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BACKGROUND: Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). METHODS: We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected P-values <0.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. RESULTS: In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal, were in linkage disequilibrium (R2 ≥ 0.2) with a SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. CONCLUSIONS: While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2 and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF.
We investigated the genetic factors contributing to atypical femur fractures (AFF), which are rare and unusual fractures in the thigh bone These fractures are related to the use of bisphosphonates, which are prescribed to prevent fractures caused by osteoporosis. Previous studies suggested potential genetic links, but their findings were not confirmed in larger groups. To address this, we analyzed genetic data from 139 European individuals with AFF and 196 individuals without AFF, all of whom used bisphosphonates, using a genetic technique called whole exome sequencing (WES). Our results suggested three genesXRN2, SORD, and PLOD2might be linked to AFF, although the evidence was not conclusive. Importantly, our findings suggest that AFF may be caused by different genes in different individuals. A much larger sample size is now needed to fully understand the genetic architecture of AFF. These findings may guide future research into the genetic causes of AFF.
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Integrating multi-omics data into predictive models has the potential to enhance accuracy, which is essential for precision medicine. In this study, we developed interpretable predictive models for multi-omics data by employing neural networks informed by prior biological knowledge, referred to as visible networks. These neural networks offer insights into the decision-making process and can unveil novel perspectives on the underlying biological mechanisms associated with traits and complex diseases. We tested the performance, interpretability and generalizability for inferring smoking status, subject age and LDL levels using genome-wide RNA expression and CpG methylation data from the blood of the BIOS consortium (four population cohorts, Ntotal = 2940). In a cohort-wise cross-validation setting, the consistency of the diagnostic performance and interpretation was assessed. Performance was consistently high for predicting smoking status with an overall mean AUC of 0.95 (95% CI: 0.90-1.00) and interpretation revealed the involvement of well-replicated genes such as AHRR, GPR15 and LRRN3. LDL-level predictions were only generalized in a single cohort with an R2 of 0.07 (95% CI: 0.05-0.08). Age was inferred with a mean error of 5.16 (95% CI: 3.97-6.35) years with the genes COL11A2, AFAP1, OTUD7A, PTPRN2, ADARB2 and CD34 consistently predictive. For both regression tasks, we found that using multi-omics networks improved performance, stability and generalizability compared to interpretable single omic networks. We believe that visible neural networks have great potential for multi-omics analysis; they combine multi-omic data elegantly, are interpretable, and generalize well to data from different cohorts.
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Redes Neurales de la Computación , Fenotipo , Humanos , Estudios de Cohortes , Metilación de ADN/genética , Masculino , Femenino , Persona de Mediana Edad , Fumar/genética , Genómica/métodos , Adulto , Biología Computacional/métodos , Islas de CpG/genética , Anciano , MultiómicaRESUMEN
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.
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BACKGROUND: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action. METHODS: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country. RESULTS: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the 'who, what, when and where' of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the 'most important change' which would improve practice. CONCLUSIONS: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels.
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Unión Europea , Asesoramiento Genético , Neoplasias , Humanos , Asesoramiento Genético/legislación & jurisprudencia , Neoplasias/genética , Pruebas Genéticas/legislación & jurisprudenciaRESUMEN
BACKGROUND: Individual differences in susceptibility to develop asthma, a heterogeneous chronic inflammatory lung disease, are poorly understood. It remains debated whether genetics can predict asthma risk and how genetic variants modulate the complex pathophysiology of asthma. AIM: To build polygenic risk scores (PRSs) for asthma risk prediction and epigenomically link predictive genetic variants to pathophysiological mechanisms. METHODS: Restricted PRSs were constructed using single nucleotide variants derived from genome-wide association studies and validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14 926 individuals. Outcomes used were asthma, childhood-onset asthma (COA), adulthood-onset asthma (AOA), eosinophilic asthma, and asthma exacerbations. Genome-wide chromatin analysis data from 19 disease-relevant cell types were used for epigenomic PRS partitioning. RESULTS: PRSs obtained predicted asthma and related outcomes, with the strongest associations observed for COA (2.55 odds ratios per PRS standard deviation, area under the curve of 0.760). PRSs allowed for the classification of individuals into high and low-risk groups. PRS partitioning using epigenomic profiles identified 5 clusters of variants within putative gene regulatory regions linked to specific asthma-relevant cells, genes, and biological pathways. CONCLUSIONS: PRSs were associated with asthma(-related traits) in a Dutch prospective cohort, with substantially higher predictive power observed for COA than for AOA. Importantly, PRS variants could be epigenomically partitioned into clusters of regulatory variants with different pathophysiological association patterns and effect estimates, which likely represent distinct genetically driven disease pathways. Our findings have potential implications for personalized risk mitigation and treatment strategies.
