Obstructive Sleep Apnea Syndrome in Siblings: An 8-Year Swedish Follow-Up Study

Jan Sundquist; Xinjun Li; Danielle Friberg; Kari Hemminki; Kristina Sundquist

doi:10.1093/sleep/31.6.817

. 2008 Jun 1;31(6):817–823. doi: 10.1093/sleep/31.6.817

Obstructive Sleep Apnea Syndrome in Siblings: An 8-Year Swedish Follow-Up Study

Jan Sundquist ¹, Xinjun Li ^1,^✉, Danielle Friberg ², Kari Hemminki ^1,³, Kristina Sundquist ¹

PMCID: PMC2442413 PMID: 18548826

Abstract

Background:

Understanding the genetic transmission of obstructive sleep apnea syndrome (OSAS) will help clinicians identify patients at risk and offer opportunities for intervention and treatment at specialist clinics.

Objective:

To estimate familial risk of hospitalization for OSAS in the adult population of Sweden, and to determine if there are any differences by age and sex.

Design, Setting, and Participants:

Using the MigMed database at the Karolinska Institute, we divided the population of Sweden into sibling groups based on a shared mother and father and ascertained the presence or absence of a primary hospital diagnosis of OSAS in each individual during the follow-up period, 1997 to 2004. Individuals were categorized as having or not having a sibling with OSAS, based on the presence or absence of the disorder in at least 1 of their siblings. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated for men and women with a sibling with OSAS, compared with men and women in the reference group (SIR = 1).

Results:

After accounting for socioeconomic status, age, geographic region, and period of diagnosis, men with at least 1 sibling who had OSAS had a SIR of 3.42 (95% CI, 2.18–5.36); the corresponding SIR in women was 3.25 (95% CI, 1.84–5.65).

Conclusions:

Our results indicate that physicians should consider family history of OSAS when deciding whether to refer a patient for further sleep examinations.

Citation:

Sundquist J; Li X; Friberg D; Hemminki K; Sundquist K. Obstructive sleep apnea syndrome in siblings: an 8-year Swedish follow-up study. SLEEP 2008;31(6):817-823.

Keywords: Heritability, population-based, sibling risk, sleep apnea

OBSTRUCTIVE SLEEP APNEA SYNDROME (OSAS) IS DISTINGUISHED BY FREQUENT APNEAS AND HYPOPNEAS (EPISODES OF BREATHING CESSATION AND shallow breathing) during sleep, which result in sleep disturbances and accompanying decreased oxygen saturation. Individual characteristics associated with OSAS are male sex, anatomic airway abnormalities,^1,2 obesity,³ weight gain with elevated cholesterol levels,³ hypertension,^4,5 and the metabolic syndrome.^4,5 Previous research also indicates that a positive family history is associated with OSAS.⁶

Untreated OSAS can have serious symptoms and health consequences, such as excessive daytime sleepiness, morning drowsiness, lower quality of life, increased risk of traffic accidents, and impaired school and work performance.^7,8 Additionally, OSAS has been associated with serious chronic diseases,^9–11 although it is not always clear if the link is causal.

OSAS is a prevalent phenomenon.^12,13 A number of cross-sectional studies, most of them on adults, have derived estimates of the prevalence of OSAS in various populations.^14,15 At least 1 longitudinal American study has derived an estimate of incidence of the disorder; according to this study, the 5-year incidence is about 7.5% for moderately severe OSAS.³ OSAS is thought to affect at least 1% to 3% of children,¹⁶ but the prevalence may be as high as 5% to 6%.¹⁷

There has been a change in clinical practice from conceiving of OSAS as a local obstructive disease of the respiratory system to OSAS as a systemic disorder.⁵ Existing studies indicate that many factors associated with sleep apnea have important genetic components and that the disorder aggregates in families.^6,18,19 Moreover, the results of some studies suggest that there may be a genetic component to OSAS that is separate from familial obesity, which is associated with the disorder.²⁰ The authors of the Cleveland Family Study of sleep-disordered breathing have reported that a person with 1 first-degree relative with OSAS has a 40% to 60% higher risk of having the condition than does an individual with no known affected relatives.^6,18 The risk of OSAS was 2-fold in first-degree relatives in a study conducted in Iceland.¹⁹

The construction of large population-based patient registers has led to the rapid development of genetic epidemiology during the past decade.^21,22 However, to our knowledge, no previous large-scale population-based study has investigated the family risk of OSAS.

