Lack of association of CTLA-4 + 49 A/G polymorphism with predisposition to type 1 diabetes in a cohort of Egyptian families

Type 1 diabetes is one of the most common chronic childhood illnesses. Interplay between genetic susceptibility and environmental factors is thought to provide the fundamental element for the disease. Apart from the Major Histocompatibility locus which is the main contributor to risk susceptibility, more than 40 loci are recognized. One among these is the CTLA-4, however data from the literature are controversial. The aim of our study was to investigate the role of CTLA4 49 A/G as a risk susceptibility factor for the development of type 1 diabetes in a cohort of Egyptian families. This is a case control study including 88 Egyptian families with one or more index cases [< 18 years]. The control group comprised 369 healthy unrelated subjects with no family history of diabetes or autoimmune disease. Using PCR-RFLP methodology, CTLA4 49 A/G was analyzed in 738 samples representing 88 families [88 patients, 125 siblings and 156 parents] and 369 control. The age of onset was 6 days-12.5 years with a mean of 5.3 +/- 3.6 and a median of 5 years. The mode of presentation was classic symptoms in 51 and diabetic ketoacidosis in 37 cases. Twenty-two cases had a history of viral infection or exanthematous disease and four had associated autoimmune diseases. No significant differences were encountered between the different groups with regard to CTLA4 +49 A/G genotype or allele frequencies. Neither was there a relation between the various genotypes and age of onset or the mode of presentation. CTLA4 49 A/G polymorphism was not recognized as a risk susceptibility factor in our cohort. This may be attributed to the low co-incidence of autoimmune diseases. Up to our best knowledge, this is the first study involving families. We recommend that all studies performed on risk susceptibility to type 1 diabetes should include proper investigation for other autoimmune diseases to exclude their confounding effect on data analysis

HLA-DQA and DQB alleles and predisposition to insulin dependent diabetes mellitus

Type I insulin-dependent diabetes mellitus [IDDM] is an autoimmune disease. Onset of the disease is attributed to interplay between genetic and environmental risk factors. It is strongly associated with the presence of arginine in position 52 of DQ alpha [alpha] chain and the absence of aspartic acid in position 57 of the DQ beta [alpha] chain. In this study we assessed the relative contribution of DQ alpha and DQ alpha chains to susceptibility to type I diabetes among the Egyptian patients. We identified those genetically at risk of development among their siblings in order to detect early development of autoantibodies allowing early application of preventive programs. Genomic DNA of forty Egyptian type I IDDM patients, 13 non diabetic siblings and 22 non diabetic controls were amplified using polymerase chain reactionamplification refractory mutation system [ARMS] and genotyped for HLA-DQA and DQB alleles. A significant high frequency of homozygous genotype for DQB1 non- Asp allele was detected in patients 50%, p=0.01, odd ratio [OR] =10 at 95% confidence interval [CI] =2.1-48.6 with susceptible results to the disease. The frequency of diabetogenic heterodimer Arg/non-Asp was significantly high in patients [82%, p=0.044, OR= 3.26, at 95% CI= 1.005-10.6]. On the other hand, a significant lower frequency of homozygous genotype for DQB1 Asp allele was detected in patients 12.5%, p=0.065; it was associated with protection from the disease. In conclusion, in Egyptian patients susceptibility and protection from type I diabetes is mainly associated with the DQ alpha chain. Siblings have potential risk to the disease. Non affected siblings should be targeted in a larger study for counselling. At risk individuals should be subjected to regular monitoring for the early development of autoantibodies which start years before the overt diabetes.