To our knowledge, our study is the first to analyze the relationships of whole genome SNPs with HZ infection among bDMARDS-treated RA patients and to identify a SNP as one of the biomarkers for HZ infection.
It has been reported that aging, high disease activity, corticosteroid use and the use of methotrexate are risk factors for HZ infection in RA patients5. In addition, it has been reported that susceptibility to HZ infection in RA varies by race8. In fact, Japanese and Taiwanese have a higher risk compared to Americans and Europeans9. In this regard, genetic background may also affect the susceptibility. However, because there are not studies that take into account genetic polymorphisms such as SNPs, it is likely that genetic polymorphisms associated with the susceptibility were overlooked. Therefore, we conducted GWAS which is powerful tool to collectively identify SNPs associated with the susceptibility.
In our study, rs10774580 located in intron region of OASL gene was significantly associated with HZ infection. The minor allele homozygous were positively associated with HZ infection. Human OASL has an antiviral activity against RNA viruses10,11. On the other hand, OASL inhibits type I interferon (IFN) induction during DNA virus infection such as herpes simplex, vaccinia and adenovirus12. This is because OASL binds to cylic GMP-AMP synthase (cGAS) known as DNA sensor, and inhibits cyclic GMP-AMP (cGAMP) synthesis in cGAS-STING (stimulator of interferon gene) pathway sensing the majority of DNA viruses12. Inhibiting IFN induction leads to enhancing DNA virus replication. Therefore, rs10774580 may affect the transcription of OASL because this SNP is intronic variation without amino acid substitution. As the result, the expression levels among OASL genotypes vary, and then differences of the susceptibility may be caused.
Interestingly, several previous studies revealed that using Janus Kinase (JAK) inhibitors increased the risk of HZ infection compared to bDMARDS13, 14. In this regard, it is unclear if rs10774580 is also associated with HZ infection in JAK inhibitors-treated RA patients. Thus, further analyses are needed in JAK inhibitors-treated RA patients.
This study has several limitations. First, rs10774580 was identified by the result of GWAS among Japanese RA patients. It is well known that allele frequencies of most SNPs vary in different ethnic groups. The allele frequency of rs10774580 we identified also varied compared with the allele frequency of other ethnic groups reported in the HapMap database (https://www.ncbi.nlm.nih.gov/snp). Therefore, rs10774580 may not be applicable to non-Japanese RA patients as the biomarker. A second limitation is that this study didn’t take into consideration the incidence of HZ in each patient. It is well known that some RA patients repeatedly develop HZ. Therefore, in order to identify the other biomarkers, further studies taking in the incidence of HZ into consideration are desired.