The present study included hospital data on all individuals in Sweden and their siblings, all of whom were born in 1932 or later, i.e., a total of 10.2 million individuals. The Swedish-born individuals included individuals of many ethnicities because the population in Sweden is relatively heterogeneous as the result of a large immigration to Sweden since World War II. The use of hospital-register data eliminates recall bias. Recall bias is a potential problem when conducting case-control studies of familial risk because patients in the case group are prone to report a positive family history of the disease or other health problem being studied.

The main aim of this study was to define familial risk of hospitalization for symptomatic OSAS in the population of Sweden. A further aim was to analyze whether there are any differences by age and sex.

METHODS

MigMed Research Database

Data used in this study were retrieved from the MigMed database, located at the Center for Family and Community Medicine at the Karolinska Institute in Stockholm. MigMed is a single comprehensive database that has been constructed using several national Swedish data registers, including, but not limited to, the Total Population Register, the Multigeneration Register, and the Swedish Hospital Discharge Register (1986–2004).^23–25 Information from the various registers in the database is linked at the individual level via the national 10-digit civic registration number assigned to each person in Sweden for his or her lifetime. Prior to inclusion in the MigMed database, civic registration numbers were replaced by serial numbers to ensure the anonymity of all individuals.

Because the database contains information from the Multigeneration Register, it is possible to link more than 10 million index persons (persons born during or after 1932 and registered in Sweden any time since 1961) with their biologic parents. The latest version of the Multigeneration Register, which has been incorporated in the MigMed database, includes supplementary data from church records on index persons domiciled in Sweden between 1947 and 1961, including information about biologic parents, children, siblings, and adoptions.

Outcome Variable

The 10^th revision of the International Classification of Diseases (ICD-10) was used to identify all first hospital admissions for the outcome variable, OSAS, during the study period (1997–2004) in adults aged 19 to 72 years. The hospitalization data were based on diagnosis at discharge. The use of hospitalization data implies that we only captured symptomatic cases of OSAS. All of the patients had symptoms and fulfilled the diagnosis of OSAS. Therefore, whenever the term OSAS is used below it refers to symptomatic OSAS. ICD-10 code G47.3 was used to define OSAS. Diagnostic codes at the individual level were retrieved from the Swedish Hospital Discharge Register in the MigMed database. For brevity, hospitalization for OSAS is referred to simply as OSAS.

Sweden has a social welfare system that includes public primary and hospital health care for all persons. During the study period, most persons with suspected OSAS would have been referred to a sleep clinic by a primary health care or hospital physician. The patients in the present study were hospitalized for at least 1 night for polysomnography either in sleep laboratories or on hospital wards and were seen by otorhinolaryngologic or pulmonary consultants. There are only a few private hospitals in Sweden, and the Swedish Hospital Discharge Register includes data from these hospitals, as well as from the public hospitals. However, several patients may have undergone ambulatory sleep apnea recordings, and, therefore, data from them are not included in the present study. In addition, the routines for the overnight studies vary between different regions and hospitals in Sweden, which we partly accounted for in the present analysis (see below).

Explanatory Variables

Explanatory variables included sex, age at first hospital diagnosis of OSAS, socioeconomic status of the men and women (defined as income), and geographic region of residence (i.e., geographic region of hospitalization). Age at first hospital diagnosis of OSAS was categorized as 19 to 29, 30 to 39, 40 to 49, 50 to 59, or older than 60 years of age. Income was divided into 3 groups based on the income level registered by the taxation authorities.

