A Genetic Risk Variant for Multiple Sclerosis Severity is Associated with Brain Atrophy.

The minor allele of the genetic variant rs10191329 in the DYSF-ZNF638 locus is associated with unfavorable long-term clinical outcomes in multiple sclerosis patients. We investigated if rs10191329 is associated with brain atrophy measured by magnetic resonance imaging in a discovery cohort of 748 and a replication cohort of 360 people with relapsing multiple sclerosis. We observed an association with 28% more brain atrophy per rs10191329*A allele. Our results encourage stratification for rs10191329 in clinical trials. Unraveling the underlying mechanisms may enhance our understanding of pathophysiology and identify treatment targets. ANN NEUROL 2023;94:1080-1085.

Child and adult adiposity and subtype-specific endometrial cancer risk: a multivariable Mendelian randomisation study.

Increased adiposity is a known risk factor for endometrial cancer (EC). This study aimed to disentangle the separate causal roles of child and adult adiposity on EC risk in adults, including endometrioid and non-endometrioid histological subtypes using multivariable Mendelian randomisation. These analyses employed genetic associations derived from UK Biobank as proxies for child and adult body size in 12,906 cases and 108,979 controls that participated in the Endometrial Cancer Association Consortium. In multivariable analyses, adult body size increased overall EC (OR 2.30, 95% CI 1.73-3.06) and endometrioid EC risk (OR 2.28, 95% CI 1.65-3.16), while child body size had minimal effect. In contrast, child body size (OR 2.26, 95% CI 1.03-4.99) but not adult body size increased non-endometrioid EC risk. As such, child adiposity has an indirect effect on endometrioid EC risk that is mediated by adult adiposity but has a direct effect on non-endometrioid EC risk that is independent of adult adiposity. These novel findings indicate that interventions targeting adiposity during distinct periods in life have a critical role in preventing subtype-specific EC.

Development and evaluation of polygenic risk scores for prediction of endometrial cancer risk in European women.

PURPOSE: Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention. METHODS: We developed PRSs from SNVs identified from a systematic review of published studies and suggestive SNVs from the Endometrial Cancer Association Consortium. These were tested in an independent study of 555 surgically-confirmed endometrial cancer cases and 1202 geographically-matched controls from Manchester, United Kingdom and validated in 1676 cases and 116,960 controls from the UK Biobank (UKBB). RESULTS: Age and body mass index predicted endometrial cancer in both data sets (Manchester: area under the receiver operator curve [AUC] = 0.77, 95% CI = 0.74-0.80; UKBB: AUC = 0.74, 95% CI = 0.73-0.75). The AUC for PRS19, PRS24, and PRS72 were 0.58, 0.55, and 0.57 in the Manchester study and 0.56, 0.54, and 0.54 in UKBB, respectively. For PRS19, women in the third tertile had a 2.1-fold increased risk of endometrial cancer compared with those in the first tertile of the Manchester study (odds ratio = 2.08, 95% CI = 1.61-2.68, Ptrend = 5.75E-9). Combining PRS19 with age and body mass index improved discriminatory power (Manchester study: AUC = 0.79, 95% CI = 0.76-0.82; UKBB: AUC =0.75, 95% CI = 0.73-0.76). CONCLUSION: An endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.

Association between genetic polymorphisms and endometrial cancer risk: a systematic review.

INTRODUCTION: Endometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be sporadic and lifestyle related. The aim of this study was to systematically review prospective and retrospective case-control studies, meta-analyses and genome-wide association studies to identify genomic variants that may be associated with endometrial cancer risk. METHODS: We searched MEDLINE, Embase and CINAHL from 2007 to 2019 without restrictions. We followed PRISMA 2009 guidelines. The search yielded 3015 hits in total. Following duplicate exclusion, 2674 abstracts were screened and 453 full-texts evaluated based on our pre-defined screening criteria. 149 articles were eligible for inclusion. RESULTS: We found that single nucleotide polymorphisms (SNPs) in HNF1B, KLF, EIF2AK, CYP19A1, SOX4 and MYC were strongly associated with incident endometrial cancer. Nineteen variants were reported with genome-wide significance and a further five with suggestive significance. No convincing evidence was found for the widely studied MDM2 variant rs2279744. Publication bias and false discovery rates were noted throughout the literature. CONCLUSION: Endometrial cancer risk may be influenced by SNPs in genes involved in cell survival, oestrogen metabolism and transcriptional control. Larger cohorts are needed to identify more variants with genome-wide significance.

Mass cytometry analysis reveals a distinct immune environment in peritoneal fluid in endometriosis: a characterisation study.

