Familial Aggregation and Natural History of Sleep Apnea

BACKGROUND:

In 1990, there was increased recognition that obstructive sleep apnea occurs commonly and may lead to serious adverse cardiopulmonary and psychoneurologic health effects. In subjects with numerous and prolonged apneas, nocturnal hypoxemia and disrupted sleep may lead to pulmonary hypertension, cor pulmonale, and excessive daytime sleepiness. Systemic hypertension is more prevalent in subjects with obstructive sleep apnea than in the general population. The health consequences of less severe disease have not been extensively studied in the context of general population studies. However, snoring, a symptom related to sleep apnea, may double the risk of ischemic heart disease. The prevalence of systemic hypertension is higher in snorers than in nonsnorers, a finding potentially of considerable public health concern. An increased number of deaths due to cardiovascular disease in elderly subjects with disordered breathing during sleep also has been demonstrated.

DESIGN NARRATIVE:

The study is cross-sectional and longitudinal in design. Index cases were identified through the Rhode Island Hospital Sleep Laboratory and controls through local industry. During home visits, questionnaire data on symptoms, medical history, and exposures were collected and the following measurements made: blood pressure, height, weight, and spirometry. Structural assessment of the upper airway was made by a brief physical examination, and facial structure was documented with a lateral photograph. Airflow, chest wall movement, oxygen saturation, and heart rate during sleep were recorded with an ambulatory monitoring device. Observations in the field were confirmed and extended with laboratory studies on a sample of families who demonstrated the greatest and the least concordance for sleep-related respiratory disturbances. These subjects had a more detailed assessment of upper airway structure with cephalometry and posterior rhinometry, assessment of ventilatory control with responses to chemical and resistive loading, and assessment of sleep staging with in-hospital polysomnography. Familial correlations with and without adjustment for specific risk factors were computed. These analyses allowed: a determination of the risk of development of sleep apnea due to familial factors; an improved understanding of the influences of genetic and acquired risk factors and their interactions on the development of sleep apnea: and characterization of a generally healthy population at increased risk for sleep apnea that were studied subsequently both longitudinally in natural history studies and with molecular genetic markers in pedigree studies.

The study was renewed in FY 1996. The cohort was expanded by the addition of 85 families identified through an affected proband, leading to a total of 300 families. These new cohort members were characterized in the fashion similar to that previously used. Follow-up was conducted on those initially recruited for apnea levels, blood pressure, body fat distribution, cranial facial dimensions, pulmonary function, and other factors of interest. For 450 of the individuals, follow-up extended through nine years. A nested case-control study was also conducted that included 24-hour ambulatory blood pressure monitoring and echocardiography. A principal analytic tool was variance component modeling.

The study was renewed in FY 2001 through March, 2005. Further studies will be conducted in the cohort of 2,200 who had previously undergone overnight sleep studies. A total of 700 cohort members from families with sleep apnea, most of whom had a genome scan performed, will undergo additional physiological and biochemical measurements and longitudinal follow-up to derive detailed phenotypic characterization of sleep apnea and related cardiovascular disease risk factors and subclinical disease. Newly available technology will be used to quantify specific and sensitive indices of obstructive breathing parameters and sleep fragmentation. Subjects will also undergo a biochemical profile and evaluations of vascular functions, including assessment of novel cardiovascular disease risk factors that may be related to sleep apnea based on common genes or their role as indices of sleep apnea disease severity.