Geographic region was divided into big cities (cities with a population of more than 200,000, i.e., Stockholm, Gothenburg, and Malmö), southern Sweden, and northern Sweden. Geographic region was included as an explanatory variable to adjust for possible differences between geographic regions in Sweden with regard to hospital admissions for OSAS.

Statistical Analysis

Using the individual-level data in the MigMed database, the entire population of Sweden was sorted into sibling groups (families) based on a shared mother and father. The database was then used to determine the presence or absence of a primary hospital diagnosis of OSAS in each individual during the follow-up period. Next, individuals were categorized as positive or negative for sibling OSAS based on presence or absence of the disorder in at least 1 of their siblings. Individuals whose siblings had no hospital diagnosis of OSAS were classified as negative for sibling OSAS. Individuals without siblings were excluded from the analysis. The individual serial numbers described in the section on the MigMed research database were used to check that those with a hospital diagnosis of OSAS appeared only once in the data set, that is, for their first hospital diagnosis of OSAS during the study period.

Person years were calculated from start of follow-up on January 1, 1997, until hospitalization for OSAS, death, emigration, or the end of the study on December 31, 2004. Age-specific incidence rates (defined as first hospitalization rates during the study period) were calculated for the whole follow-up period. The results are shown as standardized incidence ratios (SIRs) with 95% confidence intervals (CI). SIRs were calculated as the ratio of observed to expected number of cases for age, sex, time period, region, and socioeconomic status. Sibling risks were calculated for men and women categorized as positive for sibling OSAS, compared with men and women characterized as negative for sibling OSAS, using the cohort methods as described in a study by Hemminki et al.²⁶ Briefly, we defined a cohort of individuals with at least 1 affected sibling and computed the incidence rates in this cohort over the study period. In a family with 2 or more affected siblings, each affected individual is included in the cohort (as the sibling of an affected individual) after adjustment for dependence between the sibling pairs.

The incidence rates in the cohort method are given by the formula:

graphic file with name aasm.31.6.817a-e1.jpg

Where n is the number of families, n_k is the number of affected individuals with k affected siblings, p_k the number of person years contributed by unaffected individuals in families with k affected siblings, and y_k the number of person years contributed by affected siblings in families with k affected siblings, in the relevant age, sex, period, region, and socioeconomic-status category. The corresponding reference rates are given by:

graphic file with name aasm.31.6.817a-e2.jpg

The 95% CI were calculated assuming a Poisson distribution, and they were adjusted for dependence between the sibling pairs. Relative weights used to calculate the age-standardized incidence rates were based on the European standard population. We judged this standard population to be a precise choice because a study from 2002 found that the 1960 standard population (the Segi standard) was as precise as more-recent standard populations in the calculation of age-standardized rates.²⁷

Cox regression was used to calculate risk estimates, presented as hazard ratios (HR), for individuals with 1 (reference), 2, and 3 or more affected siblings.

Ethical considerations

This study was approved by the Ethics Committee of the Karolinska Institute, Stockholm, Sweden.

RESULTS

A total of 12,763 men and 3037 women between the ages of 19 and 72 years had a first hospital diagnosis of OSAS during the study period (Table 1). Men accounted for about 80% of the hospitalized patients. The first-hospitalization rates in the entire population were 65.5 per 100,000 person years for men and 16.2 per 100,000 person years for women during the study period. We also checked additional hospital diagnoses in patients who were hospitalized for OSAS. The 2 most common additional diagnoses were Fitting and adjustment of other devices (code Z46) and Dependence on enabling machines and devices (code Z99). Code Z46 and Z99 represented 32.8% and 24.4% of the total number of additional diagnoses, respectively. These additional diagnoses would most likely include treatment with continuous positive airway pressure (data not shown).

Table 1.