BACKGROUND: Endometriosis is a gynaecological condition characterised by immune cell infiltration and distinct inflammatory signatures found in the peritoneal cavity. In this study, we aim to characterise the immune microenvironment in samples isolated from the peritoneal cavity in patients with endometriosis. METHODS: We applied mass cytometry (CyTOF), a recently developed multiparameter single-cell technique, in order to characterise and quantify the immune cells found in peritoneal fluid and peripheral blood from endometriosis and control patients. RESULTS: Our results demonstrate the presence of more than 40 different distinct immune cell types within the peritoneal cavity. This suggests that there is a complex and highly heterogeneous inflammatory microenvironment underpinning the pathology of endometriosis. Stratification by clinical disease stages reveals a dynamic spectrum of cell signatures suggesting that adaptations in the inflammatory system occur due to the severity of the disease. Notably, among the inflammatory microenvironment in peritoneal fluid (PF), the presence of CD69+ T cell subsets is increased in endometriosis when compared to control patient samples. On these CD69+ cells, the expression of markers associated with T cell function are reduced in PF samples compared to blood. Comparisons between CD69+ and CD69- populations reveal distinct phenotypes across peritoneal T cell lineages. Taken together, our results suggest that both the innate and the adaptive immune system play roles in endometriosis. CONCLUSIONS: This study provides a systematic characterisation of the specific immune environment in the peritoneal cavity and identifies cell immune signatures associated with endometriosis. Overall, our results provide novel insights into the specific cell phenotypes governing inflammation in patients with endometriosis. This prospective study offers a useful resource for understanding disease pathology and opportunities for identifying therapeutic targets.

Uncovering genetic mimics in multiple sclerosis: A single-center clinical exome sequencing study.

Background: Multiple sclerosis (MS) shares clinical/radiological features with several monogenic diseases that can mimic MS. Objective: We aimed to determine if exome sequencing can identify monogenic diseases in patients diagnosed with MS according to the McDonald criteria thus uncovering them as being misdiagnosed. Methods: We performed whole exome sequencing in a cohort of 278 patients with MS, clinically or radiologically isolated syndrome without cerebrospinal fluid-specific oligoclonal bands (CSF-OCBs) (n = 228), a positive family history of MS (n = 44), or both (n = 6), thereby focusing on individuals potentially more likely to have underlying monogenic conditions mimicking MS. We prioritized 495 genes associated with monogenic diseases sharing features with MS. Results: A disease-causing variant in NOTCH3 was identified in one patient without CSF-OCBs, no spinal lesions, with non-response to immunotherapy, and a family history of dementia, thereby converting the diagnosis to cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Moreover, 18 patients (6.5% of total) carried variants of unclear significance. Conclusion: Monogenic diseases being misdiagnosed as MS seem rare in patients diagnosed with MS according to the McDonald criteria, even in CSF-OCB negative cases. The detected pathogenic NOTCH3 variant emphasizes CADASIL as a rare differential diagnosis and highlights the relevance of genetic testing in selected MS cases with atypical presentations.

Exome-based gene panel analysis in a cohort of acute juvenile ischemic stroke patients:relevance of NOTCH3 and GLA variants.

BACKGROUND: Genetic variants are considered to have a crucial impact on the occurrence of ischemic stroke. In clinical routine, the diagnostic value of next-generation sequencing (NGS) in the medical clarification of acute juvenile stroke has not been investigated so far. MATERIAL AND METHODS: We analyzed an exome-based gene panel of 349 genes in 172 clinically well-characterized patients with magnetic resonance imaging (MRI)-proven, juvenile (age ≤ 55 years), ischemic stroke admitted to a single comprehensive stroke center. RESULTS: Monogenetic diseases causing ischemic stroke were observed in five patients (2.9%): In three patients with lacunar stroke (1.7%), we identified pathogenic variants in NOTCH3 causing cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hence, CADASIL was identified at a frequency of 12.5% in the lacunar stroke subgroup. Further, in two male patients (1.2%) suffering from lacunar and cardioembolic stroke, pathogenic variants in GLA causing Fabry's disease were present. Additionally, genetic variants in monogenetic diseases lacking impact on stroke occurrence, variants of unclear significance (VUS) in monogenetic diseases, and (cardiovascular-) risk genes in ischemic stroke were observed in a total of 15 patients (15.7%). CONCLUSION: Genetic screening for Fabry's disease in cardioembolic and lacunar stroke as well as CADASIL in lacunar stroke might be beneficial in routine medical work-up of acute juvenile ischemic stroke.

Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels.

To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.

Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

BRCA1 and BRCA2 pathogenic variant carriers and endometrial cancer risk: A cohort study.

BACKGROUND: An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-reducing bilateral salpingo-oophorectomy is, therefore, of uncertain benefit. Data from a large, prospective cohort will be informative. METHODS: Data on UK BRCA pathogenic variant carriers were interrogated for endometrial cancer diagnoses. Standardised incidence ratios (SIRs) were calculated in four distinct cohorts using national endometrial cancer rates; either from 1/1/1980 or age 20, prospectively from date of personal pathogenic variant report, date of family pathogenic variant report or date of risk-reducing salpingo-oophorectomy. Somatic BRCA sequencing of 15 serous endometrial cancers was performed to detect pathogenic variants. RESULTS: Fourteen cases of endometrial cancer were identified in 2609 women (1350 BRCA1 and 1259 BRCA2), of which two were prospectively diagnosed. No significant increase in either overall or serous-like endometrial cancer risk was identified in any of the cohorts examined (SIR = 1.70, 95% confidence interval = 0.74-3.33; no cases of serous endometrial cancer diagnosed). Results were unaffected by the BRCA gene affected, previous breast cancer or tamoxifen use. No BRCA pathogenic variants were detected in any of the serous endometrial cancers tested. CONCLUSIONS: Women with a BRCA pathogenic variant do not appear to have a significant increased risk of all-type or serous-like endometrial cancer compared with the general population. These data provide some reassurance that hysterectomy is unlikely to be of significant benefit if performed solely as a preventive measure.

Author Correction: Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions.

Endometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.