Expansion of the immature B lymphocyte compartment in Graves' disease.

OBJECTIVE: The specific mechanisms driving autoimmunity in Graves' disease (GD) remain largely unknown. Kappa-deleting recombination excision circles (KRECs) are circular DNA molecules generated during B cell maturation in the bone marrow which provide a measure of B cell production and proliferation. We aimed to investigate the association between KRECs and B cell subpopulations, with thyroid status and clinical outcome in GD patients. METHODS: Kappa-deleting recombination excision circles were measured by quantitative real-time PCR using a triple-insert plasmid control in 132 GD patients and 140 healthy controls. In addition, KRECs in GD patients on withdrawal of antithyroid drug (ATD) and 6-10 weeks later were analysed according to a clinical outcome at 1 year. Flow cytometry was performed on isolated CD19+ B cells to quantitate 7 B lymphocyte subpopulations in 65 GD patients. RESULTS: Circulating KRECs were higher in GD vs. controls (P = 1.5 × 10-9) and demonstrated a positive correlation to thyroid hormones and autoantibodies (free thyroxine: P = 2.14 × 10-5, rho = .30; free triiodothyronine: P = 1.99 × 10-7, rho = .37; thyroid stimulating hormone receptor autoantibodies: P = 1.36 × 10-5, rho = .23). Higher KRECs in GD patients 6-10 weeks after ATD withdrawal were associated with relapse of hyperthyroidism at 1 year (P = .04). The KRECs were positively correlated to the total CD19+ B cell count (P = 3.2 × 10-7). CONCLUSIONS: This study reports a robust association between KRECs and GD, highlighting the importance of B cells in the pathogenesis of GD and the influence of thyroid status on B cell activity. The findings indicate a potential role for KRECs as a marker of disease activity and outcome in GD.

A survey of the young person's experience of Graves' disease and its management.

OBJECTIVE: A suboptimal quality of life (QoL) has been reported in patients with Graves' disease treated in adult life, but long-term QoL in those treated in childhood and adolescence is unclear. We wanted to understand how Graves' disease and its management impact on the physical, psychological and social well-being of young people and their longer-term QoL. DESIGN, PATIENTS AND MEASUREMENTS: Two questionnaires were used to assess QoL and patient experience of Graves' disease; PedsQL™ Generic Core Scales and a Graves' disease questionnaire devised for this project. The anonymized questionnaires were sent to young people (<30 years) diagnosed with Graves' disease in childhood and adolescence and managed at a tertiary paediatric endocrine unit in the North of England. Respondent QoL scores were compared with a healthy UK cohort. RESULTS: Questionnaires were sent to 51 young people, and 26 responded (51%). Graves' patients reported a lower total QoL score compared with the healthy cohort (p = .003). This was particularly apparent in the psychosocial domain (p = .0016). No patient regretted having definitive treatment (surgery/radioiodine), and all said they would recommend it to others. Half of those who had received definitive treatment still did not feel recovered. There was no difference in the long-term QoL in those who did/did not receive definitive treatment (p = .40). CONCLUSIONS: This study highlights short- and long-term impacts on the QoL and general well-being of young people with Graves' disease. There were no regrets regarding the choice of definitive treatment. This information will help inform the counselling of patients and their families.

An Intronic HCP5 Variant Is Associated With Age of Onset and Susceptibility to Graves Disease in UK and Polish Cohorts.

CONTEXT: The 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. OBJECTIVE: We 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. RESULTS: The 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. CONCLUSION: The 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.