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Published ahead of print on September 24, 2004, doi:10.1164/rccm.200405-616OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 1349-1353, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200405-616OC

Original Article

Angiotensin-converting Enzyme, Sleep-disordered Breathing, and Hypertension

Ling Lin, Laurel Finn, Jing Zhang, Terry Young and Emmanuel Mignot

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto; Howard Hughes Medical Institute, Stanford, California; and Department of Preventive Medicine, University of Wisconsin-Madison, Madison, Wisconsin

Correspondence and requests for reprints should be addressed to Emmanuel Mignot, M.D., Ph.D., Stanford University Center For Narcolepsy, 701 B Welch Road, 145, Palo Alto, CA 94304-5742. E-mail: mignot{at}stanford.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism influences ACE activity, cardiovascular risk, blood pressure, and possibly the risk of developing Alzheimer's dementia. We explored the association of the insertion/deletion polymorphism with sleep-disordered breathing (SDB) and hypertension in 1,100 subjects of the Wisconsin Sleep Cohort. The polymorphism did not influence body mass index or the occurrence of SDB, but was dose-dependently associated with blood pressure. Interestingly, SDB and the insertion/deletion polymorphism interacted significantly to modulate blood pressure independently of age, sex, ethnicity, and body mass index. Most specifically, the association of the deletion allele with hypertension was most pronounced in subjects with mild to moderate degrees of sleep apnea (5 <= apnea–hypopnea index <= 30). We hypothesize that in the absence of SDB the effect of the deletion allele alone may not be sufficient to increase blood pressure. At severe levels of SDB, the effect of sleep apnea on blood pressure overwhelms any association of the deletion allele with hypertension and occurs independent of any ACE gene genotype.

Key Words: angiotensin-converting enzyme • hypertension • sleep-disordered breathing • sleep apnea

The angiotensin-converting enzyme (ACE) plays an important role in blood pressure regulation and electrolyte balance by hydrolyzing angiotensin I into angiotensin II, a potent vasoconstrictor and aldosterone-stimulating peptide. The enzyme is also able to inactivate bradykinin and angiotensin 1–7, two vasodilators (1, 2). The importance of this enzyme in the regulation of blood pressure is illustrated by the beneficial effect of ACE inhibitors in hypertension. An insertion/deletion (I/D, intron 16) polymorphism of the ACE gene correlates with circulating ACE plasma activity; higher plasma ACE activity is observed in subjects with ACE-D (3–6). An increase in plasma ACE activity may increase blood pressure through increased production of angiotensin II, or increased degradation of bradykinin and angiotensin 1–7. Whereas angiotensin II levels do not differ across ACE genotype categories, a higher concentration of angiotensin 1–7 and a shorter half life of bradykinin have also been reported in subjects with the DD genotype (1, 2). Many studies have reported an association between ACE-D and hypertension (7–14) or cardiovascular disease (15–17), although other studies have failed to confirm these results (5, 14, 18–22). An association between ACE-D and type II diabetes has also been suggested (23). However, stronger associations in some ethnic groups, smokers versus nonsmokers (24), and male versus female (8, 9, 14, 18, 19, 25) have been reported; failure to account for these interactions may explain, in part, the conflicting findings.

Sleep-disordered breathing (SDB) is an established risk factor for the development of hypertension (26–30). Cross-sectional and longitudinal studies have shown an association between SDB and hypertension, even when controlled for confounding factors such as body mass index, age, sex, and ethnicity (28, 30). In some studies, even mild sleep apnea (e.g., apnea–hypopnea index [AHI] of 5–10) was associated with increased risk for hypertension (28). Recent results also suggest that treatment of obstructive sleep apnea syndrome (OSAS) using continuous positive airway pressure therapy (CPAP) reduces blood pressure in hypertensive patients with OSAS (31–35). The mechanisms underlying the effect of SDB on hypertension are controversial and may involve hypoxia or/and arousal-induced stimulation of sympathetic tone (36–38). SDB has also been associated with increased angiotensin II levels (39) and ACE plasma activity (40), suggesting synergistic effects of ACE and SDB on hypertension and cardiovascular risk.

