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Study of genetic factors associated with diabetes at young age |
| Principal Investigator : Rajni Rani Project Associates
/ Assistants Ph D Students Collaborators The
project aims to study the genetic factors associated with diabetes of the
young, which include Insulin Dependent diabetes Mellitus (IDDM) and Ketosis
Resistant Diabetes of the young (KRDY). The ultimate aim of the project is to
decipher ways that can be used for the diagnosis of the prediabetics in the
high risk groups e.g. children in the family of patients with either IDDM or
KRDY. IDDM has been shown to have autoimmune etiology, however, not much is
known about the etiology of KRDY although autoantibodies have been found in
KRDY patients suggesting an autoimmune etiology for this form of the disease
as well. The basic problem with the IDDM patients is that by the time they
report to the clinic, the insulin producing beta cells of the pancreases have
been damaged to a considerable extent. So, the treatment of choice is to give
insulin which does take care of the daily insulin requirement, however, does
not stop autoimmunity. Hence, there is a need to identify these patients
earlier in life so that further beta cell damage can be arrested by some kind
of immune intervention. For this purpose, peptides have been designed which
will be used in-vitro to inhibit autoimmune T-cell responses. Since the
disease has been shown to have genetic predisposition, to be able to identify
prediabetics, the objectives of the project are to study (i) the HLA
polymorphism in IDDM and KRDY patients from North India and ethnically matched
controls, (ii) the polymorphism of 5’-INS gene (IDDM2) or Insulin linked
polymorphic region (ILPR) in IDDM and KRDY patients and controls, (iii) the
autoantibody profile to insulin and islet cells and C-peptide levels in IDDM
and KRDY patients and controls, (iv) the association of HLA with the type of
autoantibodies found in the patients, and (v) to design and use peptides
in-vitro to inhibit autoimmune T-cell responses. A
total of 116 samples from diabetes patients were studied for HLA-DRB1, DQA1,
DQB1 and DPB1 alleles. 110 patients and 95 normal healthy controls were
studied for Insulin linked polymorphic region. 58 IDDM patient samples and 34
normal healthy controls have been studied for single nucleotide polymorphism (SNPs)
in cytokine genes which included Th1 cytokine genes IL-12, IFN-g
and TNF-a
and IL-2, Th2 cytokine genes which included IL-4RA +1902, IL-4 –1098, -590,
-33, IL-6 –174, nt565 and IL-10 -1082, -819 and -590. Other cytokine genes
studied included IL-1a,
-889 T/C, IL-1RPst 1970, IL-1RA Mspa 111000, TGFb
codon 10 and 25. The sample collection is still going on since one of the aims
of the project is to see whether there are any immunogenetic differences
between IDDM and KRDY patients and we may not have enough KRDY patient samples
yet. My collaborator Dr. R. Goswami has sent the samples and we are not aware
of their clinical diagnosis as to which samples are from IDDM patients and
which are from KRDY patients. More
diabetic blood samples have been studied for in-vitro inhibition of autoimmune
T-cell responses by peptides. Data on some of the peptides look promising,
since they induce a reduction in IFN-g spots and increase in IL-4 spots (in
Elispot assays), suggesting a shift from Th1 to Th2 phenotype, which may have
therapeutic implications. The study is ongoing and the data will be analysed
after the completion of the study to avoid any biases. Sera samples are being
collected at the time of blood collection for autoantibody study. My
collaborator is doing this part of the work, the results will be analysed only
after the completion of the data collection. Publications Original
peer-reviewed articles 1. Rani R, Sood A and Goswami R (2003) Attenuation of autoreactive TH1 cells invitro using altered peptide ligands in diabetes of the young. In: HLA 2002, Immunobiology of the human MHC, (Eds. John A). Hansen & Bo Dupont, IHWG Press (in press). |