Kochi et al

Kochi et al. of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to GD and HT and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. Known AITD-susceptibility genes E-3810 are classified into three groups: HLA genes, non-HLA immune-regulatory genes (e.g., CTLA-4, PTPN22, and CD40), and thyroid-specific genes (e.g., TSHR and Tg). In this paper, we will summarize the latest findings on AITD susceptibility genes in Japanese. == 1. Introduction == Autoimmune thyroid diseases (AITDs) are common autoimmune endocrine diseases [1], and according to one study, AITD are the commonest autoimmune diseases in the USA [2]. Even though the hallmark of AITD is infiltration of the thyroid with thyroid reactive lymphocytes, the end result is two clinically opposing syndromes: Hashimoto’s thyroiditis (HT) manifesting by hypothyroidism and Graves’ disease (GD) manifesting by hyperthyroidism. In HT, the lymphocytic infiltration of the thyroid gland leads to apoptosis of thyroid cells and hypothyroidism [3]. In contrast, in GD, the lymphocytic infiltration of the thyroid leads to activation of TSH-receptor- (TSHR) reactive B cells that secrete TSHR-stimulating antibodies causing hyperthyroidism [4]. GD and HT are complex diseases, and their etiology involves both genetic and environmental influences [1]. Up until 15 years ago, the only known gene for AITD was HLA-DR3 haplotype (DRB1*03-DQB1*02-DQA1*0501) in Caucasians. However, with the advent of new genomic tools and the completion of the human genome and the HapMap projects, new non-HLA genes have been identified and their functional effects on disease aetiology started to be dissected as well. This paper will summarize the recent advances in our understanding of the genetic contributions to the etiology of AITD in Japanese E-3810 population. Since most of the studies were performed in relatively small size samples recruited from Japanese population, the results have some limitations. == 2. A Brief Overview of AITD Genes Identified in Caucasians == In Caucasians, the first locus shown to be associated with AITDs was the HLA-DRB1 locus (reviewed in [5]). HLA-DR3 (DRB1*03) haplotype has been consistently shown to be associated with GD, with an odds ratio (OR) of 2.03.0 [68]. The literature regarding HT is less consistent with reports of associations with DR3 and DR4 in Caucasians, as well as a negative association with DR 1 and 8, suggesting a protective role [9]. Recently, Zeitlin et al. [10] investigated DRB1-DQB1-DQA1 in the largest UK Caucasian HT case control cohort to date comprising 640 HT patients and 621 controls. A strong association between HT and DR4 haplotype (DRB1*04-DQB1*03-DQA1*03) was detected, and protective effects were detected for DR13 haplotype (DRB1*13-DQB1*06-DQA1*01) and DR7 [10]. It was recently shown that arginine at position 74 of the DR1 chain (DR1-Arg74) is important for the development of GD in a significant proportion of patients [11,12]. A study from England provided evidence of a primary association of HLA-C, and, to a lesser extent HLA-B, with GD. Other genes have also been shown to influence the expression of GD in Caucasians [13]. These include the genes for cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [14,15], CD40 [16], protein tyrosine phosphatase-22 (PTPN22) [17], thyroglobulin (Tg) [18,19], and TSH-receptor (TSHR) genes [20]. == 3. HLA Genes in Japanese == Located on chromosome 6p21 is the major histocompatibility complex region that encodes for HLA glycoproteins. The HLA region is a highly polymorphic region that contains many immune response genes and has been found to be associated with various autoimmune disorders. The HLA molecule binds GNAS a peptide antigen (autoantigen in the cause of autoimmunity). It presents the antigen for recognition by the T-cell and as such the T-cell then determines if the antigen is self (and no immune response is mounted) or nonself and an immune response is mounted [21]. The HLA associations are with different alleles in Japanese. In previous studies, HLA-B35 is associated with GD and HLA-DRw53 with HT in the Japanese population E-3810 (reviewed in [22]). HLA-Bw46 is associated with GD and HLA-DR9 with HT in the Chinese population (reviewed in [22]). The European GD-associated HLA haplotype (HLA-B*08-DRB1*03-DQA1*0501-DQB1*02) is virtually absent in Japanese [23]. Dong et al. previously reported that HLA-A*02 and DPB1*0501 are associated with Japanese GD [24]. Recently, they also demonstrated that HLA-A*02 and DPB1*0202 showed association with thyroid-stimulating hormone-binding inhibitory immunoglobulins- (TBII) negative GD, indicating that TBII-negative GD may be genetically distinct from TBII-positive GD [25]. In addition, Wan et al. reported that HLA-A*02 and DPB4*0101 are associated with Japanese HT [26]. == 4. Non-HLA Immune-Regulatory Genes in Japanese == == 4.1. The CTLA-4 Gene == The E-3810 cytotoxic T-lymphocyte-associated protein 4, CTLA-4, gene is located on chromosome 2q. It.