Interesting interactions between ACE, hypertension, and SDB may also occur within the central nervous system (CNS). APOE, a genetic factor for Alzheimer's disease (AD), has been shown to be involved in the genetic predisposition to SDB—an association we hypothesize may be due to CNS-mediated disruption of the regulation of breathing during sleep (41). In the Wisconsin Sleep Cohort, we found that APOE {epsilon}4 doubled the risk of SDB in middle-aged adults (41). Recent results have confirmed this finding in middle-aged adults, but indicate decreased association of APOE {epsilon}4 with SDB in older subjects (42–43). A possible greater effect of APOE {epsilon}4 on SDB was also found in patients with hypertension or cardiovascular disease, suggesting cardiovascular–CNS interactions (43). As the ACE I allele has been shown to increase risk for AD (44–46), we hypothesized that ACE-I may also be involved in predisposition to SDB. In favor of this hypothesis, Zhang and Zhao recently found increased ACE-I allele counts in 34 Chinese hypertensive patients with moderate to severe SDB (47). In contrast, however, Barcelo and coworkers (40) did not find a significant increase in ACE-I in 44 patients with obstructive sleep apnea.

In this study, we examined the possible association of the ACE I/D polymorphism on SDB and hypertension in middle-aged adults.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Participants and Genotyping
1,100 participants, 96.7% White (1.4% African American, 0.6% Asian, 0.4% Native American, 0.4% Latino, and 0.6% other), aged 35 to 70 years, enrolled in the population-based Wisconsin Sleep Cohort Study (48) were studied (Table 1) using overnight polysomnography, morning blood sample, electrocardiography (ECG), measurement of blood pressure, and collection of body habitus (sex, age, smoking, BMI). Blood samples were collected after overnight fasting. ACE I/D and APOE genotypes were determined as described (49, 50).


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  		TABLE 1. Characteristics of the sample by angitoensin-converting enzyme status (n = 1,100)

 
Sleep Measures
Arterial oxyhemoglobin saturation, oral and nasal airflow, nasal air pressure, and rib cage and abdominal respiratory motion were used to assess SDB. Oxyhemoglobin saturation was recorded using pulse oximetry (Datex Ohmeda, Madison, WI). Stalk-mounted thermocouples detected oral/nasal airflow (Protec, Wondinville, WA). Respiratory inductance plethysmography recorded rib cage and abdominal excursions (Respitrace; Ambulatory Monitoring, Ardsley, NY). Each 30-second epoch was scored for sleep staging and the respiratory events. An apnea was defined as a cessation of airflow lasting >= 10 seconds. A hypopnea was defined as a discernable reduction in the sum of rib cage plus abdomen respiratory inductance plethysmography amplitude lasting >= 10 seconds and associated with >= 4% reduction in oxyhemoglobin saturation (with or without EEG arousal). The summary measure for SDB is the average number of apneas and hypopneas per hour of sleep (AHI) and categorized as AHI < 5, AHI 5–30, and AHI > 30.

Blood Pressure
Seated blood pressure was measured in the evening before nocturnal polysomnography using sphingomanometry. Presence of hypertension was defined as systolic blood pressure (SBP) >= 140 mm Hg or diastolic blood pressure (DBP) >= 90 mm Hg or by current antihypertensive therapy. Presence of cardiovascular disease was defined as self-reported myocardial infarction, atherosclerosis, congestive heart failure, coronary artery disease, coronary bypass, insertion of pacemaker, or angioplasty.

Statistical Analysis
Associations with body habitus and core variables (Table 1) were first compared across the three ACE genotypes using chi-square (categorical) or F-tests (continuous). Logistic and linear models in SAS (51) were then used to look at the adjusted associations of the D- or I-alleles on hypertension (linear SBP, DBP, and presence or absence of hypertension) and SDB. We assessed the association of the D- or I-alleles using dominant (DD+DI versus II), categorical (DD versus II and DI versus II) and linear models (e.g., increasing linear relationships across II, DI, DD). We found that the blood pressure variables increased in a dose–response fashion across II, DI, and DD (Table 1) and therefore used the linear formulation of the D-allele to increase statistical power. The effects of the confounding variables listed in Table 1 were examined as well as interactions between these variables and the D-allele.

