Background/aims To investigate genotype-phenotype associations in patients with KCNV2 retinopathy.Methods Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants,... Show moreBackground/aims To investigate genotype-phenotype associations in patients with KCNV2 retinopathy.Methods Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants, electroretinography (ERG) and retinal imaging. Subjects were grouped according to the combination of KCNV2 variants-two loss-of-function (TLOF), two missense (TM) or one of each (MLOF)-and parameters were compared.Results Ninety-two patients were included. The mean age of onset (mean +/- SD) in TLOF (n=55), TM (n=23) and MLOF (n=14) groups was 3.51 +/- 0.58, 4.07 +/- 2.76 and 5.54 +/- 3.38 years, respectively. The mean LogMAR BCVA ( +/- SD) at baseline in TLOF, TM and MLOF groups was 0.89 +/- 0.25, 0.67 +/- 0.38 and 0.81 +/- 0.35 for right, and 0.88 +/- 0.26, 0.69 +/- 0.33 and 0.78 +/- 0.33 for left eyes, respectively. The difference in BCVA between groups at baseline was significant in right (p=0.03) and left eyes (p=0.035). Mean outer nuclear layer thickness ( +/- SD) at baseline in TLOF, MLOF and TM groups was 37.07 +/- 15.20 mu m, 40.67 +/- 12.53 and 40.38 +/- 18.67, respectively, which was not significantly different (p=0.85). The mean ellipsoid zone width (EZW) loss ( +/- SD) was 2051 mu m ( +/- 1318) for patients in the TLOF, and 1314 mu m ( +/- 965) for MLOF. Only one patient in the TM group had EZW loss at presentation. There was considerable overlap in ERG findings, although the largest DA 10 ERG b-waves were associated with TLOF and the smallest with TM variants.Conclusions Patients with missense alterations had better BCVA and greater structural integrity. This is important for patient prognostication and counselling, as well as stratification for future gene therapy trials. Show less
Aims/hypothesis Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study... Show moreAims/hypothesis Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes.Methods One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals.Results Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAF(Afr)]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9x10(-9)); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAF(Afr)=0.0536), was associated with a reduced response to metformin (p=2.4x10(-8)), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA(1c) of 0.08% and non-carriers had an HbA(1c) increase of 0.01% after 1 year of treatment (p=3.3x10(-3)). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6x10(-5)), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology.Conclusions/interpretation We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. Show less
Moel, E.C. de; Trouw, L.A.; Terao, C.; Govind, N.; Tikly, M.; El-Gabalawy, H.; ... ; Woude, D. van der 2023
Background: Rheumatoid arthritis (RA) occurs across the globe in different ethnic populations. Most RA patients harbor anti-modified protein antibodies (AMPA); however, it is unclear whether... Show moreBackground: Rheumatoid arthritis (RA) occurs across the globe in different ethnic populations. Most RA patients harbor anti-modified protein antibodies (AMPA); however, it is unclear whether differences exist in autoantibody responses at different geographic locations and between different ethnic groups, which could provide new clues regarding factors underlying autoantibody development. We therefore investigated AMPA prevalence and association with HLA DRB1 alleles and smoking in four ethnically diverse populations on four different continents. Methods: Anti-carbamylated (anti-CarP), anti-malondialdehyde acetaldehyde (anti-MAA), and anti-acetylated protein antibodies (anti-AcVim) IgG were determined in anti-citrullinated protein antibody-positive Dutch (NL, n = 103), Japanese (JP, n = 174), First Nations Peoples in Canada (FN, n = 100), and black South African (SA, n = 67) RA patients. Ethnicity-matched local healthy controls were used to calculate cut-offs. Risk factors associated with AMPA seropositivity in each cohort were identified using logistic regression. Results: Median AMPA levels were higher in First Nations Peoples in Canada and especially South African patients, as reflected by percentage seropositivity: NL, JP, FN, and SA: anti-CarP: 47%, 43%, 58%, and 76% (p < 0.001); anti-MAA: 29%, 22%, 29%, and 53% (p < 0.001); and anti-AcVim: 20%, 17%, 38%, and 28% (p < 0.001). Total IgG levels also differed markedly, and when autoantibody levels were normalized to total IgG, differences between cohorts became less pronounced. Although there were some associations with AMPA and HLA risk alleles and smoking, none was consistent across all four cohorts. Conclusions: AMPA against various post-translational modifications could consistently be detected on different continents across ethnically diverse RA populations. Differences in AMPA levels corresponded to differences in total serum IgG levels. This suggests that, despite differences in risk factors, a common pathway may be involved in AMPA development across geographic locations and ethnicities. Show less
Moel, E.C. de; Trouw, L.A.; Terao, C.; Govind, N.; Tikly, M.; El-Gabalawy, H.; ... ; Woude, D. van der 2023
