Yaron Tomer1. 1. Division of Endocrinology, Department of Medicine, Mount Sinai Medical Center, New York, New York 10029, USA. yaron.tomer@mssm.edu
Abstract
BACKGROUND: Autoimmune thyroid diseases (AITD), including Graves' disease and Hashimoto's thyroiditis, arise due to complex interactions between environmental and genetic factors. There are sound data coming from epidemiological, family, and twin studies demonstrating a strong genetic influence on the development of AITD. In this review we summarize the new findings on the genetic susceptibility to AITD focusing on emerging mechanisms of susceptibility. SUMMARY: Candidate gene analysis, whole-genome linkage screening, genome-wide association studies, and whole-genome sequencing are the major technologies that have advanced this field, leading to the identification of at least seven genes whose variants have been associated with AITD. One of the major ones is the HLA-DR gene locus. Recently, it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide-binding pocket is key to the etiology of both Graves' disease and Hashimoto's thyroiditis. Several other genes have also been shown to confer susceptibility to AITD. These can be classified into two groups: (i) immune regulatory genes (cytotoxic T lymphocyte-associated protein 4, CD40, protein tyrosine phosphatase-22, and CD25) and (ii) thyroid-specific genes (thyroglobulin and thyrotropin receptor genes). The influence of individual genes on the development of AITD when assessed in a population appears to be weaker than would be expected from the data showing strong genetic susceptibility to AITD. Two possible mechanisms explaining this discrepancy are gene-gene interactions and subset effects. CONCLUSIONS: Significant progress has been made in our understanding of the immunogenetic mechanisms leading to thyroid autoimmunity. For the first time we are beginning to unravel these mechanisms at the molecular level. It is hoped that these new data will be translated into novel therapies and prevention strategies in AITD, such as costimulatory blockade.
BACKGROUND:Autoimmune thyroid diseases (AITD), including Graves' disease and Hashimoto's thyroiditis, arise due to complex interactions between environmental and genetic factors. There are sound data coming from epidemiological, family, and twin studies demonstrating a strong genetic influence on the development of AITD. In this review we summarize the new findings on the genetic susceptibility to AITD focusing on emerging mechanisms of susceptibility. SUMMARY: Candidate gene analysis, whole-genome linkage screening, genome-wide association studies, and whole-genome sequencing are the major technologies that have advanced this field, leading to the identification of at least seven genes whose variants have been associated with AITD. One of the major ones is the HLA-DR gene locus. Recently, it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide-binding pocket is key to the etiology of both Graves' disease and Hashimoto's thyroiditis. Several other genes have also been shown to confer susceptibility to AITD. These can be classified into two groups: (i) immune regulatory genes (cytotoxic T lymphocyte-associated protein 4, CD40, protein tyrosine phosphatase-22, and CD25) and (ii) thyroid-specific genes (thyroglobulin and thyrotropin receptor genes). The influence of individual genes on the development of AITD when assessed in a population appears to be weaker than would be expected from the data showing strong genetic susceptibility to AITD. Two possible mechanisms explaining this discrepancy are gene-gene interactions and subset effects. CONCLUSIONS: Significant progress has been made in our understanding of the immunogenetic mechanisms leading to thyroid autoimmunity. For the first time we are beginning to unravel these mechanisms at the molecular level. It is hoped that these new data will be translated into novel therapies and prevention strategies in AITD, such as costimulatory blockade.
Authors: R A Metcalfe; R S McIntosh; F Marelli-Berg; G Lombardi; R Lechler; A P Weetman Journal: J Clin Endocrinol Metab Date: 1998-04 Impact factor: 5.958
Authors: Yaron Tomer; Yoshiyuki Ban; Erlinda Concepcion; Giuseppe Barbesino; Ronald Villanueva; David A Greenberg; Terry F Davies Journal: Am J Hum Genet Date: 2003-09-12 Impact factor: 11.025
Authors: J E Collins; J M Heward; J Carr-Smith; J Daykin; J A Franklyn; S C L Gough Journal: J Clin Endocrinol Metab Date: 2003-10 Impact factor: 5.958
Authors: Ann B Begovich; Victoria E H Carlton; Lee A Honigberg; Steven J Schrodi; Anand P Chokkalingam; Heather C Alexander; Kristin G Ardlie; Qiqing Huang; Ashley M Smith; Jill M Spoerke; Marion T Conn; Monica Chang; Sheng-Yung P Chang; Randall K Saiki; Joseph J Catanese; Diane U Leong; Veronica E Garcia; Linda B McAllister; Douglas A Jeffery; Annette T Lee; Franak Batliwalla; Elaine Remmers; Lindsey A Criswell; Michael F Seldin; Daniel L Kastner; Christopher I Amos; John J Sninsky; Peter K Gregersen Journal: Am J Hum Genet Date: 2004-06-18 Impact factor: 11.025
Authors: Y Ban; T F Davies; D A Greenberg; A Kissin; B Marder; B Murphy; E S Concepcion; R B Villanueva; G Barbesino; V Ling; Y Tomer Journal: Genes Immun Date: 2003-12 Impact factor: 2.676
Authors: Deborah Smyth; Jason D Cooper; Joanne E Collins; Joanne M Heward; Jayne A Franklyn; Joanna M M Howson; Adrian Vella; Sarah Nutland; Helen E Rance; Lisa Maier; Bryan J Barratt; Cristian Guja; Constantin Ionescu-Tîrgoviste; David A Savage; David B Dunger; Barry Widmer; David P Strachan; Susan M Ring; Neil Walker; David G Clayton; Rebecca C J Twells; Stephen C L Gough; John A Todd Journal: Diabetes Date: 2004-11 Impact factor: 9.461
Authors: Mihaela Stefan; Eric M Jacobson; Amanda K Huber; David A Greenberg; Cheuk Wun Li; Luce Skrabanek; Erlinda Conception; Mohammed Fadlalla; Kenneth Ho; Yaron Tomer Journal: J Biol Chem Date: 2011-07-12 Impact factor: 5.157