title: PD-L1 gene polymorphisms and low serum level of PD-L1 protein are associated to type 1 diabetes in Chile.
abstract: BACKGROUND
  Type 1 diabetes (T1D) has a complex etiology in which genetic and environmental factors are involved, whose interactions have not yet been completely clarified. In this context, the role in PD-1 pathway and its ligands 1 and 2 (PD-L1 and PD-L2) have been proposed as candidates in several autoimmune diseases. The aim of this work was to determine the allele and haplotype frequency of six gene polymorphisms of PD-ligands (PD-L1 and PD-L2) in Chilean T1D patients and their effect on serum levels of PD-L1 and autoantibody profile (GAD65 and IA2).
  
  
  METHODS
  This study cohort comprised 205 T1D patients and 205 normal children. We performed genotypic analysis of PD-L1 and PD-L2 genes by TaqMan method. Determination of anti-GAD65 and anti-IA-2 autoantibodies was performed by ELISA. The PD-L1 serum levels were measured.
  
  
  RESULTS
  The allelic distribution of PD-L1 variants (rs2297137 and rs4143815) showed differences between T1D patients and controls (p = 0.035 and p = 0.022, respectively). No differences were detected among the PD-L2 polymorphisms, and only the rs16923189 showed genetic variation. T1D patients showed decreased serum levels of PD-L1 compared to controls: 1.42 [0.23-7.45] ng/mL versus 3.35 [0.49-5.89] ng/mL (p < 0.025). In addition, the CGG haplotype in PD-L1 associated with T1D (constructed from rs822342, rs2297137 and rs4143815 polymorphisms) showed an OR = 1.44 [1.08 to 1.93]. Finally, no association of these genetic variants was observed with serum concentrations of PD ligands or auto-antibody profile, although a correlation between PD-L1 ligand serum concentration and the age at disease onset was detected.
  
  
  CONCLUSIONS
  Two polymorphism of PD-L1 are presented in different allelic variants between T1D and healthy subjects, also PDL-1 serum levels are significantly lowered in diabetics patients. Moreover, the age of onset of the disease determine differences between serum ligand levels in diabetics, being lower in younger. These results points to a possible establishment of PDL-1 as a genetic and biochemical marker for T1D onset, at least in Chilean population.
authors.affiliation: Laboratorio de Genómica Nutricional, Departamento de Nutrición, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Pizarro
authors.forename: Diego F
authors.initials: DF
authors.lastname: García-Díaz
authors.forename: Ethel
authors.initials: E
authors.lastname: Codner
authors.forename: Francisca
authors.initials: F
authors.lastname: Salas-Pérez
authors.forename: Elena
authors.initials: E
authors.lastname: Carrasco
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Bravo
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000483:Alleles; D015551:Autoimmunity; D060890:B7-H1 Antigen / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002677:Chile / Q000453:epidemiology; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein
keywords: PD-1 ligand polymorphisms; PD-L1; PD-L2; type 1 diabetes