Estrogen receptor alpha dinucleotide repeat polymorphism in Japanese patients with autoimmune thyroid diseases

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are the most common human autoimmune diseases and are responsible for significant morbidity in premenopausal women. AITDs are caused by immune responses to the thyroid gland. In GD, the autoimmune process results in production of thyroid-stimulating antibodies and leads to hyperthyroidism, whereas in HT, the end result is thyroid cell death and hypothyroidism [1,2].

The pathogenesis of AITDs involves complex interactions between genetic and environmental factors [3,4]. The genetic relations between GD and HT and the familial and sporadic forms of these diseases are unclear. This problem, until now, has been addressed by studying a variety of candidate genes, primarily via association studies. Because it has been assumed that immune dysregulation and/or thyroid antigen presentation are involved in AITD, the candidate genes that have been tested comprised genes involved in immunoregulatory pathways and genes encoding for the major thyroid autoantigens. These genes included the human leukocyte antigen (HLA) [5], immunoglobulin H heavy chain [6], T cell receptor [7], interleukin-1 receptor antagonist [8], interferon-γ [9], thyroid stimulating hormone receptor [10,11], thyroid peroxidase [12], and cytotoxic T lymphocyte antigen-4 (CTLA-4) genes [13]. With the exception of the HLA and CTLA-4 loci, the candidate genes examined gave either negative or equivocal results. Recently, the existence of an estrogen receptor (ER)α gene polymorphism has made clear, and its association to some variant ERα genotypes with breast cancer [14,15], hypertension [16], osteoporosis [17,18], generalized osteoarthritis [19], and some autoimmune diseases such as rheumatoid arthritis [20] has been reported.

The ERα gene on chromosome 6q24-q27 is organized into eight exons and seven introns extending over approximately 140 kilobases [21]. ERα belongs to the nuclear hormone receptor superfamily and modulates the transcription of target genes in response to estrogen, a potent immunomodulatory hormone [22]. Estrogens appear to play a central role in the immune response and immune-mediated diseases [22]. In view of the possible role of estrogens in the pathogenesis of AITDs, we have analyzed a dinucleotide (TA)n repeat polymorphism lying upstream of the human ERα gene in patients with AITDs and in normal subjects.

ERα belongs to the nuclear hormone receptor superfamily and modulates the transcription of target genes in response to estrogen [22]. Recent studies have shown the presence of ERαs on the cells involved in the immune response, namely thymocyte, macrophages and endothelial cells [22]. Particular attention has been focused on the dose-dependent influence of estrogen on the immune response, which appears to be related to the clinical symptoms of autoimmunity (i.e. the effects of pregnancy or oral contraceptive pills) [22]. The influence of estrogens on cytokine production by target cells, through interference with their transcriptional activity, has also been the focus of various studies [22]. The effect of estrogens on the expression of the protooncogenes and oncosuppressor genes involved in programmed cell death (apoptosis) might also be relevant to human autoimmunity, in particular the uncontrolled synovial lining cell hyperplasia associated with rheumatoid arthritis and the prolonged T-cell survival in systemic lupus erythematosus [22]. Thus, we investigated the relation between a dinucleotide (TA)n repeat polymorphism lying upstream of the human ERα gene and AITDs. Our data did not appear to indicate any association between the ERα gene and the AITDs analyzed. This result might indicate of a large diversity in the genetic background of AITDs, although this observation deserves further analysis in a larger group of AITD patients.