The ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV1/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV1/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09). One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV1/FVC (p-value = 2.0e-04). The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV1/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV1 and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV1/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35-80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 × 10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Purpose-This analysis was undertaken to determine the long-term intraindividual variability, determinants of change, and capacity of the inflammatory marker, C-reactive protein (CRP), to predict metabolic traits and diabetes in a large community-based population.Methods-Intraindividual CRP variability, predictors of CRP change and metabolic events were evaluated in the Framingham Heart Study Offspring cohort using data from the same 2409 participants with CRP measured by the same methodology at each of 3 exam cycles, spanning 20 years.Results-Between first and second examinations (averaging 16 years apart), 23-47% of men and 27-49% of women remained within the same quintile of CRP values. An additional 24-51% of men and 24-50% of women occupied an adjacent quintile. Intermediate-term CRP variability (over 4 years) was similar to long-term variability. Both long and intermediate-term variability of CRP was significantly less than that of plasma cholesterol, measured in these same groups. Linear regression models for CRP at the intermediate examination demonstrated that CRP at the initial examination contributed the largest proportion of the variability (partial R-square=0.27) seen in the overall model after adjustment for other covariates known to affect CRP concentrations. Although logistic regression models demonstrated that CRP over the intermediate term did not predict new-onset metabolic syndrome at the final examination, CRP did predict an increase in glucose and new-onset diabetes.Conclusions-Results of this longitudinal analysis suggest the intraindividual, long-term variability of CRP concentrations is relatively small and over an intermediate-term of 4 years is predictive of new diabetes.

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images in clinical medicineT h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 359;6 www.nejm.org august 7, 2008 e7 A 26-year-old man who smoked and had a long history of poorly controlled asthma and severe environmental allergies was admitted for an exacerbation of asthma. He reported no recent hospitalizations or exposure to tuberculosis and for more than a year had not been taking any medications. A computed tomographic scan was obtained to elucidate multilobar infiltrates that were seen on chest radiographs. Areas of tubular (Panel A, arrows) and cystic (Panel A, arrowhead) bronchiectasis, predominantly in the upper lobes, and bilateral mucous plugging (Panel B, arrows) were seen, along with mediastinal and hilar lymphadenopathy. His white-cell count was 8000 per cubic millimeter with 8% eosinophils, and his IgE level was 21,494 IU per milliliter (normal range, 0 to 150). A test for human immunodeficiency virus was negative. Genetic testing for cystic fibrosis was negative for the 103 most common mutations. A sputum culture grew Aspergillus fumigatus. Serum aspergillus precipitins were positive, with an index of IgE to A. fumigatus of 9.6 (normal, <2) and an index of IgG to A. fumigatus of 2.4 (normal, <2). Taken together, these findings were consistent with a diagnosis of allergic bronchopulmonary aspergillosis. Clinical improvement was seen after a taper of glucocorticoids over a period of 2 months. Subsequently, the patient was lost to follow-up.

Bronchial thermoplasty (BT) is a treatment for severe persistent asthma which uses bronchoscopically delivered radiofrequency energy to induce smooth muscle atrophy thereby decreasing bronchoconstriction. The Pulmonary and Allergy Section of the VA Boston Healthcare System was the first Department of Veterans Affairs Medical Center to implement bronchial thermoplasty for our veteran population. METHODS: The VA Boston serves as a regional referral center for both Pulmonary and Allergy patients with a catchment area encompassing the northern New England region. The Asthma clinic also delivers care via a network of community-based outpatient clinics throughout Massachusetts, Rhode Island, New Hampshire and Maine. Via this network, referring providers were educated about the principles behind BT and its benefits in the treatment of patients with uncontrolled severe persistent asthma despite maximal medical therapy. Pulmonologists at nearby VA Medical Centers were also individually contacted to aprise them of the availability of BT. Patients screened for bronchial thermoplasty were evaluated for immunotherapy and omalizumab. All were on maximal medical therapy and had continued asthma flares. Outreach to providers supporting the procedure included presentations on the principles of BT, its relationship to conventional diagnostic bronchoscopy as well as expectations for level of anesthesia and duration of the procedure. All treatments were performed under moderate to deep sedation with anesthesiology support. Patients were pre-treated with prednisone as per the AIR2 trial and received an antisialagogue as well as a cough suppressant on the day of the procedure. Pre-and post-procedure spirometry were obtained to verify that patient's were near their baseline lung function and that they were safe for discharge subsequent to the procedure. RESULTS: In the first year, five patients with severe persistent asthma completed treatment. Referrals were drawn from within the Medical Center as well as from other regional centers. All had severe persistent asthma symptoms with elevated Astma Control Test scores as well as significant bronchodilator reversibility on spirometry. Patients had undergone allergy testing as well as immunotherapy or treatment with anti-IgE therapy where appropriate. Patients underwent the recommended three procedures at one month intervals under moderate sedation. ACT scores improved following treatment reflecting improved asthma control with decreased prednisone requirements, daily symptoms and exacerbations. CONCLUSIONS: Successful implementation of a bronchial thermoplasty program requires education of referring and participating providers as well as close coordination between multiple departments within the medical center on the day of the procedure. Close follow-up and outreach to patients ensures that the multiple procedures required are successfully completed. CLINICAL IMPLICATIONS: Development of regional bronchial thermoplasty centers in the VA network will help to serve the needs of our veterans...

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