HLA, NFKB1 and NFKBIA Gene Polymorphism Profile in Autoimmune Diabetes Mellitus Patients

Abstract

Type 1 diabetes mellitus (T1DM) is one of the long-time studied autoimmune disorders. The triggering of the autoimmune process has been ascribed to various genes active in the regulation of the cytokine gene transcription including the Rel/NF-kappaB gene family. In our study the gene polymorphism of HLA class II, NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) and NFKBIA (inhibitor of nuclear factor kappa B) was tested. Patients were divided into the subgroups in relation to the disease type: T1DM in children, T1DM in adults, and Latent Autoimmune Diabetes in Adults (LADA). HLA-DRB1 (*)04 and HLA-DQB1 (*)0302 have been detected as risk factors for T1DM in adults and particularly in children (P<0.0001, OR=22.9 and 46.5 respectively). HLA-DRB1 (*)03 has been found as a single risk factor for LADA (P<0.0001, OR=4.9). We detected 15 alleles for the NFKB1 gene polymorphism (CA-repeats) in the Czech population. The alleles were ranging in size from 114-142 bp corresponding to 10-25 CA repeats. Frequency of the A7 allele of NFKB1 gene has been significantly increased in T1DM adults (P<0.01). There was no difference in A and a G allele frequency of NFKBIA gene between the control group and patients, but the association of the AA genotype of NFKBIA gene has been found for LADA (P<0.05). Summarizing our results we concluded that there is a high probability of association of gene polymorphism from Rel/NF-kappaB family with an autoimmune diabetes course. Due to the results obtained in the epidemiological study we have been looking also for the function significance of the genetic predisposition. No significant changes have been observed by real time PCR testing of HLA-DRB1 (*)04 gene and NFKB1 gene expression between T1DM diabetic group with different HLA, NFKB1, NFKBIA genetic background.

Association of NFKB1 and NFKBIA Polymorphisms in Relation to Susceptibility of Behçet's Disease

“…In studies with type 1 diabetes mellitus, AA genotype of rs696 was a risk factor for latent autoimmune diabetes in adults [17]. rs696 variation has also been associated with development of type 2 diabetes and Crohn's diseases, resulting in Th1/Th2 imbalance as the pathogenesis [16,37].…”

“…This gene probably plays an important role in inflammatory immunological diseases such as Crohn's disease or autoimmune diabetes mellitus [16,17]. According to Goto et al [18], the alterations in the expression of IjBa protein were related to the SNP rs696 in the 3 0 UTR region of the NFKBIA gene and led to a change in NF-jB activity.…”

Association of the NFKBIA gene polymorphisms with susceptibility to autoimmune and inflammatory diseases: a meta-analysis

“…There were 41 papers relevant to the search terms. Through the step of screening the abstract, 27 of these articles were excluded (two were review; four weren't case-control study; three didn't explore NFKBIA gene polymorphism; 18 didn't explore autoimmune and inflammatory diseases), leaving 14 studies [14][15][16][17][18][19][20][21][22][23][24][25][26][27] for full publication review. Of these, the frequencies of alleles and genotypes of three studies were unavailable [15,18,19].…”

“…Many polymorphisms of the NFKBIA gene have been identified;recently, these polymorphisms have attracted widespread attention [13]. A number of case-control studies have been conducted to investigate the association of these polymorphisms with autoimmune and inflammatory diseases [14][15][16][17][18][19][20][21][22][23][24][25][26][27]. However, these studies reported conflicting results.…”

Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in Latent Autoimmune Diabetes of the Adult Differ from Those of Type 1 Diabetes Patients

“…In patients examined clinically prior to the year 2002, GADA was examined by the ELISA test from Roche Applied Science (Mannheim, Germany) with analytical sensitivity at 32 ng/mL and an arbitrary cutoff at 50 ng/mL [41]. Some of the measurements of islet cell autoantibodies have previously been analyzed in studies addressing other diabetes-associated genes [36-41, 58]. …”