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Importance: Although the effectiveness of intracameral antibiotics to prevent postoperative endophthalmitis is described, selective use of antibiotics combined with 1% povidone iodine disinfection might be equally effective and could lead to cost reduction and avoidance of unnecessary use of antibiotics. Objective: To compare the incidence of postoperative endophthalmitis when 1% povidone iodine disinfection is applied in combination with selective intracameral antibiotics with the incidence after routine use of intracameral antibiotics in combination with 5% povidone iodine. Design, Setting, and Participant: This was a retrospective cohort study using incidence data from the ongoing endophthalmitis register of the Rotterdam Eye Hospital, a specialized hospital providing both secondary and tertiary ophthalmological care, when intracameral antibiotics were used only during cataract procedures with occurrence of a posterior capsular tear in comparison with results from cohorts described in the literature where routine antibiotics were used. All patients who had cataract (phacoemulsification) surgery at the Rotterdam Eye Hospital between 1993 and 2022 were included. No cataract surgical procedures combined with other intraocular procedures were included. Exposure: Povidone iodine disinfection and intracameral antibiotics during cataract surgery either routinely or only in case of posterior capsular tears. Main Outcome and Measure: Postoperative endophthalmitis incidence. Results: Postoperative endophthalmitis incidence after 56â¯598 cataract (phacoemulsification) surgical procedures in the Rotterdam Eye Hospital between 2016 and 2022 was 0.000 (95% CI, 0.000-0.000). A PubMed literature search until September 2023 with respect to the incidence of postoperative endophthalmitis after routine antibiotic prophylaxis yielded 37 publications with an overall postoperative endophthalmitis incidence of 0.000 (95% CI, 0.000-0.000). Conclusions and Relevance: No difference was observed between the postoperative endophthalmitis incidence during the last 7 years in the Rotterdam Eye Hospital and the overall postoperative endophthalmitis incidence after routine intracameral antibiotics prophylaxis as described in the literature. Disinfection with 1% povidone iodine in combination with selective antibiotic prophylaxis may be equally effective as routine antibiotic use and 5% povidone iodine.
