Cytotoxic T lymphocyte antigen 4 heterozygous codon 49 A/G dimorphism is associated to latent autoimmune diabetes in adults (LADA)

Abstract

Autoimmune diabetes is an organ specific and multifactorial disorder with a classical onset as insulin dependent diabetes mellitus (IDDM) and with another form of onset as latent autoimmune diabetes in adults (LADA), which has a slower onset and a later progress to insulin dependency as a result of the beta cells destruction. The cytotoxic T lymphocyte-antigen 4 (CTLA4) has been identified as a susceptible marker of the disease; it is considered a down regulator of T cell function, playing a key role in autoimmunity. We analyzed CTLA4 codon 49 A/G polymorphism in 123 IDDM patients, 63 LADA patients and 168 healthy non-diabetic control individuals. The frequency of the heterozygous A/G genotype in LADA patients was significantly increased compared to IDDM patients (55.6 vs. 39.8%, p = 0.0415). There was no statistical significant difference in the distribution of the A/G dimorphism between autoimmune diabetes patients (LADA or IDDM) and non-diabetic control individuals. HLA DQ region is responsible for the genetic susceptibility to autoimmune diabetes in IDDM patients in about 50% and it has a lower effect in genetic susceptibility in LADA patients. Several other genetic loci are needed to develop autoimmune diabetes in adult patients. Therefore, LADA may be the result of a combined minor risk loci effect in a major risk haplotype.

LADA and T1D in Estonian population — Two different genetic risk profiles

“…We observed the sustained association between LADA and CTLA4 on single SNP as well as haplotype level, even after correction for multiple markers by permutation. Our results are in concordance with the data published by Caputo et al (Caputo et al, 2005, who identified CTLA4 SNP +49A/G but not −318C/T as a susceptibility marker for LADA. Moreover, the frequency of the heterozygous A/G genotype in LADA patients was significantly increased compared to T1D (Caputo et al, 2005).…”

The CTLA4 +49 A/G polymorphism is not associated with susceptibility to type 1 diabetes mellitus in the Portuguese population

“…A meta‐analysis of published studies indicated that the +49G allele conferred an increased risk for type 1 diabetes, with an OR of 1.45 (95% CI 1.28–1.65) (Kavvoura & Ioannidis, 2005). However, lack of association for the +49A/G polymorphism has also been reported in populations from the USA, Japan, Ghana, UK, France, Czech Republic, Morocco, Argentina, Brazil and Azerbaijan (Marron et al ., 1997; Caputo et al ., 2005; Hauache et al ., 2005; Kavvoura & Ioannidis, 2005; Ahmedov et al ., 2006).…”

Characterization of zinc transporter 8 (ZnT8) antibodies in autoimmune diabetic patients from Argentinian population using monomeric, homodimeric, and heterodimeric ZnT8 antigen variants

“…Finally, we consider that the differential profiles of ZnT8A exhibited by type 1 and non-obese, adult-onset diabetic patients are in line with other observations suggesting the different nature of autoimmune processes underlying both pathologies. In this sense, it has been described that the frequency of the heterozygous A/G genotype in LADA patients is significantly increased compared to type 1 diabetic patients (24). Additionally in previous reports, we have demonstrated different marker profiles (15) and different thermodynamic parameters (affinity and concentration) (25) in both groups of patients.…”