Age-Specific Hospitalization Rates of Obstructive Sleep Apnea Syndrome Per 100,000 Person Years in Men and Women Aged 19–72 Years

Age at diagnosis (years)	Men				Women
	Entire population		With sibling history		Entire population		With sibling history
	n	Hospitalization rates	n	Hospitalization rates	n	Hospitalization rates	n	Hospitalization rates
19–29	367	8.0	2	46.1	94	2.2	0	0.0
30–39	1491	33.0	36	242.9	243	5.7	4	28.4
40–49	3044	73.7	77	252.3	516	13.1	15	51.7
50–59	5263	126.8	169	398.5	1324	33.0	34	82.5
≥ 60	2598	122.7	84	392.0	860	40.5	36	161.8
All	12763	65.5	368	247.2	3037	16.2	89	54.7

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Age-specific rates per 100,000 person years for first hospitalizations for OSAS in men and women are shown in Figure 1. Figure 2 shows the age-specific hospital diagnosis rates of OSAS in men and women with and without a sibling history of the disorder. The familial hospitalization rates for both men and women were higher among those with a sibling history of OSAS.

Age-specific hospitalization rates of obstructive sleep apnea syndrome in men and women.

Age-specific hospitalization rates of obstructive sleep apnea syndrome in men and women by sibling history.

The SIRs for first hospitalization for OSAS among persons who had at least 1 sibling with the disorder are shown by age at hospital diagnosis in Table 2. Whenever “risk” is mentioned below, it refers to the risk of being investigated for OSAS in the hospital. The models are adjusted for all of the explanatory variables simultaneously. The overall SIR of OSAS among those who had at least 1 affected sibling was 3.42 (95% CI, 2.18–5.36) for men and 3.25 (95% CI, 1.84–5.65) for women, compared with the reference group of those without a sibling history of the disorder.

Table 2.

Standardized Incidence Ratios and Observed Number of Cases of Obstructive Sleep Apnea Syndrome in Men and Women Aged 19–72 Years With at Least 1 Sibling Who has Obstructive Sleep Apnea

Age at diagnosis (years)	Men				Women
Age at diagnosis (years)	O	SIR	95% CI		O	SIR	95% CI
19–29	2	5.08	0.34	26.41	0
30–39	36	7.36^a	3.64^a	14.43^a	4	5.01	0.92	18.32
40–49	77	3.37^a	1.88^a	5.97^a	15	3.95^a	1.56^a	9.25^a
50–59	169	3.17^a	1.92^a	5.22^a	34	2.48^a	1.21^a	4.90^a
≥ 60	84	3.20^a	1.80^a	5.61^a	36	4.01^a	1.98^a	7.85^a
All	368	3.42^a	2.18^a	5.36^a	89	3.25^a	1.84^a	5.65^a

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O refers to observed number of cases; SIR, standardized incidence ratio. Incidence ratios standardized for age, time period, income, and geographic region of residence. The reference group consisted of people who have siblings but whose siblings do not have obstructive sleep apnea.

95% confidence interval (CI) does not include 1.00.

Table 3 shows SIRs and the observed number of cases of OSAS in people who have at least 1 sibling with OSAS, by sex of affected siblings. When a brother had OSAS, the risk that his brother also would have the disorder was 3.53 (95% CI, 2.23–5.59). The corresponding SIR in his sister was 2.95 (95% CI, 1.60–5.36). When a woman was affected, there was a slightly higher risk that her sister would have OSAS (SIR = 4.10, 95% CI, 1.85–8.63) than that her brother would have the disorder (SIR = 3.02, 95% CI, 1.65–5.44). However, these findings are based on a relatively small number of cases.

Table 3.

Sex-Specific Standardized Incidence Ratios and Observed Number of Cases of OSA in Men and Women Aged 19–72 Years with at Least One Brother or Sister Who has OSA

	Brother with OSA				Sister with OSA
	O	SIR	95% CI		O	SIR	95% CI
Male SIRs	306	3.53^a	2.23^a	5.59^a	65	3.02^a	1.65^a	5.44^a
Female SIRs	62	2.95^a	1.60^a	5.36^a	24	4.10^a	1.85^a	8.63^a

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OSA refers to obstructive sleep apnea; O, observed number of cases; SIR, standardized incidence ratio; CI, confidence interval. Incidence ratios standardized for age, time period, income, and geographic region of residence. The reference group consisted of people who have siblings but whose siblings do not have obstructive sleep apnea.

