|dc.description.abstract||Aims/ Hypothesis: Wolcott- Rallison syndrome (WRS) is a rare autosomal recessively inherited Mendelian disorder. It is characterised by a short trunk compared to arm span, multiple epiphyseal dysplasia, multiple fractures, hepatosplenomegaly and renal insufficiency in addition to insulin dependent diabetes. The onset of diabetes in WRS families is mainly below the age of 6 months and is characterised by permanent severe non-autoimmune insulin deficiency. Mutations of the gene encoding eukaryotic translational initiation factor 2 - alpha kinase 3 (EIF2AK3) were found to account for diabetes in WRS. The aim of our study was to determine whether common polymorphisms in the EIF2AK3 gene (Candidate gene association study) could be associated with type 2 diabetes.
Methods: Direct sequencing was performed on all 17 exons/coding regions and intron/exon boundaries of EIF2AK3 gene in 48 diabetes and control subjects. Single Nucleotide Polymorphisms (SNPs) tagging the common haplotypes (tag SNPs) were identified and 11 SNPs were genotyped initially in 2,835 subjects with type 2 diabetes, 3,538 control subjects in the British Irish, Bangladeshi and South Indian Populations and 522 families (n= 1,722) in the British Irish and South Indian Populations.
Results: We identified 19 SNPs by direct sequencing. There was no association (all p>0.05) between the SNPs and type 2 diabetes in the case–control study and in the family study. In the one marker, rs7605713, that showed a nominal significance in Warren 2 European samples, further replication studies in the Dundee samples (3,334 diabetes cases and 3,456 controls) proved to be negative thereby avoiding a false positive result. The results also showed several of the SNPs had different minor allele frequencies between the British/Irish Caucasians as compared to the South Asians.
Conclusions/interpretation: Common variations in the EIF2AK3 gene were not associated with type 2 diabetes in the British Irish and the South Asian population.||en_US