Brendan T Keenan

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

Abstract Rationale Symptom subtypes have been described in clinical and population samples of patients with obstructive sleep apnea (OSA). It is unclear whether these subtypes have different cardiovascular consequences. Objectives To characterize OSA symptom subtypes and assess their association with prevalent and incident cardiovascular disease in the Sleep Heart Health Study. Methods Data from 1,207 patients with OSA (apnea–hypopnea index ≥ 15 events/h) were used to evaluate the existence of symptom subtypes using latent class analysis. Associations between subtypes and prevalence of overall cardiovascular disease and its components (coronary heart disease, heart failure, and stroke) were assessed using logistic regression. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate whether subtypes were associated with incident events, including cardiovascular mortality. Measurements and Main Results Four symptom subtypes were identified (disturbed sleep [12.2%], minimally symptomatic [32.6%], excessively sleepy [16.7%], and moderately sleepy [38.5%]), similar to prior studies. In adjusted models, although no significant associations with prevalent cardiovascular disease were found, the excessively sleepy subtype was associated with more than threefold increased risk of prevalent heart failure compared with each of the other subtypes. Symptom subtype was also associated with incident cardiovascular disease (P < 0.001), coronary heart disease (P = 0.015), and heart failure (P = 0.018), with the excessively sleepy again demonstrating increased risk (hazard ratios, 1.7–2.4) compared with other subtypes. When compared with individuals without OSA (apnea–hypopnea index < 5), significantly increased risk for prevalent and incident cardiovascular events was observed mostly for patients in the excessively sleepy subtype. Conclusions OSA symptom subtypes are reproducible and associated with cardiovascular risk, providing important evidence of their clinical relevance.

STUDY OBJECTIVES: The objective of this study was to determine whether tongue fat is increased in obese sleep apneics compared to obese subjects without sleep apnea. We hypothesized that excess fat is deposited in the tongue in obese patients with sleep apnea. DESIGN: Case-control design. SETTING: Academic medical center. PATIENTS: We examined tongue fat in 31 obese controls (apnea-hypopnea index, 4.1 ± 2.7 events/h) and 90 obese apneics (apnea-hypopnea index, 43.2 ± 27.3 events/h). Analyses were repeated in a subsample of 18 gender-, race-, age-, and BMI-matched case-control pairs. INTERVENTIONS: All subjects underwent a MRI with three-point Dixon magnetic resonance imaging. We used sophisticated volumetric reconstruction algorithms to study the size and distribution of upper airway fat deposits in the tongue and masseter muscles within apneics and obese controls. MEASUREMENTS AND RESULTS: The data supported our a priori hypotheses that after adjustment for age, BMI, gender, and race, the tongue in apneics was significantly larger (P = 0.001) and had an increased amount of fat (P = 0.002) compared to controls. Similar results were seen in our matched sample. Our data also demonstrate that within the apneic and normal tongue, there are regional differences in fat distribution, with larger fat deposits at the base of the tongue. CONCLUSIONS: There is increased tongue volume and deposition of fat at the base of tongue in apneics compared to controls. Increased tongue fat may begin to explain the relationship between obesity and obstructive sleep apnea.