Marieke J. H. Coenen

Urgency urinary incontinence (UUI) and Alzheimer’s disease (AD) are highly comorbid conditions in women, but the underlying molecular mechanisms are largely unknown. Therefore, we used network enrichment analyses and an elaborate literature search to integrate the most significant genes from four genome-wide association studies (GWASs) and other genetic, expression and functional evidence into a molecular landscape of female UUI. This molecular landscape centers around local, i.e., bladder-based, processing of the AD-associated amyloid precursor protein (APP). To further elucidate how APP processing is implicated in the comorbidity between UUI and AD, we conducted polygenic risk score (PRS)-based analyses, which showed that genetic risk factors associated with AD and a decreased amyloid beta 42/40 blood level ratio (also) contribute to UUI susceptibility. In conclusion, APP processing constitutes a putative molecular link between UUI and AD, adding further weight to their clinical comorbidity and having implications for the treatment (and prevention) of both traits.

The Dutch Pharmacogenetics Working Group (DPWG) describes gene-drug interactions to facilitate pharmacogenetic implementation in clinical practice. The current guideline describes the gene-drug interactions for TPMT, NUDT15 and thiopurines (azathioprine, 6-mercaptopurine and thioguanine). Evidence based recommendations were obtained via a literature review of published studies. This literature review showed that gene variants leading to a decreased activity of TPMT and/or NUDT15 result in higher risk of toxicities, especially bone-marrow depression. For intermediate metabolisers (IM) of TPMT or NUDT15, it is advised to start with 50% of the normal dose when treated with azathioprine or 6-mercaptopurine. For poor metabolisers (PM), it is advised to start with an alternative treatment or to reduce the dose to 10% of the normal dose. For thioguanine, a dose of 75% of the normal dose is advised for TPMT IM and 50% of the normal dose for NUDT15 IM. Alternative treatment or a start dose reduction is advised for PM. A start dose of 6-7% can be used for TPMT PM and of 10% for NUDT15 PM. For TPMT or NUDT15 IM treated for leukaemia, starting with the normal dose can be considered and then decrease the dose to the advised dose described above in case toxicities occur. For NUDT15 PM reduced starting dose is advised only if an alternative is not possible, due to a higher uncertainty in the calculated dose reduction for NUDT15 PM than for TPMT PM. DPWG classifies genotyping for TPMT and NUDT15 “essential” before thiopurine initiation.

In patients receiving allogenic hematopoietic stem cell transplantation (aHSCT) complete chimerism is desired. However, this brings a challenge when non‐invasive assessment of recipient germline DNA is required for genetic testing. Here, we aim to create awareness for (pharmaco)genetic sampling in patients following aHSCT based on a case report of a patient following aHSCT in which pharmacogenetic analysis was performed. Six pharmacogenetic genes were analyzed in DNA extracted from peripheral blood (pre‐ and post‐transplant), buccal swab, and hair follicles. To investigate the presence of donor DNA in post‐transplant samples, short tandem repeat and digital droplet PCR analysis were performed. DNA from post‐transplantation peripheral blood and the buccal swab showed identical genotypes: CYP2C9*1/*1, CYP2C19*1/*2, CYP2D6*2/*9, CYP3A4*1/*1, VKORC1‐1639TT, SLCO1B1*1/*5. Pre‐transplant DNA showed different genotypes for CYP2D6 (*1/*2) and SLCO1B1 (*1/*1). Due to the low DNA amount extracted from hair follicles, only CYP2D6 and SLCO1B1 were examined, showing identical genotypes to pre‐transplantation DNA. Short tandem repeat analysis showed that the buccal swab contained DNA from both donor and recipient. It was estimated that the buccal swab contained ~63% donor DNA, while DNA from hair follicles showed 0% donor DNA. In conclusion, pharmacogenetic profiling after allogenic HSCT should be done with consideration. Analysis of pre‐transplant peripheral blood is preferred over buccal swab due to the presence of donor DNA contamination. DNA extracted from hair is also a reliable source; however, application might be restricted due to limited DNA yield.