95% CI does not include 1.00.

Spousal correlation was also investigated (data not shown). The SIR of OSAS in husbands whose wives had the disorder was nonsignificant (SIR, 1.98; 95% CI, 0.89–4.21); the SIR of OSAS in wives whose husbands had the disorder was also nonsignificant (SIR, 1.92; 95% CI, 0.86–4.07).

Table 4 shows HRs in men and women with 1, 2, or 3 or more siblings affected with OSAS. Men and women with 1 affected sibling are used as reference. Among both men and women with 2 or 3 or more affected siblings, the risk for OSAS was increased compared with the reference group. However, among men with 3 or more affected siblings, this increased risk was not statistically significant. A dose-response effect appeared among women.

Table 4.

Hazard ratios for men and women aged 19–72 years with 1, 2, and 3 or more siblings affected with obstructive sleep apnea syndrome. Cox regression^a

Affected sibling, no.	Men				Women
Affected sibling, no.	O	HR	95% CI		O	HR	95% CI
1	10363	1.00	(reference)		2419	1.00	(reference)
2	362	1.67^b	1.51^b	1.86^b	86	1.70^b	1.37^b	2.10^b
≥ 3	6	1.80	0.81	4.00	3	4.18^b	1.34^b	13.00^b

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O refers to observed number of cases; HR, hazard ratios.

95% confidence interval (CI) does not include 1.00.

The use of Cox regression implies that the population was different compared with the SIR analysis.

DISCUSSION

Familial risks of OSAS were high in people who had at least 1 sibling with a diagnosis of OSAS: 3.42 in men and 3.25 in women. The results of the current study are consistent with those of previous studies that show evidence of familial aggregation of sleep apnea.^18,20,28,29 Most previous studies that have reported familial cases of OSAS are case-control studies; reporting or recall bias is often present in this type of study. To our knowledge, this is by far the largest study that has investigated family risk in siblings with a history of medically verified OSAS. Researchers who carried out a similar study in Iceland found that the risk in siblings born between 1925 and 1955 (164 cases in 5475 siblings) was 1.9 (95% CI, 1.4–2.2),¹⁹ which is lower than the siblings' risks in the present study. Differences in age groups and time of the study periods may explain the disparity in findings regarding risk. In addition, the medical knowledge about OSAS has increased over time.

Other studies have also shown that there is a familial clustering of OSAS.^6,19,30 It has been suggested that OSAS could be transmitted at least in part through “the associated intermediate phenotypes,” which include anatomic structures (the skeleton, the muscles, and the nerves that control the upper airways), as well as the patterns of physiologic control (sleep patterns).³⁰

The use of hospitalization data implies that we only captured symptomatic cases of OSAS. This means that this study missed a substantial proportion of individuals with repeated airway closures but without symptoms. Thus, the risk estimates reflect the risk of developing symptoms in the setting of having apnea, which could explain why our familial risk estimates and sex ratio are higher than those reported in other studies. Additionally, after 1 sibling is diagnosed with a disease or other health problem, another sibling will be more likely to seek medical help for the same disease or health problem. We have previously assessed such effects for migraine but did not find much supporting evidence for the presence of such bias.²¹ However, the OSAS diagnosis differs substantially from the migraine diagnosis in terms of awareness in the society and costs for evaluation and treatment. We assessed the evaluation bias in the present study by investigating the spouse correlation, assuming that the spouse would be more likely to seek evaluation if his or her spouse had been diagnosed with OSAS. However, no spouse correlation was found, which suggests that an evaluation bias cannot explain the increased familial risks of OSAS in siblings, at least not to a large extent. The lack of spousal correlation also indicates that an extensive adult environmental sharing is not of major importance in the development of OSAS. Finally, the familial risk estimates for adult OSAS tended to be stronger in the age group 30 to 39 years than in those aged 40 years or older. Although this age effect only represented a tendency, we have no reason to believe that an evaluation bias is stronger in younger ages. In addition, it is generally regarded that diseases that strike early in life are more severe and more likely to be genetic (e.g., premature cardiovascular disease).

