Hyperthyroidism is a common endocrine disease caused by increased synthesis and secretion of thyroid hormone (1). Graves’ disease (GD) is an autoimmune thyroid disease that results from excessive stimulation of the thyroid by circulating TSH receptor antibodies (TRAb), which is the most common cause of hyperthyroidism (1). As antithyroid drugs (ATDs) treatment avoids radiation exposure and has a low risk of hypothyroidism, it is frequently considered as the first-choice therapy for GD patients (2). However, GD patients treated with ATD have a relatively high recurrence rate after drug withdrawal (3, 4). The persistent or recurrent hyperthyroidism results in increased medical expenses and a wide spectrum of complications, such as atrial fibrillation, heart failure, and osteoporosis, even a long-term and negative impact on the quality of life (5, 6). Thus, it is of great importance to identify some predictors, prior to ATD treatment, which can indicate a higher risk of recurrence. If the likelihood of recurrence after ATD treatment is high, radioiodine therapy or thyroidectomy might be more preferable. This strategy would facilitate an appropriate therapeutic approach for a given patient at the time of GD diagnosis.

The genetic factor was widely believed to be an important pathogenesis for GD (7). Increasing studies were conducted to investigate the relationship between gene polymorphisms and the recurrence risk in GD patients after ATD withdrawal (8–13). In this article, we updated the current literatures to highlight the predictive value of gene polymorphisms on recurrence risk in GD patients after ATD withdrawal.

There are three treatment options for GD patients, including ATD, radioiodine therapy, and thyroidectomy (1). ATD treatment is frequently used as the first-choice therapy for GD patients in most countries (2). However, the recurrence rate of ATD treatment is approximately 50–60%, which is relatively higher as compared with radioiodine therapy or thyroidectomy (3, 4). The previous studies have demonstrated that the recurrence risk varies in GD patients with different clinical characteristics (4, 9, 14, 15). Therefore, the risk predictors for recurrence should be taken into account when choosing an appropriate therapeutic approach for every GD patient. Previous studies have shown that young age, high concentrations of TRAb, large goiter size, and severe thyrotoxicosis were associated with higher recurrence risk (4, 9, 14, 15). Unfortunately, the predicting ability of these factors is unsatisfactory.

Several studies have found that the occurrence of GD appeared in family aggregation (16). The evidence from further genetic studies showed that genetic factors are related to the pathogenesis of GD (7). Some immune-regulatory genes, including human leukocyte antigen (HLA), CD40, cytotoxic T-lymphocyte-associated factor 4 (CTLA4), protein tyrosine phosphatase, non-receptor type 22 (PTPN22), and Fc receptor-like protein 3 (FCRL3), have been observed to be involved in the development of GD (7). In addition, thyroid autoantigen genes are also related to the development of GD (7). Thus, researchers want to find some genetic predictors for the recurrence risk in GD patients after ATD withdrawal.

Recently, the relationship between gene polymorphisms and the recurrence risk in GD patients after ATD withdrawal have been investigated (8–13). We carried out a computerized literature search in PubMed, EMBASE, Web of Science, Cochrane database, and reference lists of relevant studies up to July 20, 2017. The keywords of retrieval were (“polymorphism” or “variant” or “mutation” or “gene” or “genotype”) and (“antithyroid drug” or “antithyroid medicine” or “antithyroid agent” or “methimazole” or “propylthiouracil” or “carbimazole”), in combination with (“hyperthyroidism” or “Graves’ disease” or “thyrotoxicosis”), without language or region restriction. In general, the ATD treatment duration is recommended as 12–18 months, so the recurrence of GD was defined as the recurrence of hyperthyroidism after at least 12 months of ATD treatment (17). The eligible studies were observational cohort or case-control studies and were identified according to the following criteria: (1) studies that investigated the association between gene polymorphism and the recurrence in GD patients after ATD withdrawal; (2) the duration of ATD therapy was 12 months or more; (3) TRAb was negative when stopping ATD treatment; (4) the follow-up duration was at least 12 months after ATD withdrawal. The exclusion criteria included: (1) duplicated studies; (2) case, reviews, letter, or books; and (3) unavailable data.

A total of 146 studies were identified through database searching. However, after manually screening the titles and abstracts, 24 studies were chosen after excluding duplicates and irrelevant papers. The remaining 24 studies were reviewed in detail. Fourteen of these were removed because they did not fulfill the inclusion criteria, and four were excluded due to overlapping data, insufficient data for analysis, or other reasons. The flowchart, including study identification, inclusion, and exclusion factors is shown in Figure 1. Finally, only 6 studies, including 4 observational cohort studies and 2 case-control studies, with a total of 1,398 GD patients, were included (8–13).

The main characteristics of the included studies are shown in Table 1. Of the six studies, three were conducted in Asian populations, and three in Caucasian populations. The types of gene polymorphism included: CTLA4 polymorphisms (rs231775, rs3087243, rs5742909, rs231777, and rs231779), PTPN22 polymorphism (rs2476601), HLA polymorphisms (DRB1*03, DQA1*05, and DQB1*02), CD40 polymorphisms (rs745307, rs11569309, rs3765457, rs1883832, rs1535045, and rs4810485), CD28 polymorphisms (rs1879877 and rs3181113), T393C SNP of Galphas gene (GNAS1), and E33SNP of thyroglobulin (Tg) (Tg E33SNP). The follow-up duration was 12–36 months after withdrawing therapy. Among these studies, two evaluated CTLA4 rs231775 (8, 9), two evaluated CTLA4 rs3087243 (8, 9), two evaluated HLA DQA1*05 (8, 13). Only one study evaluated the rest of the gene polymorphisms. Among these gene polymorphisms, CTLA4 rs231775, HLA polymorphisms (DRB1*03, DQA1*05, and DQB1*02), CD40 polymorphisms (rs745307, rs11569309, and rs3765457), PTPN22 polymorphism (rs2476601), T393C SNP of GNAS1 and Tg E33SNP were observed to be associated with the high-recurrence risk in GD patients after ATD withdrawal (8–13).

Antithyroid drug is a common choice for a new diagnosed GD patient, and some genetic factors may greatly influence therapeutic outcome for GD patients. Based on a limited number of studies, CTLA4 polymorphism (rs231775), HLA polymorphisms (DRB1*03, DQA1*05, and DQB1*02), CD40 polymorphisms (rs745307, rs11569309, and rs3765457), PTPN22 polymorphism (rs2476601), T393C SNP of GNAS1 and Tg E33SNP might be associated with the high recurrence risk in GD patients after ATD withdrawal. Further, prospective studies on patients of different ethnicities, especially studies with large sample sizes, and long-term follow-up, should be conducted to confirm the predictive roles of gene polymorphism.

JL and GW conceived and designed the review; JL, JF, YD, and GW performed the review; JL, JF, and YD analyzed the data; JL and GW wrote the paper.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.