MHC CLASS I CHAIN RELATED GENE A (MICA) ALLELES DISTINGUISHES MALNUTRITION-MODULATED DIABETES (MMDM), IDDM AND NIDDM FROM EASTERN INDIA
A Kanungo, L.Berzina, A Shtauvere, M Ghaderi, KC Samal, CB Sanjeevi. Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden and SCB Medical College, Cuttack, India
IDDM is a polygenic disorder with an autoimmune basis for disease development. MICA is located in the MHC class III region and is expressed by monocytes, keratinocytes and endothelial cells. Sequence determination of MICA 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 MICA alleles with IDDM, MMDM and NIDDM. IDDM (n=52), MMDM (n=41) and healthy controls (n=73) from Cuttack, Eastern India were studied. A total of 212 NIDDM patients were analyzed and 96 of them were found positive for either GAD65 or IA-2 antibodies (Ab). GAD65-Ab, IA2-Ab were measured by radioligand binding assay using 35S-labelled recombinant human GAD65 and IA2. Ab positive NIDDM (n=96) and adult healthy controls for NIDDM (n=113) were also compared. These Ab positive NIDDM patients are considered as slow-onset IDDM or Latent Autoimmune diabetes in Adults (LADA). The samples were analyzed for MICA by PCR amplification and fragment sizes were determined in ABI prism DNA sequencer. Allele 9 of MICA is positively (25/41-61% patients and 22/73-30% controls)(OR 3.62, p<0.001) and allele 4 is negatively associated (4/41-10% patients and 19/73-26% controls)(OR 0.31; p<0.05) with MMDM compared to controls. Allele 5 is positively associated with IDDM (20/52-38% patients and 18/73-25% controls)(OR 2.64, p<0.05)compared to controls. Allele 5.1 is positively associated in the Ab positive NIDDM patients (65/96-68% patients and 56/113-50% controls)(OR 2.07, p<0.01) compared to adult controls. Our findings show that: a) MMDM is immunogenetically different from IDDM in Eastern India. b) MIC-A is important in the pathogenesis of MMDM patients from Cuttack in Eastern India. c) MICA alleles distinguishes acute-onset IDDM from slow-onset IDDM indicating that this molecule may be important for the delaying the onset of IDDM resulting in these patients being diagnosed clinically as NIDDM.