The present study also has some other limitations. First, although the national database includes data on the entire Swedish population, it only incorporates information about hospital admissions for OSAS. In addition, during the last years of the study period, many patients were diagnosed with OSAS and treated on both private and public ambulatory wards without hospitalization. However, we were able to obtain data from central registers on hospitalizations and ambulatory investigations in Stockholm County during 2005. Among individuals aged 19 to 72 years, 1980 were registered as ambulatory patients at least once during 2005. The corresponding figure for hospitalized patients was 564. The ratio between these numbers was approximately 3.5:1 in 2005, which implies that we probably captured a relatively large number of the symptomatic cases in Sweden during the study period. Second, we had no data on individual factors associated with OSAS, such as obesity. Obesity is an important factor associated with OSAS, particularly among younger people.³ In a register that includes an entire population, it is not feasible to include individual data on weight, height, and other individual factors associated with OSAS. Many risk factors associated with OSAS are the same as the risk factors for cardiovascular disease, which, in turn, are associated with socioeconomic status.³¹ Finally, evidence indicates that men and women with suspected OSAS are referred to sleep clinics to a different extent. A study from northern Sweden found that men and women were referred to a sleep clinic for the evaluation of OSAS symptoms at a rate of 1.25:1.³² Other studies have revealed even higher underreferral of women.^33,34 Underreferral of women might have resulted in an underestimation of women's OSAS risk. We were also unable to test for validity of the OSAS diagnoses because our data were based on the entire population. However, we only used main diagnoses for OSAS recorded in the hospital registers, i.e., all patients were hospitalized mainly for OSAS, which increases the possibility that the diagnoses for OSAS are valid. Finally, our study was unable to take early environmental factors, such as nutrition status early in life, into account.

This study has a number of strengths. For example, the study population included a well-defined open cohort, the entire population of Sweden. Because of the civic registration number assigned to each individual in Sweden, it was possible to track the records of every person for the whole follow-up period. Data about income were almost 100% complete, which enabled us to adjust our models for socioeconomic status. Additionally, the data in the Swedish Hospital Discharge Register is highly complete. In 2001, the main diagnosis was missing in 0.9% and the national civic registration number in 0.4% of hospitalizations.²³ Finally, the quality of the multigenerational part of the MigMed database is very high and includes information about parents, children, siblings, and adoptions for index persons born in 1932 and onwards and domiciled in Sweden any time between 1947 and 2004. Very few pieces of data are missing. For example, for Swedish-born index persons, data on mothers are missing for only 3% of persons, and on fathers for 5%.²⁴

OSAS is a serious disorder with significant neurophysiologic, cardiovascular, and psychosocial morbidity.^4,9,35 The results of the current study show that first-hospitalization rates are much higher in men and women with a sibling history of OSAS. The observed familial clustering could be explained by shared lifestyle and environmental risk factors, hereditary factors, or a combination thereof.

Physicians who meet patients who snore and experience excessive daytime sleepiness should ask about family history of OSAS and take this factor into account when deciding whether to send a patient for further sleep examinations.

ACKNOWLEDGMENTS

This work was supported by grants from the National Heart, Lung, and Blood Institute (R01-H271084-1) and The National Institute of Child Health and Human Development (1R01HD052848-01), the Swedish Research Council (K2005-27X-15428-01A, the Swedish Council for Working Life and Social Research (2006-0386 and 2007-1754), and The Swedish Research Council Formas (2006-4255-6596-99 and 2007-1352). The authors wish to thank Kimberly Kane for useful comments on the text and Sanna Sundquist for technical assistance.

Footnotes

Disclosure Statement

This was not an industry supported study. The authors have indicated no financial conflicts of interest.

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PERMALINK

Obstructive Sleep Apnea Syndrome in Siblings: An 8-Year Swedish Follow-Up Study

Jan Sundquist, MD, PhD

Xinjun Li, MD, PhD

Danielle Friberg, MD, PhD

Kari Hemminki, MD, PhD

Kristina Sundquist, MD, PhD