Objectives: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci... Show moreObjectives: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA. Methods: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits. Results: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (SPP1/MEPE, OR=1.40, p=8.4x10(-14)) and rs11243284 (6p24.3, OR=1.35, p=4.2x10(-11)) have not been associated with OA, whereas rs11631127 (ALDH1A2, OR=1.46, p=7.1x10(-18)), and rs1800801 (MGP, OR=1.37, p=3.6x10(-13)) have previously been associated with hand OA. The association of rs1800801 (MGP) was consistent with a recessive mode of inheritance in contrast to its additive association with hand OA (OR homozygotes vs non-carriers=2.01, 95% CI 1.71 to 2.37). All four variants associated nominally with finger OA, although with substantially lower effect. We found shared genetic components between EHOA and other OA measures, grip strength, urate levels and gout, but not rheumatoid arthritis. We identified ALDH1A2, MGP and BMP6 as causal genes for EHOA, with loss-of-function Bmp6 zebrafish mutants displaying EHOA-like phenotypes. Conclusions: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints. Show less
Calamus javensis is polymorphic. Morphometry and molecular approach resulted in all names used in the complex are regarded as synonyms of C. javensis except C. tenompokensis, which is retained as a... Show moreCalamus javensis is polymorphic. Morphometry and molecular approach resulted in all names used in the complex are regarded as synonyms of C. javensis except C. tenompokensis, which is retained as a distinct species. One variety is here recognized, C. javensis var. polyphyllus (including C. acuminatus) Show less
Lakeman, I.M.M.; Rodriguez Girondo, M.D.M.; Lee, A.; Celosse, N.; Braspenning, M.E.; Engelen, K. van; ... ; Devilee, P. 2022
Background: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score ... Show moreBackground: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families. Methods: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known. Results: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM. Conclusions: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes. Show less
Because thin systems can deform along the thickness with relative ease, the interplay between surface mechanics and geometry plays a fundamental role in sculpting their three-dimensional shape.... Show moreBecause thin systems can deform along the thickness with relative ease, the interplay between surface mechanics and geometry plays a fundamental role in sculpting their three-dimensional shape. Often, deformations arise as a consequence of elastic pre-stress in the material, for example because of the small-scale geometry of the constituents or their local arrangement. In this thesis, we look at the connection between geometry, local and global, and mechanics in thin closed shells and open sheets which we consider as two-dimensional solids that we study using linear elasticity theory. In particular, we investigate the elasticity-driven shape deformations in the context of three soft matter systems: dense single-layered crystals, oil-in-water emulsions, and biological thin assemblies of tubulin. Show less
Prion diseases are fatal neurodegenerative disorders associated with the polymerization of the cellular form of prion protein (PrP(C)) into an amyloidogenic β-sheet infectious form (PrP(Sc)). The... Show morePrion diseases are fatal neurodegenerative disorders associated with the polymerization of the cellular form of prion protein (PrP(C)) into an amyloidogenic β-sheet infectious form (PrP(Sc)). The sequence of host PrP is the major determinant of host prion disease susceptibility. In mice, the presence of allele a (Prnp(a), encoding the polymorphism Leu-108/Thr-189) or b (Prnp(b), Phe-108/Val-189) is associated with short or long incubation times, respectively, following infection with PrP(Sc). The molecular bases linking PrP sequence, infection susceptibility, and convertibility of PrP(C) into PrP(Sc) remain unclear. Here we show that recombinant PrP(a) and PrP(b) aggregate and respond to seeding differently in vitro. Our kinetic studies reveal differences during the nucleation phase of the aggregation process, where PrP(b) exhibits a longer lag phase that cannot be completely eliminated by seeding the reaction with preformed fibrils. Additionally, PrP(b) is more prone to propagate features of the seeds, as demonstrated by conformational stability and electron microscopy studies of the formed fibrils. We propose a model of polymerization to explain how the polymorphisms at positions 108 and 189 produce the phenotypes seen in vivo. This model also provides insight into phenomena such as species barrier and prion strain generation, two phenomena also influenced by the primary structure of PrP. Show less
Colzato, L.S.; Does, A.J.W. van der; Kouwenhoven, C.; Elzinga, B.M.; Hommel, B. 2011
My thesis concerns different aspects of diabetic nephropathy. A pathologic classification of diabetic nephropathy is developed, a meta-analyis of genes in diabetic nephropathy is developed and the... Show moreMy thesis concerns different aspects of diabetic nephropathy. A pathologic classification of diabetic nephropathy is developed, a meta-analyis of genes in diabetic nephropathy is developed and the other chapters are about the CNDP1 gene in relation to kidney disease, mainly diabetic nephropathy. Show less
Mate choice by female cichlid fish from Lake Victoria plays an important role in speciation and the maintenance of species. Females are expected to select against males that are intermediate in... Show moreMate choice by female cichlid fish from Lake Victoria plays an important role in speciation and the maintenance of species. Females are expected to select against males that are intermediate in their phenotype during the process of speciation driven by sexual selection. To test this, we hybridized two species of cichlids that differ in male nuptial coloration. Male hybrids were intermediate in nuptial coloration compared to the parental species. Hybrids had a comparable fitness to the parental species and did not suffer from inviability, sterility, skewed sex ratios, reduced survival or reduced growth rates. Females preferred males of their own species over males of the other species. This implies that female mate preference can drive speciation. Females of one species were able to distinguish between males of their own species and hybrid males; females of the other species however, were not able to see this difference. When there is hybridization in nature, for instance when coloration becomes invisible by an increase in turbidity of the water, there would be asymmetrical selection against hybrids. An understanding of these processes is crucial in speciation research and for the maintenance of biodiversity. Show less
