BackgroundLoss-of-function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA-PD). GBA1 encodes the... Show moreBackgroundLoss-of-function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA-PD). GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), a promising target for a possible first disease-modifying therapy. LTI-291 is an allosteric activator of GCase, which increases the activity of normal and mutant forms of GCase.ObjectivesThis first-in-patient study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of 28 daily doses of LTI-291 in GBA-PD.MethodsThis was a randomized, double-blind, placebo-controlled trial in 40 GBA-PD participants. Twenty-eight consecutive daily doses of 10, 30, or 60 mg of LTI-291 or placebo were administered (n = 10 per treatment allocation). Glycosphingolipid (glucosylceramide and lactosylceramide) levels were measured in peripheral blood mononuclear cells (PBMCs), plasma, and cerebrospinal fluid (CSF), and a test battery of neurocognitive tasks, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale and the Mini-Mental State Exam, were performed.ResultsLTI-291 was generally well tolerated, no deaths or treatment-related serious adverse events occurred, and no participants withdrew due to adverse events. Cmax, and AUC0–6 of LTI-291 increased in a dose-proportional manner, with free CSF concentrations equal to the free fraction in plasma. A treatment-related transient increase in intracellular glucosylceramide (GluCer) in PBMCs was measured.ConclusionThese first-in-patient studies demonstrated that LTI-291 was well tolerated when administered orally for 28 consecutive days to patients with GBA-PD. Plasma and CSF concentrations that are considered pharmacologically active were reached (ie, sufficient to at least double GCase activity). Intracellular GluCer elevations were detected. Clinical benefit will be assessed in a larger long-term trial in GBA-PD. Show less
Potjer, T.P.; Grinten, T.W.J. van der; Lakeman, I.M.M.; Bollen, S.H.; Rodriguez-Girondo, M.; Iles, M.M.; ... ; Stoep, N. van der 2021
Background Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%-40% of familial cases carry a pathogenic variant in a known high-risk melanoma... Show moreBackground Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%-40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We investigated whether a melanoma-specific Polygenic Risk Score (PRS) is associated with melanoma risk in patients with genetically unexplained familial melanoma. Methods Dutch familial melanoma cases (n=418) were genotyped for 46 SNPs previously identified as independently associated with melanoma risk. The 46-SNP PRS was calculated and standardised to 3423 healthy controls (sPRS) and the association between PRS and melanoma risk was modelled using logistic regression. Within the case series, possible differences were further explored by investigating the PRS in relation to (1) the number of primary melanomas in a patient and (2) the extent of familial clustering of melanoma. Results The PRS was significantly associated with melanoma risk, with a per-SD OR of 2.12 (95% CI 1.90 to 2.35, p<0.001), corresponding to a 5.70-fold increased risk (95% CI 3.93 to 8.28) when comparing the top 90th to the middle 40-60th PRS percentiles. The mean PRS was significantly higher in cases with multiple primary melanomas than in cases with a single melanoma (sPRS 1.17 vs 0.71, p=0.001). Conversely, cases from high-density melanoma families had a lower (but non-significant) mean PRS than cases from low-density families (sPRS 0.60 vs 0.94, p=0.204). Conclusion Our work underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families. Show less
Acosta-Herrera, M.; Kerick, M.; Lopez-Isac, E.; Assassi, S.; Beretta, L.; Simeon-Aznar, C.P.; ... ; Australian Scleroderma Inter 2021
Objective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we... Show moreObjective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. Conclusions This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression. Show less
Background:The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF).... Show moreBackground:The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.Methods:Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and approximate to 230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.Results:We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk.Conclusions:Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF. Show less