Summary: Introduction: Chronic pain is one of the most common and severe complications after surgery, affecting quality of life and overall wellbeing of patients. Several risk factors have been identified but the mechanisms of chronic postsurgical pain development remain unclear. This study aimed to identify single‐nucleotide polymorphisms associated with developing chronic postsurgical pain after abdominal surgery, one of the most common types of surgery. Methods: A genome‐wide association study was performed on 27,603 patients from the UK Biobank who underwent abdominal surgery. The robustness of identified loci was validated by split‐half validation analysis. Functionally related top loci were selected for expression validation in clinical samples of adhesions from patients with and without pain. Results: One locus (rs185545327) reached genome‐wide significance for association with chronic postsurgical pain development, and 10 loci surpassed the suggestively significant threshold (p < 1 × 10 ^‐6 ). In the robustness analysis, eight loci had at least nominal significance. The loci passing the suggestively significant threshold were mapped to 15 genes, of which two loci contained pain‐related genes ( SRPK2 , PDE4D ). Although marginally approaching statistical significance in the expression validation of clinical samples, the detection rate and expression level of PDE4D were modestly higher in patients with pain compared with those in the control group. Discussion: This study provides preliminary evidence for genetic risk factors implicated in chronic postsurgical pain following abdominal surgery, particularly the PDE4D gene, which has been associated with pain in previous studies. The findings add to evidence suggesting potential for the future development of a clinically applicable tool for personalised risk prediction, aiding clinicians in stratifying patients and enhancing clinical decision‐making through individualised risk assessments.

The pharmacological management of musculoskeletal pain starts with NSAIDs, followed by weak or strong opioids until the pain is under control. However, the treatment outcome is usually unsatisfying due to inter-individual differences. To investigate the genetic component of treatment outcome differences, we performed a genome-wide association study (GWAS) in ~23,000 participants with musculoskeletal pain from the UK Biobank. NSAID vs. opioid users were compared as a reflection of the treatment outcome of NSAIDs. We identified one genome-wide significant hit in chromosome 4 (rs549224715, P = 3.88 × 10⁻⁸). Suggestive significant (P < 1 × 10⁻⁶) loci were functionally annotated to 18 target genes, including four genes linked to neuropathic pain processes or musculoskeletal development. Pathway and network analyses identified immunity-related processes and a (putative) central role of EGFR. However, this study should be viewed as a first step to elucidate the genetic background of musculoskeletal pain treatment.

Sirolimus is an antiproliferative and immunosuppressive compound inhibiting the mTOR pathway, which is often activated in congenital low-flow vascular malformations. Studies have demonstrated the e...

Introduction: The maintenance phase of acute lymphoblastic leukemia treatment is the final and longest stage of treatment, mainly focused on antimetabolite therapy. This phase is essential to eliminate residual leukemic clones and prevent relapse. However, dose-limiting hematotoxicity is a major problem during this phase resulting in dose reduction or treatment discontinuation. Objective: In this cohort study, the clinical features and risk factors of hematological toxicity during the maintenance phase of treatment were analyzed in pediatric patients from Ethiopia. Methods: A total of 160 patients from Tikur Anbessa specialized hospital were included in the study of which 142 had sufficient data available for analysis. Patient characteristics as well as information about the care-givers, sides-effects as reported by the care-givers and clinical factors were collected. Bivariable followed by multivariable analysis was performed to investigate which factors were associated with hematological toxicity during the maintenance phase. Results: During the first six months of maintenance phase treatment grade 4 neutropenia was detected in 52.8% of the patients. The risk of developing grade 4 neutropenia was increased by about two fold in children with the age of 6 years and less compared to those with the age of more than 6 years. Similarly, the rate of developing grade 4 neutropenia among children with less than 4,500 maintenance day 1 white blood cell counts was significantly higher than that of children with normal maintenance day 1 white blood cell counts (AHR 2.477, 95% CI = 1.461–4.200, p = 0.001). Conclusion: In conclusion, child’s age and day 1 maintenance white blood cell/absolute neutrophil counts significantly affected the occurrence of grade 4 hematotoxicity. Close monitoring for white blood cell and absolute neutrophil counts during maintenance phase treatment is recommended for early diagnosis of hematotoxicity.

Pain is the leading cause of disability worldwide, imposing an enormous burden on personal health and society. Pain is a multifactorial and multidimensional problem. Currently, there is (some) evidence that genetic factors could partially explain individual susceptibility to pain and interpersonal differences in pain treatment response. To better understand the underlying genetic mechanisms of pain, we systematically reviewed and summarized genome-wide association studies (GWASes) investigating the associations between genetic variants and pain/pain-related phenotypes in humans. We reviewed 57 full-text articles and identified 30 loci reported in more than 1 study. To check whether genes described in this review are associated with (other) pain phenotypes, we searched 2 pain genetic databases, Human Pain Genetics Database and Mouse Pain Genetics Database. Six GWAS-identified genes/loci were also reported in those databases, mainly involved in neurological functions and inflammation. These findings demonstrate an important contribution of genetic factors to the risk of pain and pain-related phenotypes. However, replication studies with consistent phenotype definitions and sufficient statistical power are required to validate these pain-associated genes further. Our review also highlights the need for bioinformatic tools to elucidate the function of identified genes/loci. We believe that a better understanding of the genetic background of pain will shed light on the underlying biological mechanisms of pain and benefit patients by improving the clinical management of pain.