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Cámara Anterior , Antibacterianos , Profilaxis Antibiótica , Endoftalmitis , Infecciones Bacterianas del Ojo , Povidona Yodada , Humanos , Endoftalmitis/prevención & control , Endoftalmitis/epidemiología , Estudios Retrospectivos , Incidencia , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Povidona Yodada/administración & dosificación , Povidona Yodada/uso terapéutico , Anciano , Masculino , Infecciones Bacterianas del Ojo/prevención & control , Infecciones Bacterianas del Ojo/epidemiología , Infecciones Bacterianas del Ojo/microbiología , Femenino , Cámara Anterior/efectos de los fármacos , Complicaciones Posoperatorias/prevención & control , Antiinfecciosos Locales/uso terapéutico , Antiinfecciosos Locales/administración & dosificación , Facoemulsificación/efectos adversos , Anciano de 80 o más Años , Extracción de Catarata/efectos adversos , Persona de Mediana Edad , Países Bajos/epidemiologíaRESUMEN
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a highly prevalent genetic disorder resulting in markedly elevated LDL cholesterol levels and premature coronary artery disease. FH underdiagnosis and undertreatment require novel detection methods. This study evaluated the effectiveness of using an LDL cholesterol cut-off ≥99.5th percentile (sex- and age-adjusted) to identify clinical and genetic FH, and investigated underutilization of genetic testing and undertreatment in FH patients. METHODS: Individuals with at least one prior LDL cholesterol level ≥99.5th percentile were selected from a laboratory database containing lipid profiles of 590,067 individuals. The study comprised three phases: biochemical validation of hypercholesterolemia, clinical identification of FH, and genetic determination of FH. RESULTS: Of 5614 selected subjects, 2088 underwent lipid profile reassessment, of whom 1103 completed the questionnaire (mean age 64.2 ± 12.7 years, 48% male). In these 1103 subjects, mean LDL cholesterol was 4.0 ± 1.4 mmol/l and 722 (65%) received lipid-lowering therapy. FH clinical diagnostic criteria were met by 282 (26%) individuals, of whom 85% had not received guideline-recommended genetic testing and 97% failed to attain LDL cholesterol targets. Of 459 individuals consenting to genetic validation, 13% carried an FH-causing variant, which increased to 19% in clinically diagnosed FH patients. CONCLUSIONS: The identification of a substantial number of previously undiagnosed and un(der)treated clinical and genetic FH patients within a central laboratory database highlights the feasibility and clinical potential of this targeted screening strategy; both in identifying new FH patients and in improving treatment in this high-risk population.
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Algoritmos , LDL-Colesterol , Pruebas Genéticas , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/sangre , Masculino , Femenino , Persona de Mediana Edad , LDL-Colesterol/sangre , Anciano , Pruebas Genéticas/métodos , Valor Predictivo de las Pruebas , Biomarcadores/sangre , Predisposición Genética a la Enfermedad , Encuestas y Cuestionarios , Fenotipo , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/sangre , Receptores de LDL/genética , Reproducibilidad de los Resultados , MutaciónRESUMEN
OBJECTIVE: Methylation of plasma cell-free DNA (cfDNA) has potential as a marker of brain damage in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, we study methylation of cfDNA in presymptomatic and symptomatic carriers of genetic FTD pathogenic variants, next to healthy controls. METHODS: cfDNA was isolated from cross-sectional plasma of 10 presymptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), 10 symptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), and 9 healthy controls. Genome-wide methylation of cfDNA was determined using a high-resolution sequencing technique (MeD-seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for presymptomatic carriers (vs. controls and symptomatic carriers), and reevaluated in a validation cohort (8 presymptomatic: 3 C9orf72, 3 GRN, and 2 MAPT; 26 symptomatic: 7 C9orf72, 6 GRN, 12 MAPT, and 1 TARDBP; 13 noncarriers from genetic FTD families). RESULTS: Presymptomatic carriers showed a distinctive methylation profile compared to healthy controls and symptomatic carriers. Cumulative DMR scores in presymptomatic carriers enabled to significantly differentiate presymptomatic carriers from healthy controls (p < 0.001) and symptomatic carriers (p < 0.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (p ≤ 0.007) only. Transcription-start-site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin-dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes. INTERPRETATION: A distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage.
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Ácidos Nucleicos Libres de Células , Demencia Frontotemporal , Enfermedad de Pick , Humanos , Demencia Frontotemporal/patología , Proteína C9orf72/genética , Estudios Transversales , Metilación de ADN , Mutación , Enfermedad de Pick/genética , Ácidos Nucleicos Libres de Células/genéticaRESUMEN
BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9â 420â 585 single nucleotide polymorphisms in up to 127â 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35â 660) and UK Biobank (n=91â 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mmâ Hg (Pinteraction=9.4e-7) and 0.20±0.06 mmâ Hg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.
