ABSTRACT
BACKGROUND: Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. METHODS: Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. RESULTS: Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). CONCLUSIONS: These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.
In a large, pediatric inflammatory bowel disease cohort comprised of 5 genetic ancestry groups, we evaluated the distribution of loss-of-function pharmacogenetic variants in TPMT and NUDT15 and predicted phenotypes (impact on thiopurine metabolism).
ABSTRACT
BACKGROUND: Significant changes in perioperative red blood cell (RBC) transfusion practice during the past two decades have been reported but similar data are not available for patients undergoing abdominal aortic aneurysm (AAA) surgery. METHODS: Adult patients who had undergone primary, elective, open AAA repair were stratified into one of two transfusion-related groups: early practice (1980-1982) or late practice (2003-2006). RBC transfusion and hemoglobin concentration (Hb) were analyzed as a continuous variable and compared between groups with use of the rank sum test. Perioperative complications were compared between groups with Fisher's exact test. Data were age adjusted, and analyses were corrected for multiple comparisons. RESULTS: Compared with the early practice group, patients in the late practice group had significantly lower intraoperative (mean 10 +/- 1.4 vs. 11.5 +/- 1.5 g/dL), postoperative (11.9 +/- 1.4 vs. 13.4 +/- 1.5 g/dL), and discharge Hbs (mean 10.8 +/- 1.2 vs. 12.5 +/- 1.5 g/dL) (p < 0.0001 for each variable). Patients in the late practice group were significantly less likely to receive intraoperative allogenic transfusions (46% vs. 99%, p < 0.0001). Additionally, significantly fewer total allogenic units of RBCs per patient were transfused in the late practice group (mean 1.7 vs. 4.3, p < 0.0001). Intraoperative autotransfusions were used in 97% of the late practice patients but in none of the early practice patients (p < 0.0001). In the late practice group, 119 patients (40%) experienced a major perioperative morbidity or mortality event compared with 106 patients (35%) in the early practice group (p = 0.27). CONCLUSION: In this retrospective analysis, we observed significantly lower perioperative Hb, fewer allogenic RBC transfusions, and more autotransfusions in open AAA repairs done in 2003-2006 versus those done in 1980-1982. Additionally, late transfusion practice patients were older and had more comorbid diseases. Despite these observations, no significant differences in perioperative morbidity or mortality were observed between groups.