Venous thrombosis (VT), the occlusion of the venous system by a blood clot, is a multicausal disorder affecting 1-2 per 1000 individuals annually. The risk of VT and its complications is not equal... Show moreVenous thrombosis (VT), the occlusion of the venous system by a blood clot, is a multicausal disorder affecting 1-2 per 1000 individuals annually. The risk of VT and its complications is not equal for all individuals. In addition to clinical or acquired risk factors, genetic variation contributes to the risk of venous thrombosis. So far, variation in seventeen genes, almost all encoding proteins related to hemostasis, have consistently been identified as genetic risk factors for a first venous thrombosis. Evidence from previous genome-wide association studies and family studies suggests that additional genetic risk variants are yet to be discovered. In addition, the extent to which the identified risk variants contribute to recurrence risk is not clear, nor whether different genetic risk factors play a role in recurrence pathophysiology than those involved in a first event. In this thesis, we used various strategies to identify variants across the allele frequency spectrum that are associated with the risk of a first or recurrent venous thrombosis. In addition, we investigated whether previously identified genetic risk variants can be used to improve risk stratification for venous thrombosis and we discussed the potential value of using genetic variation to aid causal inferences in observational research. Show less
Bijl, P. van der; Bootsma, M.; Hiemstra, Y.L.; Marsan, N.A.; Bax, J.J.; Delgado, V. 2019
Aims Genetic, dilated cardiomyopathy (DCM) can be caused by a large variety of mutations. Mutation carriers are often asymptomatic until DCM is well established, presenting with heart failure,... Show moreAims Genetic, dilated cardiomyopathy (DCM) can be caused by a large variety of mutations. Mutation carriers are often asymptomatic until DCM is well established, presenting with heart failure, arrhythmias, or sudden cardiac death. Preventive strategies can only be applied if DCM can be detected early. Echocardiographic, left ventricular (LV) global longitudinal strain (GLS) is a promising tool for early diagnosis, i.e. before a decrease in LV ejection fraction (EF) has occurred. We, therefore, investigated the role of LV GLS as an early disease marker in genetic DCM.Methods and results Genetic DCM patients and genotyped family members were evaluated. The study population was grouped as (i) genotype-positive, phenotype-positive (GPFP) patients with a pathogenic mutation and LVEF <55% (ii) genotype-positive, phenotype-negative (GPFN) individuals with a pathogenic mutation and LVEF >= 55%, and (iii) genotype-negative, phenotype-negative (GNFN) individuals without a pathogenic mutation and LVEF >= 55%. One hundred and fifteen individuals (53 +/- 15 years, 51% male) were analysed: 28 (24%) were classified as GNFN, 50 (44%) as GPFN, and 37 (32%) as GPFP. Various mutations were represented: 39 (34%) titin, 14 (12%) lamin A/C, 13 (11%) sarcomeric, and 21 (18%) less frequent mutations (grouped together). The mean LVEF was 58 +/- 14% for all subjects. The mean LV GLS in the GNFN group was -21.7 +/- 1.5% vs. -19.7 +/- 3.5% for the GPFN group (P = 0.036). The mean LV GLS was -12.9 +/- 4.3% for the GPFP category (P < 0.001 vs. GPFN and GNFN).Conclusion Decreased LV GLS discriminates GPFN individuals from normal controls, which may permit early institution of therapy for genetic DCM. Show less
BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising... Show moreBACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development. Show less
Bijl, P. van der; Delgado, V.; Bootsma, M.; Bax, J.J. 2018
The postnatal development of the mouse is characterized by a period of hypo responsiveness of the hypothalamic pituitary adrenal (HPA) axis to mild stressors. Maternal deprivation (MD) during this... Show moreThe postnatal development of the mouse is characterized by a period of hypo responsiveness of the hypothalamic pituitary adrenal (HPA) axis to mild stressors. Maternal deprivation (MD) during this period can disrupt the quiescence of the HPA-axis. The present study examined the influence of strain (outbred CD1 vs. inbred C57BL/6J mice) on some central and peripheral components of the HPA-axis in neonatal mice (5-day-old) in the presence of their mother or after 24 h MD (on postnatal day 4) under basal or mild stressful conditions. In the presence of the dam, adrenal corticosterone (CORT) secretion was low in both mouse strains. Compared to CD1 mice, C57BL/6J had lower CORT levels associated with higher ACTH levels and ACTH/CORT ratio (i.e., lower adrenal sensitivity to ACTH), and higher glucocorticoid receptor (GR) mRNA expression in the paraventricular nucleus. Although MD disinhibited the HPA-axis in both strains as reflected by increased basal CORT and ACTH, we found a strain-dependent pattern. MD increased CORT more in C57BL/6J compared to CD1 mice together with a lower ACTH/CORT ratio (i.e., higher adrenal sensitivity to ACTH), while GR mRNA was no longer different in the two strains. However, this increased adrenal sensitivity in maternally deprived C57BL/6J mice was not reflected in their CORT response to a subsequent novelty stressor, possibly due to an MD-induced ceiling effect in their steroidogenic capacity. In conclusion, the immediate outcome of MD depends on the genetic background of the mother infant dyad, suggesting that maybe also the outcome in later-life cannot be generalized. Show less
