Liver Pyruvate Kinase Polymorphisms Are Associated With Type 2 Diabetes in Northern European Caucasians

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 9; pp. 2861 - 2865
• Main Authors: Wang, Hua, Chu, Winston, Das, Swapan K., Ren, Qianfang, Hasstedt, Sandra J., Elbein, Steven C.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2002
• Subjects: Aged; Alleles; Biological and medical sciences; Chromosomes; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; DNA Transposable Elements; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Europe; Female; Gene Deletion; Gene Frequency; Gene loci; Glucose; Humans; Kinases; Laboratories; Liver; Liver - enzymology; Male; Medical sciences; Middle Aged; Mutation; Polymorphism; Polymorphism, Genetic; Pyruvate Kinase - genetics; Reference Values; Small intestine; Trinucleotide Repeats; White people; White People - genetics; Europe; Endocrinopathy; Human; Ethnic origin; Pyruvate kinase; Digestive system; Enzyme; Transferases; Liver; Caucasoid; Non insulin dependent diabetes; Polymorphism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.9.2861

Liver Pyruvate Kinase Polymorphisms Are Associated With Type 2 Diabetes in Northern European Caucasians Hua Wang 1 , Winston Chu 1 , Swapan K. Das 1 , Qianfang Ren 1 , Sandra J. Hasstedt 2 and Steven C. Elbein 1 1 Division of Endocrinology, Department of Medicine, Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Salt Lake City, Utah 2 Department of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah Abstract Pyruvate kinase is a key glycolytic enzyme. Isoforms that are expressed in the red cell, liver, pancreatic β-cells, small intestine, and proximal renal tubule are encoded by the 12 exons of the PKLR gene, which maps to chromosome 1q23. We hypothesized that common variants of the PKLR gene could account for the linkage of diabetes to this region. We screened the promoter regions, exons and surrounding introns, and the 3′ untranslated region for mutations. We identified five single-nucleotide polymorphisms (SNPs), and only one (V506I, exon 11) altered the coding sequence. We tested the five SNPs, a poly-T insertion-deletion polymorphism, and an ATT triplet repeat in 131 unrelated diabetic patients and 118 nondiabetic control subjects. The V506I variant was rare and not associated with type 2 diabetes. The four SNPs and the insertion-deletion polymorphism were associated with diabetes, with a 10% difference between individuals with diabetes and nondiabetic individuals ( P = 0.001–0.011, relative risk for minor allele 1.85). The same trend was found for the ATT repeat ( P = 0.029). Common variants in the PKLR are associated with increased risk of type 2 diabetes, but because of strong linkage disequilibrium between variants, the actual susceptibility allele may be in a different gene. Footnotes Address correspondence and reprint requests to Steven C. Elbein, Professor of Medicine, Central Arkansas Veterans Healthcare System, Endocrinology 111J-1/LR, 4300 West 7th St., Little Rock, AR 72205. E-mail: elbeinstevenc{at}uams.edu . Received for publication 9 April 2002 and accepted in revised form 10 June 2002. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the young; SNP, single-nucleotide polymorphism; SSCP, single-strand conformation polymorphism. DIABETES