Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population

作者: Laeya Abdoli Najmi , Ingvild Aukrust , Jason Flannick , Janne Molnes , Noel Burtt

DOI: 10.2337/DB16-0460

关键词:

摘要: Variants in HNF1A encoding hepatocyte nuclear factor 1α (HNF-1A) are associated with maturity-onset diabetes of the young form 3 (MODY 3) and type 2 diabetes. We investigated whether functional classification rare coding variants can inform models risk prediction general population by analyzing effect 27 identified well-phenotyped populations (n = 4,115). Bioinformatics tools classified 11 as likely pathogenic showed no association (combined minor allele frequency [MAF] 0.22%; odds ratio [OR] 2.02; 95% CI 0.73-5.60; P 0.18). However, a different set that reduced HNF-1A transcriptional activity to <60% normal (wild-type) was strongly MAF OR 5.04; 1.99-12.80; 0.0007). Our investigations indicate 0.44% carry result substantially increased for developing These results suggest characterization within MODY genes may overcome limitations bioinformatics purposes presymptomatic population.

参考文章(80)
Maria Galán, Carmen-Maria García-Herrero, Sharona Azriel, Manuel Gargallo, Maria Durán, Juan-Jose Gorgojo, Victor-Manuel Andía, Maria-Angeles Navas, Differential effects of HNF-1α mutations associated with familial young-onset diabetes on target gene regulation. Molecular Medicine. ,vol. 17, pp. 256- 265 ,(2011) , 10.2119/MOLMED.2010.00097
Maciej Małecki, Jan Skupień, Problems in differential diagnosis of diabetes types. Polskie Archiwum Medycyny Wewnetrznej-polish Archives of Internal Medicine. ,vol. 118, pp. 435- 440 ,(2008) , 10.20452/PAMW.444
Tom Alber, Robert B. Rose, J. Henri Bayle, James A. Endrizzi, Jeff D. Cronk, Gerald R. Crabtree, Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha. Nature Structural & Molecular Biology. ,vol. 7, pp. 744- 748 ,(2000) , 10.1038/78966
Caroline Poitou, Hélène Francois, Christine Bellanne-Chantelot, Christian Noel, Antoine Jacquet, Séverine Clauin, Séverine Beaudreuil, Hani Damieri, Hadia Hebibi, Yacine Hammoudi, Gérard Benoit, Bernard Charpentier, Antoine Durrbach, Maturity onset diabetes of the young: clinical characteristics and outcome after kidney and pancreas transplantation in MODY3 and RCAD patients: a single center experience Transplant International. ,vol. 25, pp. 564- 572 ,(2012) , 10.1111/J.1432-2277.2012.01458.X
Roopa Kanakatti Shankar, Sian Ellard, Debra Standiford, Catherine Pihoker, Lisa K Gilliam, Andrew Hattersley, Lawrence M Dolan, Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes Pediatric Diabetes. ,vol. 14, pp. 535- 538 ,(2013) , 10.1111/PEDI.12018
S. A. Urhammer, S. K. Rasmussen, P. J. Kaisaki, N. Oda, K. Yamagata, A. M. Møller, M. Fridberg, L. Hansen, T. Hansen, G. I. Bell, O. Pedersen, Genetic variation in the hepatocyte nuclear factor-1a gene in Danish Caucasians with late-onset NIDDM Diabetologia. ,vol. 40, pp. 473- 475 ,(1997) , 10.1007/S001250050703
Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Patrick Sulem, Hannes Helgason, Niels Grarup, Asgeir Sigurdsson, Hafdis T Helgadottir, Hrefna Johannsdottir, Olafur T Magnusson, Sigurjon A Gudjonsson, Johanne M Justesen, Marie N Harder, Marit E Jørgensen, Cramer Christensen, Ivan Brandslund, Annelli Sandbæk, Torsten Lauritzen, Henrik Vestergaard, Allan Linneberg, Torben Jørgensen, Torben Hansen, Maryam S Daneshpour, Mohammad-Sadegh Fallah, Astradur B Hreidarsson, Gunnar Sigurdsson, Fereidoun Azizi, Rafn Benediktsson, Gisli Masson, Agnar Helgason, Augustine Kong, Daniel F Gudbjartsson, Oluf Pedersen, Unnur Thorsteinsdottir, Kari Stefansson, Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes Nature Genetics. ,vol. 46, pp. 294- 298 ,(2014) , 10.1038/NG.2882
Ph. Froguel, M. Vaxillaire, F. Sun, G. Velho, H. Zouali, M. O. Butel, S. Lesage, N. Vionnet, K. Clément, F. Fougerousse, Y. Tanizawa, J. Weissenbach, J. S. Beckmann, G. M. Lathrop, Ph. Passa, M. A. Permutt, D. Cohen, Close Linkage of Glucokinase Locus on Chromosome 7p to Early-Onset Non-Insulin-Dependent Diabetes Mellitus Nature. ,vol. 356, pp. 162- 164 ,(1992) , 10.1038/356162A0
Prateek Kumar, Steven Henikoff, Pauline C Ng, Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature Protocols. ,vol. 4, pp. 1073- 1081 ,(2009) , 10.1038/NPROT.2009.86
P. S. Behn, J. Wasson, S. Chayen, I. Smolovitch, J. Thomas, B. Glaser, M. A. Permutt, Hepatocyte nuclear factor 1alpha coding mutations are an uncommon contributor to early-onset type 2 diabetes in Ashkenazi Jews. Diabetes. ,vol. 47, pp. 967- 969 ,(1998) , 10.2337/DIABETES.47.6.967