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Relation between Disease Phenotype and HLA-DQ Genotype in Diabetic Patients Diagnosed in Early Adulthood

Diabetes Research Center (I.W., B.K., F.C.S., B.V.D.A., M.R., P.D.P., F.K.G.), Vrije Universiteit Brussel, B-1090 Brussels, Belgium; Department of Endocrinology (V.S., F.F.), Hôpital Erasme, B-1070 Brussels, Belgium; Department of Endocrinology (J.-C.D., G.K.), Centre Hospitalier Universitaire, B-6000 Charleroi/B6040 Jumet, Belgium; Department of Diabetology (A.S., M.L.), Centre Hospitalier Universitaire Sart Tilman, B-4000 Liege, Belgium; Department of Endocrinology (I.H.D.L., L.V.G.), Universitair Ziekenhuis Antwerpen, B-2650 Antwerp, Belgium; Department of Endocrinology (C.M.), Universitaire Ziekenhuizen Gasthuisberg, B-3000 Leuven, Belgium; Department of Endocrinology (R.R.), Universitair Ziekenhuis Gent, B-9000 Ghent, Belgium; Department of Endocrinology (F.N.), OLV Ziekenhuis, B-9300 Aalst, Belgium; Department of Biostatistics (L.K.), Vrije Universiteit Brussel, B-1090 Brussels, Belgium; and Belgian Diabetes Registry, B-1090 Brussels, Belgium

Address all correspondence and requests for reprints to: Prof. Frans K. Gorus, Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. E-mail: . Frans.Gorus{at}az.vub.ac.be

Abstract

We investigated inaugural disease phenotype in relation to the presence or absence of diabetes-associated autoantibodies and human leukocyte antigen (HLA) DQ risk genotypes in adult-onset diabetic patients. Blood samples and questionnaires were obtained from 1584 recent-onset Belgian Caucasian patients (age 15–39 yr at diagnosis of primary diabetes) who were recruited by the Belgian Diabetes Registry over an 11-yr period. At clinical diagnosis, antibody-positive patients (n = 1198) were on average younger and had more symptoms, a more acute disease onset, lower body mass index, and random C-peptide levels, but higher insulin needs, glycemia, and prevalence of ketonuria, HLA-DQ, and 5' insulin gene susceptibility genotypes (P < 0.001 vs. antibody-negative patients; n = 386). In antibody-positive patients, these characteristics did not differ according to HLA-DQ genotype. However, in antibody-negative subjects, we found that patients were younger (P = 0.001); had a lower body mass index (P < 0.001), higher insulin needs (P = 0.014), and amylasemia (P = 0.001); and tended to have a higher glycemia and lower C-peptide in the presence of susceptible HLA-DQ genotypes. Differences according to HLA-DQ genotype subsisted after careful age-matching. In conclusion, we found no relation between initial disease phenotype and HLA-DQ genotype in antibody-positive diabetic young adults. In contrast, antibody-negative patients displayed more type 1-like features when carrying susceptible HLA-DQ genotypes known to promote the development of antibody-positive diabetes. The overrepresentation of these susceptibility genotypes in antibody-negative patients suggests the existence of an immune-mediated disease process with as yet unidentified immune markers in a subgroup of seronegative patients.

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