BackgroundRheumatoid arthritis (RA) occurs across the globe in different ethnic populations. Most RA patients harbor anti-modified protein antibodies (AMPA); however, it is unclear whether... Show moreBackgroundRheumatoid arthritis (RA) occurs across the globe in different ethnic populations. Most RA patients harbor anti-modified protein antibodies (AMPA); however, it is unclear whether differences exist in autoantibody responses at different geographic locations and between different ethnic groups, which could provide new clues regarding factors underlying autoantibody development. We therefore investigated AMPA prevalence and association with HLA DRB1 alleles and smoking in four ethnically diverse populations on four different continents.MethodsAnti-carbamylated (anti-CarP), anti-malondialdehyde acetaldehyde (anti-MAA), and anti-acetylated protein antibodies (anti-AcVim) IgG were determined in anti-citrullinated protein antibody-positive Dutch (NL, n = 103), Japanese (JP, n = 174), First Nations Peoples in Canada (FN, n = 100), and black South African (SA, n = 67) RA patients. Ethnicity-matched local healthy controls were used to calculate cut-offs. Risk factors associated with AMPA seropositivity in each cohort were identified using logistic regression.ResultsMedian AMPA levels were higher in First Nations Peoples in Canada and especially South African patients, as reflected by percentage seropositivity: NL, JP, FN, and SA: anti-CarP: 47%, 43%, 58%, and 76% (p < 0.001); anti-MAA: 29%, 22%, 29%, and 53% (p < 0.001); and anti-AcVim: 20%, 17%, 38%, and 28% (p < 0.001). Total IgG levels also differed markedly, and when autoantibody levels were normalized to total IgG, differences between cohorts became less pronounced. Although there were some associations with AMPA and HLA risk alleles and smoking, none was consistent across all four cohorts.ConclusionsAMPA against various post-translational modifications could consistently be detected on different continents across ethnically diverse RA populations. Differences in AMPA levels corresponded to differences in total serum IgG levels. This suggests that, despite differences in risk factors, a common pathway may be involved in AMPA development across geographic locations and ethnicities. Show less
Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently... Show moreBackground: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk. Show less
Aims: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was... Show moreAims: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. Methods and results: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P= 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). Conclusion: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype.[GRAPHICS]. Show less
Objective: To evaluate the long-term ipsi- and contralateral hearing of patients with a unilateral enlarged vestibular aqueduct (EVA). Study design: Multicenter retrospective cohort study. Setting:... Show moreObjective: To evaluate the long-term ipsi- and contralateral hearing of patients with a unilateral enlarged vestibular aqueduct (EVA). Study design: Multicenter retrospective cohort study. Setting: Three tertiary otology and audiology referral centers. Patients and diagnostic interventions: A total of 34 children with a unilateral enlarged vestibular aqueduct as identified on CT and/or MR imaging were evaluated with pure tone and speech perception audiometry. Mean outcome measures: Radiologic measurements of the vestibular aqueduct, ipsi- and contralateral hearing loss, ipsi- and contralateral hearing loss progression over time and DNA test results. Results: All patients in this cohort with unilateral EVA presented with hearing loss. Hearing loss was progressive in 38% of the ipsilateral ears. In 29% of the children, hearing loss was also found in the contralateral ear without EVA. In 90%, the contralateral hearing was stable, with a mean follow up of 4.2 years. We found a significant correlation between the severity of the hearing loss and the size of the EVA. A genetic diagnosis associated with EVA and/or SNHL was found in only 7%. Conclusion: About a third of the children with unilateral EVA are at risk of developing hearing loss in the contralateral ear. This indicates that at least in some patients with a unilateral EVA, a bilateral pathogenic process underlies the hearing loss, in contrary to what the imaging results suggest. These findings are important for counseling of EVA patients and their parents and have implications for follow up. Show less
Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium... Show moreAims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Show less
Abu Hamdeh, S.; Tenovuo, O.; Peul, W.; Marklund, N. 2021
Background To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete... Show moreBackground To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete understanding of the vast complexity of the biological cascades and failure to appreciate the diversity of secondary injury mechanisms in TBI. In recent years, techniques for high-throughput characterization and quantification of biological molecules that include genomics, proteomics, and metabolomics have evolved and referred to as omics. Methods In this narrative review, we highlight how omics technology can be applied to potentiate diagnostics and prognostication as well as to advance our understanding of injury mechanisms in TBI. Results The omics platforms provide possibilities to study function, dynamics, and alterations of molecular pathways of normal and TBI disease states. Through advanced bioinformatics, large datasets of molecular information from small biological samples can be analyzed in detail and provide valuable knowledge of pathophysiological mechanisms, to include in prognostic modeling when connected to clinically relevant data. In such a complex disease as TBI, omics enables broad categories of studies from gene compositions associated with susceptibility to secondary injury or poor outcome, to potential alterations in metabolites following TBI. Conclusion The field of omics in TBI research is rapidly evolving. The recent data and novel methods reviewed herein may form the basis for improved precision medicine approaches, development of pharmacological approaches, and individualization of therapeutic efforts by implementing mathematical "big data" predictive modeling in the near future. Show less
