Abstract
The presented comprehensive review of current knowledge about genetic factors predisposing to Graves’ disease (GD) put emphasis on functional significance of observed associations. In particular, we discuss recent efforts aimed at refining diseases associations found within the HLA complex and implicating HLA class I as well as HLA-DPB1 loci. We summarize data regarding non-HLA genes such as PTPN22, CTLA4, CD40, TSHR and TG which have been extensively studied in respect to their role in GD. We review recent findings implicating variants of FCRL3 (gene for FC receptor-like-3 protein), SCGB3A2 (gene for secretory uteroglobin-related protein 1- UGRP1) as well as other unverified possible candidate genes for GD selected through their documented association with type 1 diabetes mellitus: Tenr–IL2–IL21, CAPSL (encoding calcyphosine-like protein), IFIH1(gene for interferon-induced helicase C domain 1), AFF3, CD226 and PTPN2. We also review reports on association of skewed X chromosome inactivation and fetal microchimerism with GD. Finally we discuss issues of genotype-phenotype correlations in GD.
Highlights
Graves’ disease (GD) is an autoimmune disorder in which antibodies activate the thyrotropin receptor (TSHR) causing a hyperfunction of the thyroid gland
The familial occurrence of autoimmunological thyroid disorders (AITD) has been noticed a relatively long time ago when it was reported that a third of siblings of GD patients developed AITD and over half of asymptomatic children had thyroid antibodies in their blood [1]
Whereas linkage analysis has proved valuable in analysis of Mendelian traits its use for examining complex disorders like GD is limited by the requirement for multiplex families and by its low power to detect weak effects
Summary
Linkage analysis is based on study of family(ies) allowing to evaluate the co-segregation of a genetic variant with disease. The likelihood of linkage between a disease and genetic marker is described by the odds calculated as the ratio of the likelihood of a given distribution of genotypes in a family assuming linkage vs assuming random segregation This likelihood ratio is typically presented as a logarithm with the base of 10 and is called LOD (logarithm of odds) score. Whereas linkage analysis has proved valuable in analysis of Mendelian traits its use for examining complex disorders like GD is limited by the requirement for multiplex families and by its low power to detect weak effects. Another limitation of linkage analysis is low resolution which makes it usually impossible to separate effects of loci within 2-3 Mb
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