A Genome-Wide Association Study of Pulmonary Function Measures in the Framingham Heart Study

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

Positive Pressure Therapy: A Perspective on Evidence-based Outcomes and Methods of Application

The sleep medicine community has increasingly recognized the necessity that clinical care be based on high-quality levels of evidence. Although research supports a favorable influence of positive airway pressure (PAP) therapy on risk for significant adverse outcomes in patients with severe obstructive sleep apnea–hypopnea (OSAH), well-designed trials are still required to elucidate the effect of PAP on health, quality of life, and economic risks in patients with milder OSAH. Similarly, although there is strong evidence supporting various PAP titration strategies and PAP modalities in patients with severe OSAH without significant medical and psychiatric comorbidities, there is insufficient high-level evidence assessing and comparing the clinical efficacy and health care cost implications of various titration paradigms and various PAP modalities in individuals with milder OSAH and those with comorbid conditions. For ethical and other reasons, it may not be possible to apply a randomized controlled design to address all questions. However, whichever design is employed, it must be rigorously developed with attention to all potential confounders with adequate power to provide compelling, high-quality evidence