Genetic Markers of Graves’ Disease: A Historical View and Up-date

Two decades of intensive but quite chaotic and decentralized population studies on susceptibility to Graves’ disease (GD) provided a bulk of inconsistent data resulted in finding of proven association only for the HLA class II region that exerts a major effect in the genetics of GD. Using low-resolution microsatellite-based human genome-wide scans revealed several regions of linkage harboring putative susceptibility variants. Further, high throughput genotyping of large population cohorts with help of high dense panels of single nucleotide polymorphisms (SNPs) and application of advanced tools for analysis of extended blocks of linkage disequilibrium within a candidate gene (SNP tagging, etc.) revealed the presence of several susceptibility genes in the regions of linkage on chromosome 2q (CTLA-4), 8q (Tg), 14q (TSHR), 20q (CD40), 5q (SCGB3A2/UGRP1) and, probably, Xp (FOXP3). The list of GD-predisposing loci was then extended with three more genes (PTPN22, IL2RA/CD25, and FCRL3). In the nearest future, implementation of even more robust technology such as whole-genome sequencing is expected to catch any disease-associated genetic variation in the patient’s individual DNA. In this review, the historical development of our knowledge on genetic factors predisposing to GD is considered, with special emphasis on the functional significance of observed associations and discussion of possible mechanisms of their contribution to GD pathogenesis.