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Enfoques Dietéticos para Detener la Hipertensión , Hipertensión , Humanos , Presión Sanguínea/genética , Dieta , GenotipoRESUMEN
BACKGROUND: Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations. METHODS: We applied colocalization between T2D and 20 related metabolic traits, across 243 loci, to obtain inferences of shared casual variants. Network-based unsupervised hierarchical clustering was performed on variant-trait associations. Partitioned polygenic risk scores (PRSs) were generated for each cluster using T2D summary statistics and validated in 21,742 individuals with T2D from 3 cohorts. Inferences of directionality and causality were obtained by applying Mendelian randomization Steiger's Z-test and further validated in a pediatric cohort without diabetes (aged 9-12 years old, n = 3866). RESULTS: We identified 146 T2D loci that colocalized with at least one metabolic trait locus. T2D variants within these loci were grouped into 5 clusters. The clusters corresponded to the following pathways: obesity, lipodystrophic insulin resistance, liver and lipid metabolism, hepatic glucose metabolism, and beta-cell dysfunction. We observed heterogeneity in associations between PRSs and metabolic measures across clusters. For instance, the lipodystrophic insulin resistance (Beta - 0.08 SD, 95% CI [- 0.10-0.07], p = 6.50 × 10-32) and beta-cell dysfunction (Beta - 0.10 SD, 95% CI [- 0.12, - 0.08], p = 1.46 × 10-47) PRSs were associated to lower BMI. Mendelian randomization Steiger analysis indicated that increased T2D risk in these pathways was causally associated to lower BMI. However, the obesity PRS was conversely associated with increased BMI (Beta 0.08 SD, 95% CI 0.06-0.10, p = 8.0 × 10-33). Analyses within a pediatric cohort supported this finding. Additionally, the lipodystrophic insulin resistance PRS was associated with a higher odds of chronic kidney disease (OR 1.29, 95% CI 1.02-1.62, p = 0.03). CONCLUSIONS: We successfully partitioned T2D genetic variants into phenotypic pathways using a colocalization first approach. Partitioned PRSs were associated to unique metabolic and clinical outcomes indicating successful partitioning of disease heterogeneity. Our work expands on previous approaches by providing stronger inferences of shared causal variants, causality, and directionality of GWAS variant-trait associations.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Niño , Diabetes Mellitus Tipo 2/genética , Puntuación de Riesgo Genético , Resistencia a la Insulina/genética , Análisis por Conglomerados , Obesidad/genéticaRESUMEN
Osteoarthritis (OA) is a multifactorial degenerative joint disease of which the underlying mechanisms are yet to be fully understood. At the molecular level, multiple factors including altered signaling pathways, epigenetics, metabolic imbalance, extracellular matrix degradation, production of matrix metalloproteinases, and inflammatory cytokines, are known to play a detrimental role in OA. However, these factors do not initiate OA, but are mediators or consequences of the disease, while many other factors causing the etiology of OA are still unknown. Here, it is revealed that microenvironmental osmolarity can induce and reverse osteoarthritis-related behavior of chondrocytes via altered intracellular molecular crowding, which represents a previously unknown mechanism underlying OA pathophysiology. Decreased intracellular crowding is associated with increased sensitivity to proinflammatory triggers and decreased responsiveness to anabolic stimuli. OA-induced lowered intracellular molecular crowding could be renormalized via exposure to higher extracellular osmolarity such as those found in healthy joints, which reverse OA chondrocyte's sensitivity to catabolic stimuli as well as its glycolytic metabolism.
