Can Pharmacogenetic Variants in TPMT, MTHFR and SLCO1B1 Genes Be Used as Potential Markers of Outcome Prediction in Systemic Sclerosis Patients?

Abstract

Systemic sclerosis (SSc) is a rare connective tissue disorder with highest morbidity and mortality among rheumatologic diseases. Disease progression is highly heterogeneous between patients, implying a strong need for individualization of therapy. Four pharmacogenetic variants, namely TPMT rs1800460, TPMT rs1142345, MTHFR rs1801133 and SLCO1B1 rs4149056 were tested for association with severe disease outcomes in 102 patients with SSc from Serbia treated either with immunosuppressants azathioprine (AZA) and methotrexate (MTX) or with other types of medications. Genotyping was performed using PCR-RFLP and direct Sanger sequencing. R software was used for statistical analysis and development of polygenic risk score (PRS) model. Association was found between MTHFR rs1801133 and higher risk for elevated systolic pressure in all patients except those prescribed with MTX, and higher risk for kidney insufficiency in patients prescribed with other types of drugs. In patients treated with MTX, variant SLCO1B1 rs4149056 was protective against kidney insufficiency. For patients receiving MTX a trend was shown for having a higher PRS rank and elevated systolic pressure. Our results open a door wide for more extensive research on pharmacogenomics markers in patients with SSc. Altogether, pharmacogenomics markers could predict the outcome of patients with SSc and help in prevention of adverse drug reactions.

Impaired Regulation by IL-35 in Systemic Sclerosis

“…Plasmatic IL-35, compared to other published biomarkers, is easy to obtain via non-invasive techniques, as are its dynamics, and it can be associated with severity and classification regardless of the received treatment. However, it would be interesting to evaluate whether plasmatic IL-35 can be associated with other recent predictor markers, such as nailfold videocapillaroscopy or pharmacogenetic variant genes [ 37 , 38 , 39 ].…”

Genomic Profiling for Predictive Treatment Strategies in Fibrotic Interstitial Lung Disease

“…Patients with RA who are heterozygous for the TPMT3A allele have an increased risk of azathioprine-related haematopoietic and gastrointestinal toxicity compared to those with the wild-type allele [89,90]. A recent study investigated whether genetic variants in genes encoding enzymes involved in the methotrexate and azathioprine metabolic pathways, such as TPMT, MTHFR and SLCO1B1, are associated with disease severity in SSc patients receiving immunosuppressive drugs [76]. The authors confirmed the hypothesis that carriers of the alternative TPMT*3A allele have reduced TPMT enzyme activity, resulting in toxic metabolites and consequent AEs when azathioprine is administered.…”