Background and Aims: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course... Show moreBackground and Aims: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes.Methods: Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n= 1097; cohort B, n= 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (false-discovery rate [FDR] corrected p<0.05) associations identified in cohort A were put forward for replication in cohort B.Results: Crohn's disease [CD] GRS were associated with fibrostenotic CD [R-2= 7.4%, FDR = 0.02] and ileocaecal resection [R-2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R-2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R-2 . 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R-2 = 1.7%, FDR = 0.04].Conclusions: Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes. Show less
Ghatan, S.; Costantini, A.; Li, R.; Bruin, C. de; Appelman-Dijkstra, N.M.; Winter, E.M.; ... ; Medina-Gomez, C. 2021
Purpose of Review Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped... Show morePurpose of Review Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped by the individual genetic background influencing the acquisition of bone mineral density, and therefore, the skeletal fragility as shown in adults. Here, we examine paediatric fractures from the perspective of monogenic and complex trait genetics.Recent Findings Large-scale genome-wide studies in children have identified similar to 44 genetic loci associated with fracture or bone traits whereas similar to 35 monogenic diseases characterized by paediatric fractures have been described.Genetic variation can predispose to paediatric fractures through monogenic risk variants with a large effect and polygenic risk involving many variants of small effects. Studying genetic factors influencing peak bone attainment might help in identifying individuals at higher risk of developing early-onset osteoporosis and discovering drug targets to be used as bone restorative pharmacotherapies to prevent, or even reverse, bone loss later in life. Show less
Boer, I. de; Terwindt, G.M.; Maagdenberg, A.M.J.M. van den 2020
Migraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least... Show moreMigraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least understood. Given the evidence from epidemiological studies in cohorts and families that the genetic contribution is highest in migraine with aura, this seems paradoxical. Various genetic approaches have been applied to identify genetic factors that confer risk for migraine. Initially, so-called candidate gene associations studies (CGAS) have been performed that test DNA variants in genes prioritized based on presumed a priori knowledge of migraine pathophysiology. More recently, genome-wide association studies (GWAS) tested variants in any gene in an hypothesis-free manner. Whereas GWAS in migraine without aura, or the more general diagnosis migraine have already identified dozens of gene variants, the specific hunt for gene variants in migraine with aura has been disappointing. The only GWAS specifically investigating migraine with aura yielded only one single associated single nucleotide polymorphism (SNP), near MTDH and PGCP, with genome-wide significance. However, interrogation of all genotyped SNPs, so beyond this one significant hit, was more successful and led to the notion that migraine with aura and migraine without aura are genetically more alike than different. Until now, most relevant genetic discoveries related to migraine with aura came from investigating monogenetic syndromes with migraine aura as a prominent phenotype (i.e. FHM, CADASIL and FASPS). This review will highlight the genetic findings relevant to migraine with aura. Show less
Houwink, E.J.F.; Hortensius, O.R.; K. van boven; Sollie, A.; Numans, M.E. 2019
BACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP... Show moreBACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.METHODS: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.RESULTS: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.CONCLUSIONS: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype. Show less
Bos, M.M.; Noordam, R.; Blauw, G.J.; Slagboom, P.E.; Rensen, P.C.N.; Heemst, D. van 2019
Recent technical advances in genetics made large-scale genome-wide association studies (GWAS) in migraine feasible and have identified over 40 common DNA sequence variants that affect risk for... Show moreRecent technical advances in genetics made large-scale genome-wide association studies (GWAS) in migraine feasible and have identified over 40 common DNA sequence variants that affect risk for migraine types. Most of the variants, which are all single nucleotide polymorphisms (SNPs), show robust association with migraine as evidenced by the fact that the vast majority replicate in subsequent independent studies. However, despite thorough bioinformatic efforts aimed at linking the migraine risk SNPs with genes and their molecular pathways, there remains quite some discussion as to how successful this endeavour has been, and their current practical use for the diagnosis and treatment of migraine patients. Although existing genetic information seems to favour involvement of vascular mechanisms, but also neuronal and other mechanisms such as metal ion homeostasis and neuronal migration, the complexity of the underlying genetic pathophysiology presents challenges to advancing genetic knowledge to clinical use. A major issue is to what extent one can rely on bioinformatics to pinpoint the actual disease genes, and from this the linked pathways. In this Commentary, we will provide an overview of findings from GWAS in migraine, current hypotheses of the disease pathways that emerged from these findings, and some of the major drawbacks of the approaches used to identify the genes and pathways. We argue that more functional research is urgently needed to turn the hypotheses that emerge from GWAS in migraine to clinically useful information. Show less
Berg, N. van den; Rodriguez-Girondo, M.; Craen, A.J.M. de; Houwing-Duistermaat, J.J.; Beekman, M.; Slagboom, P.E. 2018