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Cartílago Articular , Osteoartritis , Humanos , Cartílago Articular/metabolismo , Cartílago Articular/patología , Osteoartritis/metabolismo , Condrocitos/metabolismo , Condrocitos/patología , Citocinas/metabolismo , Concentración OsmolarRESUMEN
To determine the changes in surveillance category by adding a polygenic risk score based on 311 breast cancer (BC)-associated variants (PRS311), questionnaire-based risk factors and breast density on personalized BC risk in unaffected women from Dutch CHEK2 c.1100delC families. In total, 117 unaffected women (58 heterozygotes and 59 non-carriers) from CHEK2 families were included. Blood-derived DNA samples were genotyped with the GSAMDv3-array to determine PRS311. Lifetime BC risk was calculated in CanRisk, which uses data from the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Women, were categorized into three surveillance groups. The surveillance advice was reclassified in 37.9 % of heterozygotes and 32.2 % of non-carriers after adding PRS311. Including questionnaire-based risk factors resulted in an additional change in 20.0 % of heterozygotes and 13.2 % of non-carriers; and a subanalysis showed that adding breast density on top shifted another 17.9 % of heterozygotes and 33.3 % of non-carriers. Overall, the majority of heterozygotes were reclassified to a less intensive surveillance, while non-carriers would require intensified surveillance. The addition of PRS311, questionnaire-based risk factors and breast density to family history resulted in a more personalized BC surveillance advice in CHEK2-families, which may lead to more efficient use of surveillance.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/epidemiología , Densidad de la Mama , Puntuación de Riesgo Genético , Predisposición Genética a la Enfermedad , Quinasa de Punto de Control 2/genética , Factores de Riesgo , Estilo de Vida , Células GerminativasRESUMEN
Objective: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP). Methods: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses. Results: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. Conclusion: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.
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BACKGROUND: Familial hypercholesterolemia (FH) is a common but underdiagnosed genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease. Current sequencing methods to diagnose FH are expensive and time-consuming. In this study, we evaluated the accuracy of a low-cost, high-throughput genotyping array for diagnosing FH. METHODS: An Illumina Global Screening Array was customized to include probes for 636 variants, previously classified as FH-causing variants. First, its theoretical coverage was assessed in all FH variant carriers diagnosed through next-generation sequencing between 2016 and 2022 in the Netherlands (n=1772). Next, the performance of the array was validated in another sample of FH variant carriers previously identified in the Dutch FH cascade screening program (n=1268). RESULTS: The theoretical coverage of the array for FH-causing variants was 91.3%. Validation of the array was assessed in a sample of 1268 carriers of whom 1015 carried a variant in LDLR, 250 in APOB, and 3 in PCSK9. The overall sensitivity was 94.7% and increased to 98.2% after excluding participants with variants not included in the array design. Copy number variation analysis yielded a 89.4% sensitivity. In 18 carriers, the array identified a total of 19 additional FH-causing variants. Subsequent DNA analysis confirmed 5 of the additionally identified variants, yielding a false-positive result in 16 subjects (1.3%). CONCLUSIONS: The FH genotyping array is a promising tool for genetically diagnosing FH at low costs and has the potential to greatly increase accessibility to genetic testing for FH. Continuous customization of the array will further improve its performance.
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Hiperlipoproteinemia Tipo II , Proproteína Convertasa 9 , Humanos , Proproteína Convertasa 9/genética , LDL-Colesterol , Variación Genética , Genotipo , Variaciones en el Número de Copia de ADN , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genéticaRESUMEN
BACKGROUND: To accurately measure ultrathin Descemet stripping automated endothelial keratoplasty (DSAEK) donor lamella thickness during the first postoperative year and to correlate this with pre-operative and other postoperative measurements. METHODS: Donor lamella thickness in 41 eyes undergoing DSAEK for Fuchs endothelial dystrophy (FED) was measured using the Tomey Casia OCT directly after graft preparation and at 1 week and 1, 3, 6 and 12 months postoperatively. Visual acuity and endothelial cell density were measured as the secondary parameters. RESULTS: Individual graft thickness profiles were shown to be fairly regular within the optically relevant area. There was a strong and highly significant correlation between the pre- and postoperative lamellar thicknesses at all time points (p < 0.0001). Compared with the measurements directly after preparation at the cornea bank, the lamella thickness decreased by 12% after 12 months. Between 1 and 12 months postoperatively, the lamella thickness (mean ± SD) changed from 112 ± 27 µm to 101 ± 21 µm. Best spectacle-corrected visual acuity (BSCVA) changed from 0.46 ± 0.30 logMAR pre-operatively through 0.36 ± 0.33 at 1 month to 0.13 ± 0.16 at 1 year postoperatively. The endothelial cell counts were comparable to those reported in previous studies. CONCLUSIONS: Thickness profiles of individual grafts were fairly regular within the optically relevant area. A strong relationship between pre- and postoperative graft thicknesses was detected, and ultrathin DSAEK grafts prepared using methods similar to that applied in this study are expected to show a deswelling of around 12% during the first postoperative year. No correlation was detected between graft thickness and BSCVA.
