ABSTRACT
AIMS/HYPOTHESIS: The suppressor of cytokine signalling 1 (SOCS1) is a natural inhibitor of cytokine and insulin signalling pathways and may also play a role in obesity. In addition, SOCS1 is considered a candidate gene in the pathogenesis of both type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective was to perform mutation analysis of SOCS1 and to test the identified variations for association to T2D-related quantitative traits, T2D or T1D. METHODS: Mutation scanning was performed by direct sequencing in 27 white Danish subjects. Genotyping was carried out by TaqMan allelic discrimination. A total of more than 8100 individuals were genotyped. RESULTS: Eight variations were identified in the 5' untranslated region (UTR) region. Two of these had allele frequencies below 1% and were not further examined. The six other variants were analysed in groups of T1D families (n = 1461 subjects) and T2D patients (n = 1430), glucose tolerant first-degree relatives of T2D patients (n = 212) and normal glucose tolerant (NGT) subjects. The rs33977706 polymorphism (-820G > T) was associated with a lower body mass index (BMI) (p = 0.004). In a second study (n = 4625 NGT subjects), significant associations of both the rs33977706 and the rs243330 (-1656G > A) variants to obesity were found (p = 0.047 and p = 0.015) respectively. The rs33977706 affected both binding of a nuclear protein to and the transcriptional activity of the SOCS1 promoter, indicating a relationship between this polymorphism and gene regulation. CONCLUSIONS/INTERPRETATION: This study demonstrates that functional variations in the SOCS1 promoter may associate with alterations in BMI in the general white population.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Insulin Resistance/genetics , Obesity/genetics , Polymorphism, Genetic/genetics , Suppressor of Cytokine Signaling Proteins/genetics , White People/genetics , Adult , Body Mass Index , Diabetes Mellitus, Type 1/ethnology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 2/ethnology , Diabetes Mellitus, Type 2/genetics , Female , Humans , Linkage Disequilibrium , Male , Middle Aged , Obesity/metabolism , Suppressor of Cytokine Signaling 1 Protein , Suppressor of Cytokine Signaling Proteins/metabolismABSTRACT
AIMS/HYPOTHESIS: Beta cell loss in Type 1 and Type 2 diabetes mellitus may result from apoptosis and necrosis induced by inflammatory mediators. The suppressor of cytokine signalling (SOCS)-3 is a natural inhibitor of cytokine signalling and also influences insulin signalling. SOCS3 could therefore be a candidate gene in the development of Type 1 and Type 2 diabetes mellitus. METHODS: Mutation analysis of the SOCS3 gene was performed in 21 patients with Type 1 diabetes mellitus and in seven healthy subjects. An identified promoter variant was examined in (i) 250 families with Type 1 diabetic family members (1097 individuals); (ii) 212 glucose-tolerant first-degree relatives of Type 2 diabetic patients; and (iii) 370 population-based young, healthy subjects who were unrelated. RESULTS: Three mutations were identified in the promoter region, but none in the coding region or the 3'UTR. Two of the three mutations had allele frequencies below 1% whereas the C -920-->A substitution had a minor allele frequency of 8%. In the group of young healthy subjects the insulin sensitivity index was higher among homozygous carriers of the A-allele than among heterozygous and wild-type subjects ( p=0.027, uncorrected). The same trend was found in the group of first-degree relatives of Type 2 diabetic patients. No association or linkage was found to Type 1 diabetes mellitus. CONCLUSIONS/INTERPRETATION: Homozygosity for the A-allele of the C -920-->A promoter polymorphism of the SOCS3 gene may be associated with increased whole-body insulin sensitivity, but deserves further investigation.
Subject(s)
Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 2/genetics , Insulin/physiology , Polymorphism, Single Nucleotide/genetics , Repressor Proteins/genetics , Transcription Factors/genetics , Adolescent , Adult , Base Sequence , Child , Child, Preschool , DNA Mutational Analysis , DNA Primers , Family , Humans , Infant , Polymerase Chain Reaction , Signal Transduction , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling ProteinsABSTRACT
Cytokine-induced beta-cell death is an important factor in the pathogenesis of type 1 diabetes mellitus (T1DM). The transcription factor NFkappaB plays an important role in cytokine-induced gene activation. Hence, NFKB1 is a possible candidate gene for T1DM disposition. A polymorphic (CA) dinucleotide repeat microsatellite has been identified near the NFKB1 gene. In a recent case-control study certain alleles of this NFKB1 microsatellite marker showed strong association to T1DM. The aim of our study was to investigate whether the association between the NFKB1 marker and T1DM could be confirmed in a Danish family collection. No T1DM association for any allele of the NFKB1 microsatellite marker could however be demonstrated in Danish T1DM families. In conclusion, we could not confirm the highly significant T1DM association of certain alleles of the NFKB1 marker previously reported.
