3′ polymorphisms of ETS1 are associated with different clinical phenotypes in SLE

Abstract

A microsatellite repeat polymorphism was identified in the 3' flanking region of the human ETS1 gene. Sequencing revealed two CA repeat segments in close proximity. Seven different alleles comprising various combinations of CA repeat units were identified in a healthy control population. Because ETS1 plays a role in lymphocyte development and function, apoptosis, and inflammation, we examined whether any of these polymorphisms were associated with a systemic inflammatory condition, systemic lupus erythematosus (SLE). Inheritance of this disease is polygenic and a recent genome-wide screen for SLE susceptibility loci revealed linkage with chromosome 11q14-23, the region in which the ETS1 gene lies. This region has also been identified as a general autoimmune susceptibility region. None of the seven distinct ETS1 alleles appeared statistically more frequently in SLE patients than controls, however, two alleles were associated with particular clinical manifestations. Allele 1 is associated with discoid lesions and allele 7 is associated with vasculitis. While this polymorphism does not directly affect the coding region of ETS1, it may be a marker for overexpression of a particular isoform or inheritance of another polymorphism which does affect function. These data suggest that ETS1 may be involved in the phenotypic expression of systemic lupus erythematosus.

Altered sequence of theETS1transcription factor may predispose to rheumatoid arthritis susceptibility

“…These two polymorphisms were also revealed to predispose different ethnic groups to different immune diseases (20). In addition, an allele of a microsatellite repeat polymorphism in the 3 0 flanking region of the ETS1 gene, even though it was mainly found in Caucasian individuals compared to African Americans, has been associated with vasculitis mainly in African American SLE patients (8). These findings seem to indicate that different linkage disequilibrium patterns of the ETS1 polymorphisms studied, along with other adjacent or non-adjacent ETS1 variants, or with polymorphisms of other relevant genes may predispose different ethnic groups to autoimmune diseases.…”

“…Polymorphisms of the ETS1 gene have been implicated in systemic lupus erythematosus (SLE) and coeliac disease (CD), which is also characterized by aberrant activation of the immune system (6)(7)(8)(9). ETS1 belongs to the ETS family of transcription factors (10).…”

Copy number variations of interleukin‐17F, interleukin‐21, and interleukin‐22 are associated with systemic lupus erythematosus

“…Th17 cells are associated with the production of mediators of inflammation; thus, they have potentially pathogenic roles in autoimmune disease. It has been shown that IL‐17–producing cells play a role in progression of SLE both in humans (4, 5) and in mouse models (6). Th17 cells produce IL‐6, TNFα, IL‐21, IL‐22, IL‐1β, and granulocyte–macrophage colony‐stimulating factor in addition to IL‐17A and IL‐17F (2).…”

“…The involvement of Th17 cells in rheumatoid arthritis (RA) has been explored (3). Furthermore, there is increasing evidence both in humans (4, 5) and in mouse models (6) suggesting that IL‐17–producing cells play a role in the progression of systemic lupus erythematosus (SLE).…”

Intrinsic Defects in the T-Cell Lineage Results in Natural Killer T-Cell Deficiency and the Development of Diabetes in the Nonobese Diabetic Mouse

“…Our preliminary results showed that the T-cell lineage of NOD mice expresses the Ets1 gene at a level identical to that in T-cells in AKR mice and that there is no mutation in the Ets1 gene coding frame (unpublished data). However, it was reported that polymorphism in the 3Ј nontranslating region of Ets1 may be associated with autoimmune syndromes (47). The mechanisms of the NKT cell deficiency in NOD mice remain to be elucidated.…”