal: Diabetes Date: 2009-10-15 Impact factor: 9.461
Authors: Alena Stancáková; Teemu Kuulasmaa; Jussi Paananen; Anne U Jackson; Lori L Bonnycastle; Francis S Collins; Michael Boehnke; Johanna Kuusisto; Markku Laakso Journal: Diabetes Date: 2009-06-05 Impact factor: 9.461