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4 is associated with obstructive sleep apnea/hypopnea
From Boston University School of Medicine and VA Boston Healthcare System (Dr. Gottlieb), MA; Boston University School of Public Health (Dr. DeStefano), MA; National Institute on Aging (D.J. Foley), Bethesda, MD; Stanford University (Dr. Mignot), CA; Case Western Reserve University (Dr. Redline), Cleveland, OH; University of Pittsburgh (Dr. Givelber), PA; and University of Wisconsin-Madison (Dr. Young).
Address correspondence and reprint requests to Dr. Daniel J. Gottlieb, The Pulmonary Center, Boston University School of Medicine, 715 Albany Street, R-304, Boston, MA 02118-2394; e-mail: dgottlieb{at}lung.bumc.bu.edu
Background: Obstructive sleep apnea/hypopnea (OSAH) has a strong heritable component, although its genetic basis remains largely unknown. One epidemiologic study found a significant association between the APOE 
4 allele and OSAH in middle-aged adults, a finding that was not replicated in a cohort of elderly adults. The objective of this study was to further examine the association of the APOE 4 allele with OSAH in a community-dwelling cohort, exploring age dependency of the association.
Methods: A genetic association study was performed, nested within a prospective cohort study of the cardiovascular consequences of OSAH. Unattended, in-home nocturnal polysomnography was used to measure apnea-hypopnea index (AHI) in 1,775 participants age 40 to 100 years. OSAH was defined as an AHI 
15. The relation of APOE genotype to prevalent OSAH was analyzed using generalized estimating equations to account for non-independent observations of individuals from the same sibship.
Results: At least one APOE 4 allele was present in 25% of subjects, with 1.3% 4/4 homozygotes. The prevalence of OSAH was 19%. After adjustment for age, sex, and BMI, the presence of any APOE 4 allele was associated with increased odds of OSAH (OR 1.41, 95% CI 1.06 to 1.87, p = 0.02). The effect was approximately twice as great in subjects <75 (OR 1.61, CI 1.02 to 2.54) as in those 75 years old (OR 1.32, CI 0.91 to 1.90). Exploratory analyses revealed that the strongest effect of APOE 4 was in subjects age <65 (OR 3.08, CI 1.43 to 6.64), and was stronger in those with hypertension or cardiovascular disease than in those without.
Conclusion: The APOE 4 allele is associated with increased risk of OSAH, particularly in individuals under age 65. The mechanisms underlying this association are uncertain. Age-dependency of the APOE-OSAH association may explain previous conflicting results.
Received November 14, 2003. Accepted in final form April 26, 2004.
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