Abstract
Objective Antithyroid drug (ATD)-induced agranulocytosis (TIA) is the most
serious adverse effect during ATD treatment of Graves’ disease (GD).
Previously, the MICA gene was reported to be associated with TIA.
MICA protein is an important ligand for the NKG2D protein, which is
encoded by the KLRK1 gene and KLRC4-KLRK1 read-through
transcription. This study further investigated the association between
KLRC4-KLRK1 gene polymorphisms and susceptibility to TIA.
Methods Twenty-eight candidate single nucleotide polymorphisms (SNPs) on
KLRC4-KLRK1 read-through transcription were evaluated by the iPLEX
MassARRAY system in 209 GD control patients and 38 TIA cases.
Results A significant association of rs2734565 polymorphism with TIA was
found (p=0.02, OR=1.80, 95%
CI=1.09–2.96). The haplotype C-A-A-C-G, including rs2734565-C,
was associated with a significantly higher risk of TIA (p=4.79E-09,
OR=8.361, 95% CI=3.737–18.707). In addition, the
interval time from hyperthyroidism to agranulocytosis onset was shorter in
patients carrying the rs2734565-C allele than in non-carrying groups (45.00
(14.00–6570.00) d vs. 1080.00 (30.00–3600.00) d,
p=0.046), and the interval from ATD treatment to
agranulocytosis onset was also shorter in patients carrying rs2734565-C allele
(29.00 (13.00–75.00) d vs. 57.50 (21.00–240.00) d,
p=0.023).
Conclusions The findings suggest that the KLRC4-KLRK1 gene
polymorphism is associated with susceptibility and progression of ATD-induced
agranulocytosis. Patients carrying the rs2734565-C allele had a higher
susceptibility and faster onset time of TIA.
Key words
KLRC4-KLRK1 - antithyroid drug - induced agranulocytosis - natural killer group 2D - Graves’ disease - association