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Trasplante de Córnea , Distrofia Endotelial de Fuchs , Humanos , Donantes de Tejidos , Córnea , Agudeza VisualRESUMEN
Importance: Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts. Objective: To evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor-based model. Design, Setting, and Participants: Two observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands. Exposure: Traditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score. Main Outcomes and Measures: Model discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed. Results: The median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, -0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2<20). Subgroup analysis stratified by the median age demonstrated similar findings. Similar findings were observed for 10-year risk in RS and in longer-term follow-up in MESA (median, 16.0 years). Conclusions and Relevance: In 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.
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Aterosclerosis , Enfermedad Coronaria , Anciano , Humanos , Persona de Mediana Edad , Aterosclerosis/diagnóstico por imagen , Calcio , Enfermedad Coronaria/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Factores de Riesgo , Medición de RiesgoRESUMEN
Atypical femur fractures (AFFs), considered rare associations of bisphosphonates, have also been reported in patients with monogenic bone disorders without bisphosphonate use. The exact association between AFFs and monogenic bone disorders remains unknown. Our aim was to determine the prevalence of monogenic bone disorders in a Dutch AFF cohort. AFF patients were recruited from two specialist bone centers in the Netherlands. Medical records of the AFF patients were reviewed for clinical features of monogenic bone disorders. Genetic variants identified by whole-exome sequencing in 37 candidate genes involved in monogenic bone disorders were classified based on the American College of Medical Genetics and Genomics (ACMG) classification guidelines. Copy number variations overlapping the candidate genes were also evaluated using DNA array genotyping data. The cohort comprises 60 AFF patients (including a pair of siblings), with 95% having received bisphosphonates. Fifteen AFF patients (25%) had clinical features of monogenic bone disorders. Eight of them (54%), including the pair of siblings, had a (likely) pathogenic variant in either PLS3, COL1A2, LRP5, or ALPL. One patient carried a likely pathogenic variant in TCIRG1 among patients not suspected of monogenic bone disorders (2%). In total, nine patients in this AFF cohort (15%) had a (likely) pathogenic variant. In one patient, we identified a 12.7 Mb deletion in chromosome 6, encompassing TENT5A. The findings indicate a strong relationship between AFFs and monogenic bone disorders, particularly osteogenesis imperfecta and hypophosphatasia, but mainly in individuals with symptoms of these disorders. The high yield of (likely) pathogenic variants in AFF patients with a clinical suspicion of these disorders stresses the importance of careful clinical evaluation of AFF patients. Although the relevance of bisphosphonate use in this relationship is currently unclear, clinicians should consider these findings in medical management of these patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Conservadores de la Densidad Ósea , Fracturas del Fémur , ATPasas de Translocación de Protón Vacuolares , Humanos , Prevalencia , Variaciones en el Número de Copia de ADN , Fracturas del Fémur/epidemiología , Fracturas del Fémur/genética , Difosfonatos/uso terapéutico , Fémur , ATPasas de Translocación de Protón Vacuolares/genéticaRESUMEN
Trials show that low-dose computed tomography (CT) lung cancer screening in long-term (ex-)smokers reduces lung cancer mortality. However, many individuals were exposed to unnecessary diagnostic procedures. This project aims to improve the efficiency of lung cancer screening by identifying high-risk participants, and improving risk discrimination for nodules. This study is an extension of the Dutch-Belgian Randomized Lung Cancer Screening Trial, with a focus on personalized outcome prediction (NELSON-POP). New data will be added on genetics, air pollution, malignancy risk for lung nodules, and CT biomarkers beyond lung nodules (emphysema, coronary calcification, bone density, vertebral height and body composition). The roles of polygenic risk scores and air pollution in screen-detected lung cancer diagnosis and survival will be established. The association between the AI-based nodule malignancy score and lung cancer will be evaluated at baseline and incident screening rounds. The association of chest CT imaging biomarkers with outcomes will be established. Based on these results, multisource prediction models for pre-screening and post-baseline-screening participant selection and nodule management will be developed. The new models will be externally validated. We hypothesize that we can identify 15-20% participants with low-risk of lung cancer or short life expectancy and thus prevent ~140,000 Dutch individuals from being screened unnecessarily. We hypothesize that our models will improve the specificity of nodule management by 10% without loss of sensitivity as compared to assessment of nodule size/growth alone, and reduce unnecessary work-up by 40-50%.
