About this research group
A few years ago the research of our group mainly focussed on pharmacogenetics of biological treatment in rheumatoid arthritis. We published the first genome-wide association analysis for anti-TNF treatment outcome and the first large-scale genetic study using other disease outcome measures as proxy for the standard clinical outcome measure.
For gene-finding research we now mainly focus on the pharmacogenetics in paediatric (cancers). We have set up the Genetics of Osteosarcoma (GO) consortium consisting of Dutch researchers and seven international groups. We have access to the world-wide largest osteosarcoma cohort for pharmacogenetics. We are expanding this research to childhood brain tumours for which we already collaborate with 5 international groups. We start to apply pharmacogenetics to other paediatric diseases (e.g. haemophilia).
Concerning implementation studies, we lead the world-wide largest randomized controlled trial for cost-effectiveness of thiopurine-S-methyltransferase genotyping prior to thiopurine treatment in inflammatory bowel disorders patients. This study showed that pre-treatment genotyping results in a statistically significant reduction of leukopenia without any additional costs. A similar multicentre study ongoing in psychiatry focussing on cost-effectiveness of pharmacogenetic testing prior to tricyclic anti-depressant treatment. Within the department of Human Genetics, we are also responsible for diagnostic pharmacogenetic testing.
We have several aims:
To identify genetic variants associated with treatment outcome in osteosarcoma.
Identify genetic variants (osteosarcoma)
To identify genetic variants associated with treatment outcome in osteosarcoma. We will perform genome-wide association studies to identify genetic variants associated with treatment response and side-effects. Identified genetic variants will be further characterised using functional studies.
To identify genetic variants linked to treatment outcome in patients with paediatric brain tumours.
Identify genetic variants (paediatric)
To identify genetic variants linked to treatment outcome in patients with paediatric brain tumours. For this study we are collecting samples and the first genome-wide association analysis is planned to identify genes linked to side-effects (ototoxicity and renal failure) and treatment response (survival).
To investigate if pharmacogenetic testing before treatment with tri-cyclic anti-depressants is (cost)effective in patients with severe depression.
(Cost)effectiveness of pharmacogenetic testing
To investigate if pharmacogenetic testing before treatment with tri-cyclic anti-depressants is (cost)effective in patients with severe depression. For this we have set-up a multi-centre randomized clinical trial. Once patient inclusion is finished we will perform a cost-effectiveness analysis.
To keep diagnostic pharmacogenetic testing up-to-date.
Pharmacogenetics of osteosarcoma
We have identified five variants significantly associated with 5-year disease free survival ((DFS), interval between diagnosis and progression/recurrence): FasL rs763110, MSH2 rs4638843, CASP3 rs939338, ABCC5 rs2720376 and CYP3A4 rs4646437, using Dutch GO-samples. Patients carrying only a few risk alleles (based on the combined effects of the five investigated variants) showed a significant improved 5-year DFS (PMID: 25829401).
In addition, we tried to replicate previously reported associations between TPMT, COMT and ACYP2 and therapy induced ototoxicity. We could not replicate the association between genetic variants in TPMT and COMT and ototoxicity (PMID: 25551397). The association between ACYP2 and ototoxicity could be confirmed in our osteosarcoma patient cohort (PMID:26928270). We obtained similar results for patients with head and neck cancer (PMID: 30999660).
Cost effectiveness of thiopurine-S-methyltransferase (TPMT) genotyping prior to thiopurine treatment in inflammatory bowel disorders patients.
We proved that prior-to-treatment TPMT genotype-guided dosing followed by dose adjustment results in a statistically significant decrease in myelotoxicity (p=0.011) in patients carrying a genetic variant in TPMT (PMID:26072396). In addition we showed that this intervention is cost-effective (PMID: 30698675). However, not all cases of the life-threatening myelotoxicity nor other severe ADRs, can be prevented by pre-emptive TPMT genotyping therefore we performed several other studies to investigate if other factors can explain these cases (PMID: 28914446, 28644183, 28045129, 27943397, 27402913, 29120908).