MHC Class I Chain‐Related Gene A Alleles Distinguish Malnutrition‐Modulated Diabetes, Insulin‐Dependent Diabetes, and Non‐Insulin‐ Dependent Diabetes Mellitus Patients from Eastern India

Abstract

Insulin-dependent diabetes mellitus (IDDM) is a polygenic disorder with an autoimmune basis for disease development. In addition to HLA, a second susceptibility locus for IDDM has been identified to lie in the major histocompatibility class III region. MIC-A is located in the MHC class III region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MIC-A gene identifies trinucleotide repeat (GCT) microsatellite polymorphism in exon 5. Five alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional nucleotide insertion (GGCT) are identified. The alleles are A4, A5, A5.1, A6, and A9. The aim of our study was to find the association of MIC-A alleles with IDDM, malnutrition-modulated diabetes mellitus (MMDM), and non-insulin-dependent diabetes mellitus (NIDDM) patients. IDDM (n = 52), MMDM (n = 41), NIDDM (n = 212), and healthy controls (n = 73) from Cuttack, in eastern India, were studied. Of the 212 NIDDM patients analyzed, 96 of them were found to be positive for either GAD65 or IA-2 antibodies. Autoantibodies to GAD65 and IA-2 were measured by radioligand binding assay using (35)S-labeled recombinant human GAD65 and IA-2 in an in vitro transcription/translation system. Autoantibody-positive NIDDM patients (n = 96) and adult healthy controls for NIDDM (n = 113) were also compared. These autoantibody-positive NIDDM patients are considered as slow-onset IDDM or latent autoimmune diabetes in adults (LADA) patients. The samples were analyzed for MIC-A by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. The results of the MIC-A typing are: allele 9 of MIC-A is positively associated (OR 3.62; P < 0.001), and allele 4 is negatively associated (OR 0.31; P < 0.05) with MMDM patients compared to controls. Allele 5 is positively associated with IDDM (OR 2.64; P < 0.05) when compared to controls. Allele 5.1 is positively associated in the autoantibody-positive NIDDM patients compared to adult controls. Our findings of a significant increase of allele A9 in MMDM patients compared to healthy controls suggest that MMDM is immunogenetically different from IDDM in eastern India. MIC-A is important in the pathogenesis of MMDM patients from Cuttack. MIC-A alleles distinguish acute-onset IDDM from slow-onset IDDM, indicating that this molecule may be important for delaying the onset of IDDM with the result that these patients are diagnosed clinically as NIDDM.