| 1. |
- Juodakis, Julius, et al.
(författare)
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Time-varying effects are common in genetic control of gestational duration
- 2023
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Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 32:14, s. 2399-2407
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Tidskriftsartikel (refereegranskat)abstract
- Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent - gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31 000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy 'clock'. We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new fetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm, periods and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant and should help design further experimental studies.
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| 2. |
- Petersen, Inga, et al.
(författare)
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Multivalent design of the monoclonal SynO2 antibody improves binding strength to soluble α-Synuclein aggregates
- 2023
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Ingår i: mAbs. - : Taylor & Francis. - 1942-0862 .- 1942-0870. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Soluble aggregates are reported to be the most neurotoxic species of alpha-Synuclein (alpha Syn) in Parkinson's disease (PD) and hence are a promising target for diagnosis and treatment of PD. However, the predominantly intracellular location of alpha Syn limits its accessibility, especially for antibody-based molecules and prompts the need for exceptionally strong soluble alpha Syn aggregate binders to enhance their sensitivity and efficacy for targeting the extracellular alpha Syn pool. In this study, we have created the multivalent antibodies TetraSynO2 and HexaSynO2, derived from the alpha Syn oligomer-specific antibody SynO2, to increase avidity binding to soluble alpha Syn aggregate species through more binding sites in close proximity. The multivalency was achieved through recombinant fusion of single-chain variable fragments of SynO2 to the antibodies' original N-termini. Our ELISA results indicated a 20-fold increased binding strength of the multivalent formats to alpha Syn aggregates, while binding to alpha Syn monomers and unspecific binding to amyloid beta protofibrils remained low. Kinetic analysis using LigandTracer revealed that only 80% of SynO2 bound bivalently to soluble aSyn aggregates, whereas the proportion of TetraSynO2 and HexaSynO2 binding bi- or multivalently to soluble alpha Syn aggregates was increased to similar to 95% and 100%, respectively. The overall improved binding strength of TetraSynO2 and HexaSynO2 implies great potential for immunotherapeutic and diagnostic applications with targets of limited accessibility, like extra-cellular alpha Syn aggregates. The ability of the multivalent antibodies to bind a wider range of alpha Syn aggregate species, which are not targetable by conventional bivalent antibodies, thus could allow for an earlier and more effective intervention in the progression of PD.
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| 3. |
- Ytterberg, Karin, et al.
(författare)
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Exploring the association of parity and its interaction with history of preterm delivery on gestational duration.
- 2023
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Ingår i: Annals of epidemiology. - 1047-2797 .- 1873-2585. ; 87
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Tidskriftsartikel (refereegranskat)abstract
- Preterm delivery is a major cause of child mortality. While the relationship between parity and preterm delivery is known, its association with gestational duration and variability remains underexplored. Differences in variance may suggest interaction with other well-established risk factors.With 1.1 million spontaneous deliveries (1990-2012) from the Swedish Medical Birth Register, we assessed while accounting for potential confounders the effects of parity on the mean and variance of gestational duration, and its possible interactions with history of preterm delivery. Pedigrees allowed to account for nonobserved, shared confounders using linear mixed models.Parity has a modest association with mean gestational duration, but a large effect on its variance. For example, the first pregnancy had the shortest mean gestational duration, 0.29days shorter (95% CI: -0.33, -0.25) than the second, and the largest variance (σ2 =135days2). Accounting for shared unobserved confounders highlighted a group effect bias, likely linked to the mothers' total number of offspring. Parity interacts with other risk factors, including previous preterm delivery where the magnitude of its effect increases with parity (up to 4.6days effect difference).Nonshared factors across a mother's pregnancies highlight parity's importance to gain insight into the mechanisms governing the timing of delivery.
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