Genetic variation in the farnesoid X-receptor predicts Crohn's disease severity in female patients
Authors: Wilson, Aze; Wang, Qian; Almousa, Ahmed A.; Jansen, Laura E.; Choi, Yun-hee; Schwarz, Ute I.; Kim, Richard B.
The farnesoid X receptor (FXR) is implicated in Crohn's disease (CD) pathogenesis. It is unclear how genetic variation in FXR impacts CD severity versus genetic variation in nuclear receptors such as pregnane X receptor (PXR) and the multi-drug resistance protein 1 (MDR1, ABCB1). To evaluate FXR-1G>T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. A retrospective study (n=542) was conducted in a Canadian cohort of CD patients. Genotypic analysis (FXR-1G>T, MDR1 3435C>T and PXR -25385C>T) as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19 was performed. Primary outcomes included risk and time to first CD-related surgery. The effect of estrogen on wild type and variant FXR activity was assessed in HepG2 cells. The FXR-1GT genotype was associated with the risk of (odds ratio, OR=3.34, 95% CI=1.58-7.05, p=0.002) and earlier progression to surgery (hazard ratio, HR=3.00, 95% CI=1.86-4.83, p<0.0001) in CD. Female carriers of the FXR-1GT genotype had the greatest risk of surgery (OR=14.87 95% CI=4.22-52.38, p<0.0001) and early progression to surgery (HR=6.28, 95% CI=3.62-10.90, p<0.0001). Women carriers of FXR-1GT polymorphism had a three-fold lower FGF19 plasma concentration versus women with FXR-1GG genotype (p<0.0001). In HepG2 cells cotransfected with estrogen receptor (ER) and FXR, presence of estradiol further attenuated variant FXR activity. MDR1 and PXR genotypes were not associated with surgical risk. Unlike MDR1 and PXR, FXR-1GT genetic variation is associated with earlier and more frequent surgery in women with CD. This may be through ER-mediated attenuation of FXR activation.
Diagnosis and treatment of gonorrhoea: 2019 Belgian National guideline for primary care
ACTA CLINICA BELGICA
Authors: Jespers, Vicky; Stordeur, Sabine; Vanden Berghe, Wim; Mokrane, Saphia; Libois, Agnes; Kenyon, Chris; Jones, Clare; Dekker, Nicole; De Canniere, Anne-Sophie; De Baetselier, Irith; Crucitti, Tania
Objectives Gonorrhoea continues to be a public health concern in Belgium with pharyngeal and rectal infections increasing in persons with high-risk sexual behaviour. Belgian health care practitioners rely on international guidance when managing gonorrhoea resulting in non-adapted suboptimal care for the Belgian patient. This guideline will rectify this situation. Methods This guideline was developed following an evidence-based approach and involving a guideline development group (GDG). Research questions were prioritised by the GDG and researchers conducted a systematic review of the evidence that was assessed using GRADE approach. Results The guideline offers recommendations for gonorrhoea diagnosis, treatment and management for primary care professionals in Belgium and applies a risk group approach. This approach aims for improved identification of at-risk persons and targeted testing of at-risk groups; it includes behavioural questioning when deciding on diagnostic sampling and provides clear advice on treatment. The guideline defines when to add surveillance testing for antibiotic resistance, and what consists of good follow-up. Results A concerted application of this guideline by all stakeholders in Belgium may result in improving the diagnosis of infections and eventually addressing the emerging multi-drug resistance.