The impact of <em>CYP2C9</em>, <em>VKORC1</em>, and <em>CYP4F2</em> polymorphisms on warfarin dose requirement in Saudi patients

Copyright \ua9 2025 Jokhab, AlRasheed, Bakheet, AlMomen, AlAboud and Kamali. Background: Limited data are available on factors that affect warfarin dose requirement in Saudi patients. Saudis are among the underrepresented ethnic groups in warfarin pharmacogenetics research. The present study investigated the frequency of CYP2C9*2 and*3, CYP4F2 (G1347A) and VKORC1 –1639G&gt;A genotypes and their impact on warfarin dose requirement in a cohort of Saudi patients requiring anticoagulation therapy. Methods: 193 patients on chronic warfarin therapy and with stable anticoagulation took part in the study. Genotyping for VKORC1 1639G&gt;A, CYP4F2 G1347A, CYP2C9*2 430C&gt;T and CYP2C9*3 1075A&gt;C were performed using TaqMan genotyping assays. Analysis of variance was carried out to determine the association between CYP2C9, CYP4F2, and VKORC1 genotype and warfarin dose requirement in two groups based on target INR range. Backward linear regression analysis identified genetic and clinical factors influencing doe requirements. Results: Patients with CYP2C9 and VKORC1 polymorphisms required significantly lower warfarin doses compared to wild-type patients. Carriers of two mutant alleles required lower doses than those with one mutant allele. In contrast, CYP4F2 polymorphisms did not influence warfarin dose. Age and genetic variants in CYP2C9 and VKORC1 were negatively correlated with dose requirements, while body surface area (BSA) was positively correlated. Conclusion: Saudi patients with polymorphisms in CYP2C9 and VKORC1 required lower warfarin doses than those with the wild-type allele. CYP4F2 polymorphism had no effect on warfarin dose requirement. Integrating patient clinical factors, including age and BSA, and genetic polymorphisms in CYP2C9 and VKORC1 provides the best estimation of factors contributing to warfarin dose in the Saudi patient population

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

Background: Congenital fibrinogen deficiency is an ultra-rare disorder in which patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder. Methods: Hemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA\uae, Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a four-point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined. Results: Twenty-five afibrinogenemia patients were treated with HFC: 24 for on-demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92-0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95-0.999). Mean&nbsp;\ub1&nbsp;standard deviation (SD) increase in MCF was 5.8&nbsp;\ub1&nbsp;2.5&nbsp;mm one hour after the first HFC infusion (mean&nbsp;\ub1&nbsp;SD dose, 61.88&nbsp;\ub1&nbsp;11.73&nbsp;mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80&nbsp;mg/kg [34.09-225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82-1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralizing antifibrinogen antibodies. Conclusions: Human fibrinogen concentrate was efficacious for on-demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia

Heterogenicity of SMA genetics and carrier profile among Saudi patient cohort

Abstract IntroductionSpinal Muscular atrophy (SMA) is an inherited, neuromuscular disease which is characterized by the deterioration of spinal motor neurons, causing progressive muscular atrophy and weakening. It is an autosomal recessive disease with the absence or mutation of the survival motor neuron 1 (SMN1) gene as a hallmark; and SMN2 gene modulates the severity of the disease. SMA has been classified based on the motor function achieved. This study aims at describing the genetic makeup and characteristics of an SMA cohort in the Kingdom of Saudi Arabia (KSA).MethodsData from families presenting with SMA children was collected between (January 2018 till December 2020). Blood samples were collected from patients and family members. Genetic testing for SMA and mutations were performed at a central lab in Europe.Results and discussion17 families were enrolled in the study including 52 children. Among the 34 parents, 28 were carriers with heterozygous deletion (82.3%), 1(2.9%) had no deletion detected by MLPA but had point mutation by sequencing, 1(2.9%) had homozygous deletion and was symptomatic, 3(8.8%) had no deletion or point mutation and presumed to have 2 + 0, and 1 (2.9%) was not tested.ConclusionThis study provides insight on the carrier mutational analysis of parents’ of SMA patients, Further studies are needed to understand the burden of SMA in the KSA.</jats:p

Clinical and Genomic Crosstalk between Glucocorticoid Receptor and Estrogen Receptor α In Endometrial Cancer

Summary: Steroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus, and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic-binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is altered significantly by estradiol with GR recruited to ER-bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol but with additional regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer. : Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus and have differential effects on growth. Vahrenkamp et al. find that expression of both receptors is associated with poor outcome in endometrial cancer and that simultaneous induction of ER and GR leads to molecular interplay between the receptors. Keywords: estrogen receptor, glucocorticoid receptor, endometrial cance

Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer

SummarySteroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is significantly altered by estradiol with GR recruited to ER bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol, but with novel regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer.</jats:p