Genome-wide analysis of methotrexate pharmacogenomics in rheumatoid arthritis shows multiple novel risk variants and leads for TYMS regulation

Abstract

In this first ever genome-wide analysis on MTX treatment response in RA patients, 10 new risk loci were identified. These preliminary findings warrant replication in independent studies. Further, TYMS expression at the post-transcriptional level seems to be probably regulated through an antisense-RNA involving the 6-bp ins/del marker in the overlapping segment at 3'UTR of TYMS-ENOSF1, a finding with impending pharmacogenetic applications.

Medical genetics and genomic medicine in India: current status and opportunities ahead

“…Pharmacogenomics is also an important area of work of many scientists (Senapati et al. ). However, the contribution of Indian scientists to gene mapping has been limited.…”

Does a family history of RA influence the clinical presentation and treatment response in RA?

“…Alleles influencing response only to specific drugs would also be expected, for example, those involved in the drug's metabolism. However, no clinically useful alleles have yet been identified, with genome-wide association studies identifying only a handful of non-replicated loci for response to methotrexate (MTX)4 and tumour necrosis factor inhibitors (TNFi) 5–7. For HLA-DRB1 , the main risk locus for developing RA, most studies report no association of the ‘shared epitope’ alleles with response to MTX8–10 or TNFi,8 11–14 but a recent study found that alleles altering several amino acids in HLA-DRB1 were associated with radiological progression and response to TNFi 15…”

Associations between single-nucleotide polymorphisms of RFC-1, GGH, MTHFR , TYMS, and TCII genes and the efficacy and toxicity of methotrexate treatment in patients with rheumatoid arthritis

“…39 There is a chance that future individualization of therapy will allow to adapt the applied treatment to a particular molecular subtype of a disease and the patient's genotype. The further development of pharmacogenetics will contribute to improved efficacy of therapies…”