title: Phenotypic and molecular evaluation of a chromosome 1q region with linkage and association to type 2 diabetes in humans.
abstract: 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.
  
  
  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.affiliation: Department of Internal Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Hays
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Das
authors.forename: Rebekah L
authors.initials: RL
authors.lastname: Craig
authors.forename: Winston S
authors.initials: WS
authors.lastname: Chu
authors.forename: Neeraj
authors.initials: N
authors.lastname: Sharma
authors.forename: Steven C
authors.initials: SC
authors.lastname: Elbein
mesh_terms: D000328:Adult; D044383:Black People / Q000235:genetics; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011770:Pyruvate Kinase / Q000235:genetics; D017384:Sequence Deletion; D044465:White People / Q000235:genetics; D055815:Young Adult; D001741:Black or African American
chemical_list: D011770:Pyruvate Kinase