How much of the predisposition to Hashimoto’s thyroiditis can be explained based on previously reported associations?

Abstract

PurposeOur insight in the genetics of Hashimoto’s thyroiditis (HT) has become clearer through information provided by genome-wide association studies and candidate gene studies, but remains still not fully understood. Our aim was to assess how many different genetic risk variants contribute to the development of HT.Methods147 HT cases (10.2% men) and 147 controls (13.6% men) were qualified for the analysis. Intrinsic and environmental factors were controlled for. Polymorphisms (SNP) were chosen based on the literature and included markers of the genes PTPN22, CTLA4, TG, TPO among others, and of genomic regions pointed by GWAS studies. SNP were typed on a microarray. Variants in the HLA-DRB1 gene were identified by Sanger sequencing.ResultsMultivariate predisposition to HT was modeled. Based on the investigated group, a model of seven variables was obtained. The variability explained by this model was assessed at only 5.4821% (p = 2 × 10−6), which indicates that many dozens of factors are required simultaneously to explain HT predisposition.ConclusionsWe analyzed genetic regions commonly and most significantly associated with autoimmune thyroid disorders in the literature, on a carefully selected cohort. Our results indicated a lack of possibility to predict the risk of HT development, even with a multivariate model. We therefore conclude that strong associations of single genetic regions with HT should be interpreted with great caution. We believe that a change in the attitude towards genetic association analyses of HT predisposition is necessary. Studies including multiple factors simultaneously are needed to unravel the intricacies of genetic associations with HT.Electronic supplementary materialThe online version of this article (10.1007/s40618-018-0910-4) contains supplementary material, which is available to authorized users.

An update on the pathogenesis of Hashimoto’s thyroiditis

“…Most attempts to look at the genes which predispose to autoimmune thyroid disease have recently focussed on Graves’ disease rather than HT but an attempt has been to look at how much the established or tentative polymorphisms associated with HT actually contribute. In a relatively small series of 142 Polish cases, only seven polymorphisms could be confirmed as being associated, contributing 5.5% of the overall variability, and none of the usual environmental factors appeared to be associated with susceptibility either, presumably due to sample size [ 5 ]. Another study from Croatia of 405 patients, with a confirmation cohort of a further 303, identified three novel variants contributing 4.8% of the genetic variance in HT, but due to limited power the authors could not confirm associations already established by conventional association studies [ 6 ].…”

Genetic Susceptibility to Joint Occurrence of Polycystic Ovary Syndrome and Hashimoto’s Thyroiditis: How Far Is Our Understanding?

“…Several GWAS for AITD (HT or GD), hypothyroidism, positivity for anti-thyroid (anti-TPO or anti-Tg) antibodies, and thyroid function parameters (including TSH or fT 4 levels), have been undertaken ( Table 2 ) ( 133 – 135 , 139 – 146 , 148 , 154 , 155 , 157 – 160 ). Some GWAS-identified AITD susceptibility loci have been replicated in different populations ( Table 2 ) ( 136 – 138 , 147 , 149 – 153 , 156 ); however, HT is rather poorly represented among GWAS. Numerous studies have been performed using small cohorts or patients with HT and GD grouped together ( 128 , 161 ).…”

“…Indeed, the non-synonymous TG variant, W1999R, can interact with HLA-DRβ1-Arg74, and together these two variants confer a high risk for AITD ( 182 ). Recently, among Polish patients, HLA-DRB1 with phenylalanine at position 67 (encoded by the rs17886918T variant) was significantly associated with HT ( 138 ).…”

“…Moreover, all susceptibility loci identified to date together account for only a small proportion of the heritability of HT ( 209 ). It is estimated that < 5.5% of total HT variance can be explained by common genetic variants ( 138 , 157 ), indicating that a substantial number of HT predisposing factors remain to be discovered.…”

Autosomal dominant Hashimoto’s thyroiditis with a mutation in <i>TNFAIP3</i>

“…Thus, we considered that HA20 might drive other genetic factors associated with autoimmune disorders such as HLA . HT is linked to particular HLA antigens or HLA alleles such as A2 (7), A*02:07 (8), DR3 (9), DRB1*03:01 (10), DR4 (DR53, DRB4) (7-9), DR5 (11), and DRB1*11:04 (12). Furthermore, because both the TNFAIP3 and HLA are located on chromosome 6, we speculate that an association exists between TNFAIP3 and HLA .…”