ABSTRACT
BACKGROUND: Several Type 1 diabetes susceptibility loci have been located to chromosome 2q12-21. However, results have not always been consistent and this may reflect study design and the population analysed. We have used a family-based design to look for an association between Type 1 diabetes and markers located to 2q12-21. METHODS: Ninety-one South Indian families consisting of subjects with Type 1 diabetes and their parents were genotyped for eight polymorphic markers localised to 2q12-21, which includes the interleukin-1 gene cluster. Radiation hybrid mapping was used to localise the map position of D2S308 and D2S363 on 2q12-21. The extended transmission disequilibrium test was used for statistical analysis. RESULTS: No associations were found between Type 1 diabetes and markers located in and around the interleukin-1 gene cluster or the interleukin-1 Type 1 receptor. In contrast, a suggestive association was found between Type 1 diabetes and two closely-linked markers telomeric of the interleukin-1 gene cluster (D2S308 and D2S363, separated by 3.3 cR) (p=0.004 and p=0.002, respectively). CONCLUSION: This preliminary study suggests that a locus close to D2S308 and D2S363 is involved in the aetiology of Type 1 diabetes in the South Indian population.
Subject(s)
Chromosomes, Human, Pair 2 , Diabetes Mellitus, Type 1/genetics , Interleukin-1/genetics , Adolescent , Adult , Age of Onset , Chromosome Mapping , Diabetes Mellitus, Type 1/immunology , Female , Genetic Markers , Humans , India , Linkage Disequilibrium , Male , Multigene FamilyABSTRACT
Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.
