title: T-cell receptor repertoire variation may be associated with type 2 diabetes mellitus in humans.
abstract: BACKGROUND
  Recent work in Pima Indians, a population with high rates of obesity and type 2 diabetes mellitus (T2DM), demonstrated that human leukocyte antigen haplotype DRB1*02 carriers have an increased acute insulin response and decreased risk for the development of T2DM, implicating loss of self-tolerance in the pathogenesis of T2DM. Advances in genomic sequencing have made T-cell receptor repertoire analysis a practical mode of investigation.
  
  
  METHODS
  High-throughput sequencing of T-cell receptor complementarity-determining region 3 was carried out in male Pima Indians with normal glucose regulation (n = 11; age = 31 ± 8 years; %fat = 30.2 ± 8.7%) and the protective DRB1*02 haplotype versus those with T2DM without DRB1*02 (n = 7; age = 34 ± 8 years; %fat = 31.2 ± 4.7%). Findings were partially replicated in another cohort by assessing the predictive ability of T-cell receptor variation on risk of T2DM in Pima Indian men (n = 27; age = 28.9 ± 7.1 years; %fat = 28.8 ± 7.1%) and women (n = 20; age = 29 ± 7.0 years; %fat = 37.1 ± 6.8%) with baseline normal glucose regulation but without the protective haplotype who were invited to follow-up examinations as frequently as every 2 years where diabetes status was assessed by a 75-g oral glucose tolerance test. Of these subjects, 13 developed diabetes.
  
  
  RESULTS
  T-cell receptor complementarity-determining region 3 length was shorter in those with T2DM, and a one-nucleotide decrease in complementarity-determining region 3 length was associated with a nearly threefold increase in risk for future diabetes. The frequency of one variable gene, TRBV7-8, was higher in those with T2DM. A 1% increase in TRBV7-8 frequency was associated with a greater than threefold increase in diabetes risk.
  
  
  CONCLUSIONS
  These results indicate that T-cell autoimmunity may be an important component in progression to T2DM in Pima Indians.
authors.affiliation: Obesity and Diabetes Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Frankl
authors.affiliation: Obesity and Diabetes Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA.
authors.forename: Marie S
authors.initials: MS
authors.lastname: Thearle
authors.affiliation: Adaptive Biotechnologies, Seattle, WA, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Desmarais
authors.affiliation: Obesity and Diabetes Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA.
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.affiliation: Obesity and Diabetes Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krakoff
mesh_terms: D000328:Adult; D022801:Complementarity Determining Regions / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005951:Glucose Tolerance Test; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007198:Indians, North American; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*
chemical_list: D022801:Complementarity Determining Regions; D059811:HLA-DRB1 Chains; C521115:HLA-DRB1*02 antigen; D011948:Receptors, Antigen, T-Cell
keywords: Pima Indians; T-cell receptor; autoimmunity; human; survival analysis; type 2 diabetes mellitus