Cytokine-induced molecular responses in airway smooth muscle cells inform genome-wide association studies of asthma.

BACKGROUND: A challenge in the post-GWAS era is to assign function to disease-associated variants. However, available resources do not include all tissues or environmental exposures that are relevant to all diseases. For example, exaggerated bronchoconstriction of airway smooth muscle cells (ASMCs) defines airway hyperresponsiveness (AHR), a cardinal feature of asthma. However, the contribution of ASMC to genetic and genomic studies has largely been overlooked. Our study aimed to address the gap in data availability from a critical tissue in genomic studies of asthma. METHODS: We developed a cell model of AHR to discover variants associated with transcriptional, epigenetic, and cellular responses to two AHR promoting cytokines, IL-13 and IL-17A, and performed a GWAS of bronchial responsiveness (BRI) in humans. RESULTS: Our study revealed significant response differences between ASMCs from asthma cases and controls, including genes implicated in asthma susceptibility. We defined molecular quantitative trait loci (QTLs) for expression (eQTLs) and methylation (meQTLs), and cellular QTLs for contractility (coQTLs) and performed a GWAS of BRI in human subjects. Variants in asthma GWAS were significantly enriched for ASM QTLs and BRI-associated SNPs, and near genes enriched for ASM function, many with small P values that did not reach stringent thresholds of significance in GWAS. CONCLUSIONS: Our study identified significant differences between ASMCs from asthma cases and controls, potentially reflecting trained tolerance in these cells, as well as a set of variants, overlooked in previous GWAS, which reflect the AHR component of asthma.

The Incidence of Perioperative Adverse Events in the Very Elderly Undergoing Urogynecologic Surgery.

OBJECTIVES: To determine the incidence of perioperative adverse events in very elderly women (age ≥ 80 years) undergoing urogynecologic procedures and to examine the effect of preoperative functional status/capacity on these outcomes. METHODS: This is a retrospective analysis of all women aged 80 years or older who underwent a urogynecologic procedure at a tertiary care specialty practice between 2006 and 2014. Subjects were identified by their Current Procedural Terminology codes and the electronic medical record was queried for demographic and perioperative data. Functional status was recorded using data from the preoperative anesthesia assessment, and included the functional status score (range, 1-4) and a functional capacity evaluation (metabolic equivalents [METs, range, 1 to 8+]). RESULTS: One hundred sixty-four women aged 80 years or older underwent a urogynecologic procedure during the study period. Mean age was 83 years (±3; range, 80-95 years). The median functional status was 2 (1-4) and median functional capacity was 5.5 METs (1.75-8.0). The overall postoperative adverse event rate was 18.3%; the incidence of serious events was 7.8%. Most serious events were associated with preexisting medical conditions. Presence of 3 or more comorbid conditions was associated with a higher risk of postoperative readmission, need for transfusion and deep vein thrombosis/pulmonary embolism. Preoperative functional status and functional capacity were not associated with postoperative adverse events. Patients with METs scores of 4.5 or less were more likely to need home services or a skilled nursing facility (SNF) postoperatively compared with patients with higher scores (28.9% vs 6.7%, P < 0.0001; odds ratio, 4.3; 95% confidence interval, 1.6-11.9). Dementia was also associated with SNF admission (36.3% vs 10%; P = 0.01; odds ratio, 3.6; 95% confidence interval, 1.1-12.8). CONCLUSIONS: The incidence of serious postoperative adverse events is low in very elderly patients undergoing urogynecologic procedures. Dementia and poor functional capacity appear to be associated with a higher need for postoperative home services or SNF admission.