Final models were chosen after examining changes in magnitude and statistical significance (Wald chi-squares, p < 0.05) in ß coefficients with confounding variables. Associations were expressed as odds ratios and 95% confidence intervals.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Distribution of ACE I/D Polymorphism Frequencies in the Wisconsin Cohort Sample
In 1,100 subjects, frequencies for the three ACE genotypes (II, DI, and DD) were 20, 52, and 28%, respectively. The distribution was consistent with Hardy Weinberg Equilibrium ({chi}2 = 1.78, p = 0.32) and a D allele frequency of 0.54. The D allele frequency was consistent with reported values in a mostly White population (13, 19, 22). Age, sex, BMI, smoking, APOE {epsilon}4 and ethnic distribution did not vary across ACE genotypes (Table 1).

Association of ACE I/D with SDB and Blood Pressure
Snoring (percent reporting habitual snoring) and SDB, either defined as mean AHI or percent with AHI higher than various cutpoints (for example AHI >= 20 in Table 1) did not differ significantly across genotypes overall. The absence of associations was evident whether the comparison was made assuming linear or dominant models of ACE genotype effects and in both subjects with and without hypertension. We also explored whether the association of ACE with SDB was modified by the presence of APOE {epsilon}4, a genetic factor for SDB in our sample, and found no difference.

We found that the ACE I/D polymorphism had significant or marginally significant associations, unadjusted for potential confounding factors, with blood pressure in the overall sample (see Table 1). ACE I/D polymorphism associations with hypertension were found to be allele dose–dependent in most cases. Highest values for percent with hypertension, percentage treated with blood pressure mediation, mean diastolic and systolic blood pressure were found in subjects with DD, and lowest values in subjects with II.

The associations of the ACE genotype on continuous systolic and diastolic blood pressure, adjusted for age, sex, ethnicity, and body mass index are given in Table 2. Antihypertensive medication, snoring, or smoking did not modify or interact with the effect of ACE on blood pressure and thus these variables were not retained in the model. Given the hypothesis that SDB and the deletion allele may interact on blood pressure, we added a categorical variable for SDB severity and an interaction term with the deletion allele. These adjusted means stratified by SDB severity and the deletion allele are also given in Table 2. Interestingly, the association of the ACE genotype with hypertension was more pronounced in patients with SDB (AHI >= 5), although the significance of the interaction term varied depending on cutpoints for the categorical SDB and use of linear versus categorical ACE genotype modeling terms.


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  		TABLE 2. Systolic and diastolic blood pressure levels across apnea–hypopnea index categories and angiotensin-converting enzyme genotypes

 
With approximately 30% of all cohort subjects treated with blood pressure medications, there was considerable error in actual blood pressure measurements in a large subset of the sample (especially in the DD genotype category; see Table 1), so further analyses focused on the presence of hypertension (SDB >= 140 mm Hg or DBP >= 90 mm Hg or use of antihypertensive medication) as the outcome variable. Unadjusted and adjusted odd ratios for hypertension in DD and ID versus II are reported in Table 3 (Overall). When adjusted for age, sex, BMI, and ethnicity, increased odds of hypertension with ACE DD and ID were highly significant for each genotype category in comparison to the reference II group and ranged from 1.68 to 1.97 in the overall sample. When adding a term for SDB severity and an interaction between SDB severity and the ACE genotype, we found that SDB significantly interacted with ACEI/D in predicting hypertension. In the case of modeling hypertension, the interaction terms were consistently significant and strong (p = 0.004). It is important to note that while the statistical significance of the logistic model term for the interaction of AHI and allele status on hypertension was statistically significant, a chance finding cannot be conservatively dismissed. Most strikingly, the dose dependent association of the ACE-D allele with hypertension was more evident at moderate levels of AHI (AHI from 5–30); the odds ratio for hypertension at this level of SDB was higher compared with the odds ratios in the mild or no SDB (AHI < 5) or severe SDB (AHI > 30 Categories) (Table 3).


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  		TABLE 3. Relationship between angiotensin-converting enzyme allele* and hypertension stratified by apnea–hypopnea index severity level

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our study confirms the previous observation of increased blood pressure in subjects with ACE-D in a large, well characterized population-based sample. Contrary to a recent report, however, current smoking did not modulate the association of ACE-D with hypertension (24), but as the sample size in our study is smaller, statistical power to detect this interaction may have been insufficient.

