Genome-wide study of longitudinal brain imaging measures of multiple sclerosis progression across six clinical trials.

While the genetics of MS risk susceptibility are well-described, and recent progress has been made on the genetics of disease severity, the genetics of disease progression remain elusive. We therefore investigated the genetic determinants of MS progression on longitudinal brain MRI: change in brain volume (BV) and change in T2 lesion volume (T2LV), reflecting progressive tissue loss and increasing disease burden, respectively. We performed genome-wide association studies of change in BV (N = 3401) and change in T2LV (N = 3513) across six randomized clinical trials from Biogen and Roche/Genentech: ADVANCE, ASCEND, DECIDE, OPERA I & II, and ORATORIO. Analyses were adjusted for randomized treatment arm, age, sex, and ancestry. Results were pooled in a meta-analysis, and were evaluated for enrichment of MS risk variants. Variant colocalization and cell-specific expression analyses were performed using published cohorts. The strongest peaks were in PTPRD (rs77321193-C/A, p = 3.9 × 10-7) for BV change, and NEDD4L (rs11398377-GC/G, p = 9.3 × 10-8) for T2LV change. Evidence of colocalization was observed for NEDD4L, and both genes showed increased expression in neuronal and/or glial populations. No association between MS risk variants and MRI outcomes was observed. In this unique, precompetitive industry partnership, we report putative regions of interest in the neurodevelopmental gene PTPRD, and the ubiquitin ligase gene NEDD4L. These findings are distinct from known MS risk genetics, indicating an added role for genetic progression analyses and informing drug discovery.

Racial/Ethnic Disparities and Determinants of Sufficient Physical Activity Levels.

Introduction: Adequate physical activity is an integral requirement for achieving cardiovascular health. Physical inactivity is the fourth leading cause of death worldwide. Hence, it is important to identify racial/ethnic groups that are less likely to achieve sufficient physical activity levels, and to address barriers to meeting physical activity requirements. Methods: Cross-sectional data from the 2006-2015 National Health Interview Survey (NHIS) were used to compare self-reported sufficient physical activity among different racial/ethnic groups: non-Hispanic (NH) Whites, NH Blacks, NH Asians, and Hispanics in the United States. Sufficient physical activity was defined as ≥ 150 minutes per week of moderate-intensity physical activity, ≥ 75 minutes per week of vigorous-intensity physical activity, or ≥ 150 minutes per week of moderate and vigorous physical activity. Results: The study sample consisted of 296,802 individuals, mean age ± standard error age 46.4 ± 0.10 years, 52% women, 70% NH White, 12% NH Black, 5% NH Asian, and 14% Hispanic. The prevalence of sufficient physical activity in the overall population was 46%, while it was 48% among NH Whites, 39% among NH Blacks, 45% among NH Asians, and 40% among Hispanics. In multivariable-adjusted models (odds ratio; 95% confidence interval), NH Blacks (0.79; 0.64,0.97), NH Asians (0.72; 0.62,0.85) and Hispanics (0.71; 0.61,0.82) were significantly less likely to engage in sufficient physical activity compared with NH Whites. Older age, women, and low income were inversely associated with sufficient physical activity, while a college education or higher was associated directly with it. Conclusions: NH Black and Asian Americans and Hispanic adults were less likely to engage in sufficient physical activity levels compared with Whites. It is important to address barriers to meeting physical activity thresholds to help achieve optimal cardiovascular health.

Performance of High-Sensitivity Cardiac Troponin Assays to Reflect Comorbidity Burden and Improve Mortality Risk Stratification in Older Adults With Diabetes.

OBJECTIVE: Incorporation of comorbidity burden to inform diabetes management in older adults remains challenging. High-sensitivity cardiac troponins are objective, quantifiable biomarkers that may improve risk monitoring in older adults. We assessed the associations of elevations in high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) with comorbidities and improvements in mortality risk stratification. RESEARCH DESIGN AND METHODS: We used logistic regression to examine associations of comorbidities with elevations in either troponin (≥85th percentile) among 1,835 participants in the Atherosclerosis Risk in Communities (ARIC) Study with diabetes (ages 67-89 years, 43% male, 31% black) at visit 5 (2011-2013). We used Cox models to compare associations of high cardiac troponins with mortality across comorbidity levels. RESULTS: Elevations in either troponin (≥9.4 ng/L for hs-cTnI, ≥25 ng/L for hs-cTnT) were associated with prevalent coronary heart disease, heart failure, chronic kidney disease, pulmonary disease, hypoglycemia, hypertension, dementia, and frailty. Over a median follow-up of 6.2 years (418 deaths), both high hs-cTnI and high hs-cTnT further stratified mortality risk beyond comorbidity levels; those with a high hs-cTnI or hs-cTnT and high comorbidity were at highest mortality risk. Even among those with low comorbidity, a high hs-cTnI (hazard ratio 3.0 [95% CI 1.7, 5.4]) or hs-cTnT (hazard ratio 3.3 [95% CI 1.8, 6.2]) was associated with elevated mortality. CONCLUSIONS: Many comorbidities were reflected by both hs-cTnI and hs-cTnT; elevations in either of the troponins were associated with higher mortality risk beyond comorbidity burden. High-sensitivity cardiac troponins may identify older adults at high mortality risk and be useful in guiding clinical care of older adults with diabetes.

Risk Assessment of Stroke in Patients with Atrial Fibrillation: Current Shortcomings and Future Directions.

Atrial fibrillation is a well-known risk factor for cardioembolic stroke; a number of risk stratification scoring systems have been developed to help differentiate which patients would stand to benefit from anticoagulation. However, these scoring systems cannot be utilized in patients whose atrial fibrillation has not been diagnosed. As implantable cardiac monitors become more prevalent, it becomes possible to identify occult, subclinical atrial fibrillation. With this data, it is also possible to examine the relationship between episodes of paroxysmal atrial fibrillation and thromboembolism and the total burden of paroxysmal atrial fibrillation and thromboembolic risk. The data gleaned from these devices provides insight and raises questions regarding the underlying mechanism of thromboembolism in atrial fibrillation, and in doing so, exposes shortcomings in the present clinical use of current risk scoring systems, specifically, the inability to account for atrial fibrillation burden and to apply scores at all in subclinical atrial fibrillation.