T-cell receptor repertoire variation may be associated with type 2 diabetes mellitus in humans

• Published in: Diabetes/metabolism research and reviews Vol. 32; no. 3; pp. 297 - 307
• Main Authors: Frankl, Joseph A., Thearle, Marie S., Desmarais, Cindy, Bogardus, Clifton, Krakoff, Jonathan
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2016; Wiley Subscription Services, Inc
• Subjects: Adult; autoimmunity; Complementarity Determining Regions - genetics; Diabetes Mellitus, Type 2 - genetics; Female; Glucose Tolerance Test; Haplotypes - genetics; HLA-DRB1 Chains - genetics; human; Humans; Indians, North American; Longitudinal Studies; Male; Pima Indians; Polymorphism, Single Nucleotide - genetics; Receptors, Antigen, T-Cell - genetics; survival analysis; T-cell receptor; type 2 diabetes mellitus; T-cell receptor; type 2 diabetes mellitus; Pima Indians; autoimmunity; survival analysis; human
• ISSN: 1520-7552; 1520-7560; 1520-7560
• DOI: 10.1002/dmrr.2720

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. Copyright © 2015 John Wiley & Sons, Ltd.