Established genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.
Objectives/Hypothesis: To investigate the association between PM 10 concentration and the severity of rhinitis symptoms.Study Design: Retrospective cohort study.Methods: Retrospective analysis of the data of 590 participants prospectively enrolled in a regional population-based cohort study was performed. The ambient PM 10 concentrations were measured at 12 different observatories located in three cities. All participants were screened for allergic sensitization by skin prick tests and asked to complete questionnaires regarding their rhinitis symptoms. The severity and duration of rhinitis were analyzed and compared at different levels of PM 10 concentration .Results: On multivariate analysis, the PM 10 concentration significantly correlated with the severity of symptoms when adjusting for age, sex, presence of sensitized allergen, region, and the time of enrolment (β = 0.102, P = .021). Positive correlation was found between PM 10 concentration and the duration of allergic rhinitis symptoms (β = 0.082, P = .077). In the stratified analysis on the atopic status, there was a significant correlation between PM 10 concentration and the severity and duration of rhinitis symptoms in those without allergic sensitization (β = 0.104; P = .032 and β = 0.104; P = .011, respectively).Conclusions: The significant correlation between the annual PM10 concentration and severity and duration of rhinitis symptoms suggests the necessity of intensive management of rhinitis patients exposed to elevated levels of ambient PM10 concentration.
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