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Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Humanos , Detección Precoz del Cáncer/métodos , Pulmón , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Tamizaje Masivo/métodos , Nódulos Pulmonares Múltiples/patología , PronósticoRESUMEN
Age-related macular degeneration (AMD) has a strong genetic basis, but environmental factors such as smoking and a healthy diet can decrease the genetic fate by up to 50%. Current guidelines for clinical management include recommendations for a healthy lifestyle and antioxidant supplementation. However, many ophthalmologists do not inform their patients of this AMD-beneficial lifestyle. An important reason is the lack of trust that transition of lifestyle will be feasible in persons of advanced age and lack of methodology to measure lifestyle or its biological effects. To address these issues, we set up the lifestyle intervention study AMD-Life. It aims to investigate whether personalized risk-profiling (including genetic testing) and/or additional coaching can motivate patients to change their lifestyle. It also explores which biomarkers best reflect lifestyle change beneficial for AMD. The first year is a three-arm, self-contained open-label randomized clinical trial. A total of 150 AMD patients aged 55-85 years were randomized into three arms: (A) merely standard recommendations; (B) A conditions plus personalized risk profiling based on genetics and lifestyle, (C) B conditions plus coaching. The second year tests sustainability of lifestyle changes without active intervention. AMD-Life can provide further insight into the relevance of these interventions for the clinical management of AMD.
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Estilo de Vida , Degeneración Macular , Humanos , Antioxidantes , Pruebas Genéticas , Dieta Saludable , Degeneración Macular/prevención & control , Degeneración Macular/genéticaRESUMEN
Acanthamoeba keratitis is almost universally associated with contact lens (CL) use. Until today, however, CL solution manufacturing protocols lack testing of anti-amoebic activity. This study investigates the effectiveness of CL solutions available on the Dutch market against trophozoites and cysts of Acanthamoeba castellanii and Acanthamoeba polyphaga. Sixteen CL solutions were tested: 13 multiple purpose solutions (MPS), 2 hydrogen peroxidase solutions (HPS) and 1 povidone-iodine-based solution (PIS). The Spearman-Karber (SK) log reduction method and an XTT colorimetric assay were used to evaluate the effectiveness at the manufacturer's minimum recommended disinfection time (MMRDT) and after eight hours. At the MMRDT, one MPS showed an SK mean log reduction (MLR) of >3.0 against A. castellanii trophozoites. Two additional MPS and both HPS reached this threshold after eight hours. The SK MLR values for A. polyphaga trophozoites were between 1 and 3 at all time points. Using the XTT colorimetric assay, only HPS 1 showed >99.9% reduction (equivalent to 3 log reduction) in metabolic activity of A. castellanii trophozoites after eight hours. For A. polyphaga, both HPS and PIS showed a metabolic reduction of >99.9% after eight hours. Cysts were resistant against all solutions. We conclude that following the manufacturer's guidelines, few solutions provide sufficient effectiveness against Acanthamoeba trophozoites and none against cysts. The results underline the importance of adequate hygiene when handling CLs.