Abstract
ContextThe genetic background of young-onset Graves disease (GD) remains largely unknown. An intronic variant in human leukocyte antigen (HLA) complex P5 (HCP5) has previously been associated with GD susceptibility and age of onset in a cohort of Polish patients.ObjectiveWe aimed to investigate the association of the HCP5 variant rs3094228 with GD susceptibility and age of onset in a UK cohort and conduct a meta-analysis of UK and Polish data.Design and Participants rs3094228 was genotyped in 469 UK patients with GD using Taqman chemistry. Genotype frequencies were compared with genotypic data available from the Wellcome Trust case-control consortium using logistic regression analysis. To determine whether rs3094228 is independently associated with age of GD onset, the HLA DRB1*0301 tagging variant, rs535777, was also genotyped.ResultsThe C allele of rs3094228 was overrepresented in the UK GD cohort compared with controls (P allele=5.08 × 10–9, odds ratio 1.76; [95% confidence interval, 1.46-2.13]). This association was more marked in young-onset GD (<30 years) (P allele=1.70 × 10–10 vs P allele=0.0008). The meta-analysis of UK and Polish data supported the association of the C allele with GD susceptibility (P allele=1.79 × 10–5) and age of onset (P allele=5.63 × 10–8). Haplotype analysis demonstrated that rs3094228 is associated with age of GD onset (P = 2.39 × 10-6) independent of linkage disequilibrium with HLA DRB1*0301.ConclusionThe rs3094228 HCP5 polymorphism is independently associated with GD susceptibility and age of onset in a UK GD cohort. Our findings indicate a potential role of long noncoding ribonucleic acids, including HCP5, in GD pathogenesis, particularly in the younger population.
Highlights
Design and Participants: rs3094228 was genotyped in 469 UK patients with Graves disease (GD) using Taqman chemistry
GD is characterized by the presence of thyroid receptor autoantibodies (TRAbs) that stimulate the cell-surface thyroid-stimulating hormone (TSH) receptor, directly resulting in excessive, autonomous thyroid hormone secretion
The frequency of the C allele was significantly increased in the GD cohort as a whole (303/938; 32%) compared with Wellcome Trust case-control consortium (WTCCC2) controls (2118/10 754; 20%: P = 5.08 × 10– 9; odds ratio (OR) 1.76 [95% confidence intervals (CI), 1.46-2.13])
Summary
Participants A total of 469 patients were included in the UK cohort, including 118 patients with YOGD (aged
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