HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion

• Published in: Diabetologia 2011-07, Vol.54 (7), p.1684-1692
• Main Authors: Williams, R. C., Muller, Y. L., Hanson, R. L., Knowler, W. C., Mason, C. C., Bian, L., Ossowski, V., Wiedrich, K., Chen, Y. F., Marcovina, S., Hahnke, J., Nelson, R. G., Baier, L. J., Bogardus, C.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Disease; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gene expression; Genetic Predisposition to Disease; Genomes; Glucose; HLA-DR alpha-Chains; HLA-DR Antigens - genetics; HLA-DR Antigens - metabolism; HLA-DRB1 Chains; Human Physiology; Humans; Insulin - metabolism; Insulin resistance; Insulin Secretion; Internal Medicine; Laboratories; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Muscle, Skeletal - metabolism; Musculoskeletal system; Plasma; Polymorphism; Polymorphism, Single Nucleotide - genetics
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2122-8

Aims/hypothesis We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona. Methods Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLA-DRA , and with type 2 diabetes mellitus and prediabetic traits. Results The A allele at rs9268852, which tags HLA-DRB1*02(1602) , was associated both with higher HLA-DRB1 mRNA expression ( n  = 133, p  = 4.27 × 10 −14 ) and decreased risk of type 2 diabetes ( n  = 3,265, OR 0.723, p  = 0.002). Among persons with normal glucose tolerance ( n  = 266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test ( p  = 0.005), higher mean 30 min insulin concentration during an oral glucose tolerance test ( p  = 0.017) and higher body fat percentage ( p  = 0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity. Conclusions/interpretation HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion.