OBJECTIVE: Linkage to type 2 diabetes (T2D) is well replicated on chromosome 1q21-q23. Within this region, T2D was associated with common single nucleotide polymorphisms that marked an extended linkage disequilibrium block, including the liver pyruvate kinase gene (PKLR), in several European-derived populations. In this study we sought to determine the molecular basis for the association and the phenotypic consequences of the risk haplotype. RESEARCH DESIGN AND METHODS: Genes surrounding PKLR were resequenced in European-American and African-American cases and controls, and association with T2D was tested. Copy number variants (CNVs) were tested for four regions with real-time PCR. Expression of genes in the region was tested in adipose and muscle from nondiabetic subjects with each genotype. Insulin secretion, insulin sensitivity, and hepatic glucose production were tested in nondiabetic individuals with each haplotype combination. RESULTS: No coding variant in the region was associated with T2D. CNVs were rare and not associated with T2D. PKLR was not expressed in available tissues, but expression of genes HCN3, CLK2, SCAMP3, and FDPS was not associated with haplotype combinations in adipose or muscle. Haplotype combinations were not associated with insulin secretion or peripheral insulin sensitivity, but homozygous carriers of the risk haplotype had increased hepatic glucose production during hyperinsulinemia. CONCLUSIONS: Noncoding variants in the PKLR region likely alter gene expression of one or more genes. Our extensive physiological and molecular studies suggest increased hepatic glucose production and reduced hepatic insulin sensitivity, thus pointing to PKLR itself as the most likely candidate gene in this population.
OBJECTIVE: Linkage to type 2 diabetes (T2D) is well replicated on chromosome 1q21-q23. Within this region, T2D was associated with common single nucleotide polymorphisms that marked an extended linkage disequilibrium block, including the liver pyruvate kinase gene (PKLR), in several European-derived populations. In this study we sought to determine the molecular basis for the association and the phenotypic consequences of the risk haplotype. RESEARCH DESIGN AND METHODS: Genes surrounding PKLR were resequenced in European-American and African-American cases and controls, and association with T2D was tested. Copy number variants (CNVs) were tested for four regions with real-time PCR. Expression of genes in the region was tested in adipose and muscle from nondiabetic subjects with each genotype. Insulin secretion, insulin sensitivity, and hepatic glucose production were tested in nondiabetic individuals with each haplotype combination. RESULTS: No coding variant in the region was associated with T2D. CNVs were rare and not associated with T2D. PKLR was not expressed in available tissues, but expression of genes HCN3, CLK2, SCAMP3, and FDPS was not associated with haplotype combinations in adipose or muscle. Haplotype combinations were not associated with insulin secretion or peripheral insulin sensitivity, but homozygous carriers of the risk haplotype had increased hepatic glucose production during hyperinsulinemia. CONCLUSIONS: Noncoding variants in the PKLR region likely alter gene expression of one or more genes. Our extensive physiological and molecular studies suggest increased hepatic glucose production and reduced hepatic insulin sensitivity, thus pointing to PKLR itself as the most likely candidate gene in this population.
Authors: Nicholette D Palmer; Jennifer L Bento; Josyf C Mychaleckyj; Carl D Langefeld; Joel K Campbell; Jill M Norris; Stephen M Haffner; Richard N Bergman; Donald W Bowden Journal: Diabetes Date: 2004-11 Impact factor: 9.461
Authors: Eleftheria Zeggini; Laura J Scott; Richa Saxena; Benjamin F Voight; Jonathan L Marchini; Tianle Hu; Paul I W de Bakker; Gonçalo R Abecasis; Peter Almgren; Gitte Andersen; Kristin Ardlie; Kristina Bengtsson Boström; Richard N Bergman; Lori L Bonnycastle; Knut Borch-Johnsen; Noël P Burtt; Hong Chen; Peter S Chines; Mark J Daly; Parimal Deodhar; Chia-Jen Ding; Alex S F Doney; William L Duren; Katherine S Elliott; Michael R Erdos; Timothy M Frayling; Rachel M Freathy; Lauren Gianniny; Harald Grallert; Niels Grarup; Christopher J Groves; Candace Guiducci; Torben Hansen; Christian Herder; Graham A Hitman; Thomas E Hughes; Bo Isomaa; Anne U Jackson; Torben Jørgensen; Augustine Kong; Kari Kubalanza; Finny G Kuruvilla; Johanna Kuusisto; Claudia Langenberg; Hana Lango; Torsten Lauritzen; Yun Li; Cecilia M Lindgren; Valeriya Lyssenko; Amanda F Marvelle; Christa Meisinger; Kristian Midthjell; Karen L Mohlke; Mario A Morken; Andrew D Morris; Narisu Narisu; Peter Nilsson; Katharine R Owen; Colin N A Palmer; Felicity Payne; John R B Perry; Elin Pettersen; Carl Platou; Inga Prokopenko; Lu Qi; Li Qin; Nigel W Rayner; Matthew Rees; Jeffrey J Roix; Anelli Sandbaek; Beverley Shields; Marketa Sjögren; Valgerdur Steinthorsdottir; Heather M Stringham; Amy J Swift; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Nicholas J Timpson; Tiinamaija Tuomi; Jaakko Tuomilehto; Mark Walker; Richard M Watanabe; Michael N Weedon; Cristen J Willer; Thomas Illig; Kristian Hveem; Frank B Hu; Markku Laakso; Kari Stefansson; Oluf Pedersen; Nicholas J Wareham; Inês Barroso; Andrew T Hattersley; Francis S Collins; Leif Groop; Mark I McCarthy; Michael Boehnke; David Altshuler Journal: Nat Genet Date: 2008-03-30 Impact factor: 38.330