Polymorphisms in drug metabolism genes predict the risk of refractory myasthenia gravis.

Abstract

Nearly 10% to 20% of myasthenia gravis (MG) patients are refractory to conventional treatment for unclear reasons. The study aimed to explore the relationship between drug metabolism gene polymorphisms and refractory MG. One hundred and thirty-one MG patients (33 in the refractory group; 98 in the non-refractory group) admitted to Tongji Hospital were included in this retrospective study. Improved multiplex ligation detection reaction (iMLDR) was used to genotype 13 polymorphisms (NR3C1 rs17209237, rs9324921; FKBP5 rs1360780, rs4713904, rs9296158; HSP90AA1 rs10873531, rs2298877, rs7160651; MDR1 rs1045642, rs1128503, rs2032582; CYP3A4 rs2242480; and CYP3A5 rs776746). We applied multivariable logistic regression to investigate the association between refractory MG and nucleotide polymorphisms. Generalized multifactor dimensionality reduction (GMDR) was used to examine gene-gene interactions. CC genotype of HSP90AA1 rs7160651 was associated with the increased risk of refractory MG than CT genotype [odds ratio (OR) =0.26; P=0.041] and CT + TT genotype (dominant model, OR =0.24; P=0.022). For CYP3A5 rs776746, AA genotype was associated with refractory MG compared with AG genotype (OR =0.11; P=0.017), GG genotype (OR =0.18; P=0.033), and AG + GG genotype (dominant model, OR =0.16; P=0.020). The frequency of CAT haplotype of HSP90AA1 rs10873531, rs2298877, rs7160651 was less common in refractory patients (OR =0.33; P=0.044). No significant gene-gene interactions were observed. HSP90AA1 rs7160651 and CYP3A5 rs776746 were significantly associated with refractory MG. Further studies are warranted to confirm the results and investigate the use of polymorphisms for treatment individualization.