Genetic Analysis in Young-Age-of-Onset Graves' Disease Reveals New Susceptibility Loci

Abstract

Context: Genetic and environmental factors play an essential role in the pathogenesis of Graves' Disease (GD). Children with GD have less exposure time to environmental factors and therefore are believed to harbor stronger genetic susceptibility than adults. Objective: The aim of the study was to identify susceptibility loci that predispose to GD in patients with young-age-of-onset (YAO) GD. Setting and Design: One hundred six patients with YAO GD (onset <30 y) and 855 healthy subjects were studied. Cases and controls were genotyped using the Illumina Infinium Immunochip, designed to genotype 196,524 polymorphisms. Case control association analyses were performed using the PLINK computer package. Ingenuity Pathway Analysis program (QIAGEN) was used to carry out pathway analyses. Results: Immunochip genetic association analysis identified 30 single-nucleotide polymorphisms in several genes that were significantly associated with YAO GD, including major histocompatibility complex class I and class II genes, BTNL2, NOTCH4, TNFAIP3, and CXCR4. Candidate gene analysis revealed that most of the genes previously shown to be associated with adult-onset GD were also associated with YAO GD. Pathway analysis demonstrated that antigen presentation, T-helper cell differentiation, and B cell development were the major pathways contributing to the pathogenesis of YAO GD. Conclusions: Genetic analysis identified novel susceptibility loci in YAO GD adding a new dimension to the understanding of GD etiology.