We next explored possible modifications of the association between ACE and hypertension by SDB, another well-known risk factor for hypertension (26–30). Interestingly, we found that the association between ACE-D and blood pressure was most evident in subjects with intermediate levels of SDB (Table 3). The lack of association of ACE-D with hypertension in subjects with severe SDB may be due to a ceiling effect and the definition of hypertension used in our study (SBP >= 140 mm Hg or DBP >= 90 mm Hg), as 70 to 80% of subjects in the AHI > 30 category already had hypertension (Table 3). This important interaction may explain variability in previous reports regarding ACE-D relationships with hypertension. For example, most studies have found more significant associations of ACE-D with blood pressure in male subjects and with increasing age (14, 25, 52) two well known factors predisposing to SDB. Additional studies with sleep evaluations and ACE typing in other cohorts are needed to confirm our finding.

The observation that ACE-D is related to increased blood pressure in subjects with SDB suggests synergistic effects of the ACE genotype and SDB on the renin-angiotensin pathway. Studies have suggested a role for volume retention and activation of the renin angiotensin system in mediating SDB-induced hypertension (39, 53). Moller and colleagues (39), for example, recently found increased angiotensin II and aldosterone in patients with sleep apnea. Levels decreased significantly and in proportion with blood pressure after CPAP therapy (39). ACE is a key enzyme converting angiotensin I to angiotensin II. Modulation of ACE may therefore be an underestimated factor in inducing hypertension in subjects with SDB. Indeed, SDB has also been shown to increase ACE activity (40). This increase may be magnified in SDB subjects with the ACE-D allele, resulting in higher blood pressure and cardiovascular risk. Studies using ACE inhibitors in these subjects may also shed light on the importance of this pathway in this subgroup of patients.

The genetics of SDB is complex and largely unknown. Familial aggregation has been demonstrated and genetic screening in multiplex families initiated (54). Major risk factors for SDB include obesity, facial soft tissue/bone anatomy (reducing upper-airway space), and central factors (controlling breathing and muscle tone during sleep). Familial aggregation is generally explained by the fact most of these risk factors are also genetically determined. Interestingly, two recent reports have found increased SDB in subjects with APOE {epsilon}4, a genetic factor associated with Alzheimer's disease (41, 43). The association of APOE {epsilon}4 with SDB has been suggested to be mediated by damage to the CNS and resulting abnormal regulation breathing during sleep (41). In APOE {epsilon}4 subjects with associated hypertension or cardiovascular disease, CNS damage may be more severe leading to even greater SDB; a similar deleterious effect of hypertension has been suggested in AD (55, 56).

ACE-I has been shown to predispose to Alzheimer's disease (44–46), a condition associated with SDB (57). We hypothesized that ACE-I, like APOE, may be involved in modulating central factors regulating breathing and muscle tone during sleep. This hypothesis was supported by the report that in 34 Chinese patients with moderate to severe SDB (AHI > 20), a significantly larger than expected number of subjects were of the II genotype (47). In our study, however, like that of Barcelo and coworkers (40), ACE-I was not associated with SDB. A possible explanation for this discrepancy may be that the Chinese study included patients with both hypertension and SDB, and the fact that their definition of hypopnea was more liberal and included a need for either a 4% oxygen desaturation or an arousal. Additional issues include the small sample size of all studies for subjects with severe SDB and possible ethnic differences. Further research will be needed to further explore these possibilities.

In conclusion, we found that a polymorphism in the ACE gene is associated with hypertension most significantly in subjects with mild SDB. This finding illustrates the complexity of studying the genetic basis of hypertension and indicates the need for controlling for SDB in these studies.


   Acknowledgments
 
The authors thank participants in the Wisconsin Sleep Cohort Study. They also thank L. Evans, J. Paterno and A. Voros for their technical assistance.


   FOOTNOTES
 
Funded by NIH grants HL071515 and NS 23,724 to E.M.; HL62252, AG14124 and RR03186 to T.Y. E.M. (Investigator) is funded by the Howard Hughes Medical Institute.

Conflict of Interest Statement: L.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form May 12, 2004; accepted in final form September 20, 2004


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