The EIF2AK3 gene region and type 1 diabetes in subjects from South India

Mutations in the EIF2AK3 gene underlie susceptibility to the Wolcott-Rallison syndrome, which is a monogenic disease associated with insulin-deficient neonatal diabetes. Furthermore, suggestive evidence of linkage between type 1 diabetes (T1DM) and the EIF2KA3 chromosomal region has been reported in Scandinavian families. We have investigated the hypothesis that polymorphic variants in and around the EIF2AK3 gene might partially account for susceptibility to T1DM in South Indian subjects. Excess transmission of the common alleles of two polymorphic markers (D2S1786 and 15INDEL, located within the gene) downstream of EIF2AK3, either singly ( D2S1786, P = 0.01) and 15INDEL ( P = 0.02) or as a combination ( P<0.001), were found in 234 families with a T1DM proband. There was also a clear paternal effect for the 15INDEL marker ( P = 0.005) on disease susceptibility. The presence of the common allele of both markers was found in decreased frequency in the subjects with normal glucose tolerance compared to probands with T1DM ( both P<0.0001). Major common mutations of the EIF2AK3 gene in T1DM were excluded. In conclusion, this pilot study demonstrates an association between the region around the EIF2AK3 locus and T1DM susceptibility.