Background The genetic drivers of multiple sclerosis (MS) clinical course are essentially unknown with limited data arising from severity and clinical phenotype analyses in genome-wide association studies. Methods Prospective cohort study of 127 first demyelinating events with genotype data, where 116 MS risk-associated single nucleotide polymorphisms (SNPs) were assessed as predictors of conversion to MS, relapse and annualised disability progression (Expanded Disability Status Scale, EDSS) up to 5-year review (ΔEDSS). Survival analysis was used to test for predictors of MS and relapse, and linear regression for disability progression. The top 7 SNPs predicting MS/relapse and disability progression were evaluated as a cumulative genetic risk score (CGRS). Results We identified 2 non-human leucocyte antigen (HLA; rs12599600 and rs1021156) and 1 HLA (rs9266773) SNP predicting both MS and relapse risk. Additionally, 3 non-HLA SNPs predicted only conversion to MS; 1 HLA and 2 non-HLA SNPs predicted only relapse; and 7 non-HLA SNPs predicted ΔEDSS. The CGRS significantly predicted MS and relapse in a significant, dose-dependent manner: those having ≥5 risk genotypes had a 6-fold greater risk of converting to MS and relapse compared with those with ≤2. The CGRS for ΔEDSS was also significant: those carrying ≥6 risk genotypes progressed at 0.48 EDSS points per year faster compared with those with ≤2, and the CGRS model explained 32% of the variance in disability in this study cohort. Conclusions These data strongly suggest that MS genetic risk variants significantly influence MS clinical course and that this effect is polygenic.
Purpose: Studies have shown stable or improved physical function over time in people with symptomatic knee osteoarthritis (OA). Most longitudinal studies have included complete cases data only, excluding those with a worse functional trajectory. Including physical function values for missing visits and pre-surgical values of those with total knee replacement (TKR) may identify modifiable predictors of functional decline. The purpose of this study was to identify modifiable predictors for self-reported and performance-based functional decline over 7 years in all those with symptomatic knee OA in a longitudinal cohort. We hypothesized that knee extensor muscle weakness would be significantly associated with functional decline over time. Methods: Subjects with symptomatic knee OA at baseline were included from the Multicenter Osteoarthritis (MOST) Study. We defined tibiofemoral symptomatic knee OA as present when a person had a painful knee with Kellgren and Lawrence (KL) grade 2 in that knee. Physical function was measured with the WOMAC physical function subscale, the Chair Stands test, and the 20-meter walk test over 7 years. Predictors included baseline knee extensor isokinetic muscle strength (for symptomatic knee), knee flexion contracture by exam, body mass index (BMI), the Charlson Comorbidity score, the CES-D (depression) score, and baseline WOMAC pain and stiffness. We imputed missing values using 5 multiple imputations. Predicted pre-TKR values just prior to TKR in addition to data from all pre-TKR visits were included for those who got TKR during the follow-up time. We conducted mixed models with the following covariates: age, sex, race, baseline KL grade, and time variable. Results: The 834 study participants with symptomatic knee osteoarthritis at baseline (65.8% females) were on average 62.9 (±7.9) years, with a mean BMI of 33.1 (±7.1) kg/m2. Modifiable predictors for WOMAC physical function were extensor muscle weakness in the symptomatic knee (p¼0.004), higher BMI (p¼0.001), pain (p<0.000), stiffness (p¼0.003), and knee flexion contracture (p¼0.023). Modifiable predictors for the Chair Stands test included knee extensor muscle weakness (p<0.000), higher BMI (p<0.000), pain (p¼0.002 for left knee and 0.025 for right knee), and for the 20-meter walk test; knee extensor muscle weakness (p<0.000), BMI (p<0.000), comorbidity (p¼0.007), depression score (p<0.000), and knee pain (p¼0.002).Conclusions: In the MOST study, knee extensor muscle weakness was significantly associated with self-reported and performance-based functional decline over time in people with symptomatic knee osteoarthritis. Other modifiable predictors were higher BMI, pain, stiffness, and knee flexion contracture. People with symptomatic knee osteoarthritis would benefit from tailored exercises and weight loss programs to prevent functional decline over time.Purpose: There is credible evidence that high bone mineral density (BMD) is associated with an increased risk of incident radiographic osteoarthritis (ROA) of the knee. However, les...
Background Previous studies show evidence that more than 21 genetic variants and polygenic risk were associated with Alzheimer’s disease (AD). But the relationship between AD polygenic risk scores (ADPRS) and cognitive function/decline was unclear due to the lack of longitudinal data. This study investigated the potential association between ADPRS and changes in cognitive function. Method The TBHP is an ongoing longitudinal prospective study of 459 healthy older adults. Participants with available genotype data (N = 325) were included in analysis. ADPRS was calculated by using sets of AD susceptibility variants identified by a meta‐analysis of GWAS data. The cognitive function domain scores at baseline and year 1, 2, 3 and 5 were calculated using factor analysis (principal components extraction method). Single factor scores for episodic memory, working memory, executive function, and language processing domains were combined by using factor coefficients via regression analysis. Linear mixed‐effects model analysis was performed to investigate the association between ADPRS and cognitive function longitudinally. Result The ADPRS was significantly associated with an increase of working memory and executive function over 60 months, particularly in APOE ε4 carriers. In BDNF met carriers, ADPRS was associated with the decline of executive function. There were no direct associations between ADPRS and longitudinal changes in cognitive function. Conclusion The relationship between ADPRS and changes in specific cognitive domains were highly being driven by APOE and BDNF status. These findings strongly support the potential role of common variants in predicting the changes in cognitive function before AD.
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