Abstract
BackgroundGraves’ disease (GD) is a complex disease in which genetic predisposition is modified by environmental factors. Each gene exerts limited effects on the development of autoimmune disease (OR = 1.2–1.5). An epidemiological study revealed that nearly 70% of the risk of developing inherited autoimmunological thyroid diseases (AITD) is the result of gene interactions. In the present study, we analyzed the effects of the interactions of multiple loci on the genetic predisposition to GD. The aim of our analyses was to identify pairs of genes that exhibit a multiplicative interaction effect.Material and MethodsA total of 709 patients with GD were included in the study. The patients were stratified into more homogeneous groups depending on the age at time of GD onset: younger patients less than 30 years of age and older patients greater than 30 years of age. Association analyses were performed for genes that influence the development of GD: HLADRB1, PTPN22, CTLA4 and TSHR. The interactions among polymorphisms were analyzed using the multiple logistic regression and multifactor dimensionality reduction (MDR) methods.ResultsGD patients stratified by the age of onset differed in the allele frequencies of the HLADRB1*03 and 1858T polymorphisms of the PTPN22 gene (OR = 1.7, p = 0.003; OR = 1.49, p = 0.01, respectively). We evaluated the genetic interactions of four SNPs in a pairwise fashion with regard to disease risk. The coexistence of HLADRB1 with CTLA4 or HLADRB1 with PTPN22 exhibited interactions on more than additive levels (OR = 3.64, p = 0.002; OR = 4.20, p < 0.001, respectively). These results suggest that interactions between these pairs of genes contribute to the development of GD. MDR analysis confirmed these interactions.ConclusionIn contrast to a single gene effect, we observed that interactions between the HLADRB1/PTPN22 and HLADRB1/CTLA4 genes more closely predicted the risk of GD onset in young patients.
Highlights
Autoimmune thyroid diseases (AITDs) are multifactorial diseases involving both susceptibility alleles of a number of genes and environmental factors [1,2]
Graves’ disease (GD) patients stratified by the age of onset differed in the allele frequencies of the HLADRB1*03 and 1858T polymorphisms of the PTPN22 gene (OR = 1.7, p = 0.003; odd ratio (OR) = 1.49, p = 0.01, respectively)
In contrast to a single gene effect, we observed that interactions between the HLADRB1/ PTPN22 and HLADRB1/CTLA4 genes more closely predicted the risk of GD onset in young patients
Summary
Autoimmune thyroid diseases (AITDs) are multifactorial diseases involving both susceptibility alleles of a number of genes and environmental factors [1,2]. An epidemiological study revealed that nearly 70% of the risk of developing inherited AITD is the result of the interaction of multiple genes [8]. The complex interactions among genes and environmental factors complicates the identification of polymorphisms of susceptible genes involved in the development of GD. Young patients are susceptible to environmental factors for a shorter time than older patients, potentially simplifying the identification of a genetic predisposition for the development of complex diseases such as AITDs [11]. An epidemiological study revealed that nearly 70% of the risk of developing inherited autoimmunological thyroid diseases (AITD) is the result of gene interactions. The aim of our analyses was to identify pairs of genes that exhibit a multiplicative interaction effect
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