Genetic interaction among three genomic regions creates distinct contributions to early- and late-onset type 1 diabetes mellitus

Abstract

There are two peaks in the distribution of the age of onset of type 1 diabetes mellitus (T1DM)--the first in early childhood and the second at the time of puberty. Although T1DM results from the interaction of genetic and non-genetic factors, it has not been established which factors contribute to the bimodal distribution. The genetic component of T1DM is in large part related to genes from the human leukocyte antigen (HLA) complex (IDDM1); however, loci from the variable nucleotide tandem repeat (VNTR) region of the insulin (INS) gene (IDDM2) and more recently, the cytotoxic T-lymphocyte-associated protein-4 region (CTLA4, IDDM12) have also been implicated. Therefore, we examined the potential interaction between these loci through the influence of the age of onset of T1DM in diabetic and control Caucasian individuals. We discovered that younger individuals with HLA-DRB1*0301/DRB1*04 and INS I/I genotypes exhibited increased susceptibility to T1DM, whereas the interaction of INS I/I and CTLA4 G/G genotypes was more common in older children with T1DM. Combining the age of onset of T1DM with specific genotypes may operate to produce a single disease through different underlying causes.

Diabetic Ketoacidosis: Demographic Data, Clinical Profile and Outcome in a Tertiary Care Hospital

“…As we know, the second and much greater peak incidence of diabetes in children is during early puberty (i.e. ages between 10 -14 years) (14). These data, therefore, were attributed to the high number of new-onset cases presenting with DKA.…”

The UVA/PADOVA Type 1 Diabetes Simulator

“…Thus, we needed to associate duration of T1DM to each in silico subject in a way that it was compatible with model parameters related to glucagon secretion. Using literature on T1DM incidence, [18][19][20][21][22] we generated a distribution of age at onset (which then can be easily transformed in T1DM duration by using the subject's age). Random sampling form this distribution, conditioned by age of in silico patient, allowed the generation of the duration of T1DM for each in silico subject, while respecting the incidence characteristics of the disease.…”

Polymorphisms in the cathepsin L2 (CTSL2) gene show association with type 1 diabetes and early-onset myasthenia gravis

“…Previous studies have indicated that the genetic contribution to disease could be higher among patients with an earlier disease onset. For example, the HLA class II association is stronger in early-onset T1D [32], and the same is seen for the insulin gene association [33].…”