Journal Article

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

Cheetham, Timothy, Lane, Laura Claire, Jurecka-Lubieniecka, Beata, Bednarczuk, Tomasz, Cordell, Heather Jane, Pearce, Simon Henry Schofield, Bossowski, Artur, Kuś, Aleksander, Mitchell, Anna Louise, Daroszewski, Jacek

2020

Overview

Abstract 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.

• Publisher: Oxford University Press,Copyright Oxford University Press
• Subject: Adolescent / Adult / Age / Age of Onset / Aged / Aged, 80 and over / Alleles / Case-Control Studies / Child / Child, Preschool / Cohort Studies / Comparative analysis / Consortia / Disease susceptibility / Drb1 protein / Female / Gene Frequency / Gene polymorphism / Genetic aspects / Genetic Association Studies / Genetic polymorphisms / Genetic Predisposition to Disease / Graves disease / Graves Disease - epidemiology / Graves Disease - genetics / Haplotypes / Histocompatibility antigen HLA / Histocompatibility antigens / HLA histocompatibility antigens / Humans / Introns - genetics / Linkage disequilibrium / Male / Meta-analysis / Middle Aged / Online Only / Poland - epidemiology / Polymorphism, Single Nucleotide / RNA, Long Noncoding - genetics / Susceptibility / Trusts and trustees / United Kingdom - epidemiology / Young Adult