Chapter 5

Genetic aspects of OSA in adults and children

R.L. Riha

Summary
Obstructive sleep apnoea (OSA) is known to be hereditary but a number of environmental and developmental factors can affect its expression, e.g. obesity, hormonal changes, nasal occlusion and lymphoid tissue growth. For this reason, OSA is generally considered to be a sum of its component parts with relative contributions in each individual from craniofacial morphology, susceptibility to sleepiness, ventilatory control, obesity, upper airway control and lymphoid tissue overgrowth. The phenotypic complexity of OSA makes establishment of a single genetic basis elusive. Furthermore, unlike other polygenic disease models, such as chronic obstructive pulmonary disease, asthma and hypertension, funding for studies in OSA has been limited. A number of genetic approaches have been utilised, including genome-wide studies, casecontrol studies and genome-wide association studies. The results of these demonstrate our first tentative, but hopeful, steps of uncovering some of the markers of disease expression, as well as disease progression. Future efforts aimed at exploring the sequelae of OSA and possible genetic modulators of these are more likely to yield clinically useful data, which will ultimately result in improved patient care. Keywords: Casecontrol studies, genetics, genomics, obstructive sleep apnoea
Correspondence: R.L. Riha, Dept of Sleep Medicine, The Royal Infirmary of Edinburgh, 51 Little France Crescent, EH16 4SA, Edinburgh, UK, Email rlriha@hotmail.com

Eur Respir Mon 2010. 50, 6985. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00024109

any questions regarding sleep biology remain unanswered, despite intensive research in the last few decades. Even fundamental issues such as the functions of sleep, individual differences in response to sleep deprivation and inter-individual differences in sleep duration requirements continue to perplex us [1]. The genetic underpinnings and influences on the sleep/wake cycle, let alone of the various sleep disorders ranging from parasomnias through to narcolepsy, remain imperfectly investigated and understood.

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Technology and studies of genetic traits

Rapid advances have been made in the technologies utilised in molecular biology and genomics; however, basic issues such as phenotyping remain imperfectly resolved. Over the last few decades, time and resources (albeit many orders of magnitude smaller in comparison to other chronic diseases such as hypertension) have been invested in defining the genetic basis of the sleep apnoea/hypopnoea syndrome. However, the results of studies are difficult to interpret meaningfully as a whole and replication studies are minimal. This is partly attributable to the lack of funding that has been forthcoming at all levels of research in this area and partly because this area of medicine is still relatively new and only recently recognised (decades, rather than centuries). Increasingly, incontrovertible evidence of the harmful effects of recurrent breathing pauses during sleep and associated intermittent hypoxia due to obstructive sleep apnoea (OSA) are creating exciting new avenues for exploring the genetic basis of their expression and, thus, potentially leading to better understanding of disease modulation and prevention.

Aims
This chapter will focus on the current issues surrounding human genetic studies in OSA across the lifespan and will include a brief discussion of the technological aspects which have helped to bring about advances in the field.

The phenotypic complexity of OSA

Heterogeneity of OSA
GENETIC ASPECTS OF OSA

The first issue that requires adequate resolution prior to commencing any genetic study is the phenotyping of the disorder or disease in question. OSA is a heterogeneous disorder whose key pathophysiological feature is the occurrence of upper airway obstruction during sleep only. Additional factors influence the severity and degree of upper airway dysfunction and these will be discussed below.

The role of obesity

Obesity and ageing are the strongest risk factors for OSA [2, 3]. Morbid obesity, defined as a body mass index (BMI) of .30 kg?m-2, is present in 6090% of patients with OSA. In particular, central obesity and increased neck circumference are strongly correlated with OSA. However, not all obese subjects will snore or have sleep-disordered breathing (SDB) [4]. The severity of OSA has also been shown to vary with weight loss and gain, most recently in the longitudinal study of the Wisconsin Sleep Cohort Study [5].

Sex
OSA is more common in males. However, the ratio of males to females with OSA, previously thought to be as high as 9:1, is more likely to be in the order of 23:1 when presentation bias is taken into account [5]. The risk of OSA is higher in females who are obese and post-menopausal compared to pre-menopausal females [6].

Craniofacial phenotype
OSA is also associated with craniofacial abnormalities, particularly of the midface and jaw, with these abnormalities playing a more prominent role in thinner OSA patients [7]. Race and certain congenital conditions affecting craniofacial characteristics such as Marfans syndrome, Downs

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syndrome and the Pierre Robin sequence can predispose to the development of OSA. Acquired conditions such as acromegaly and hypothyroidism are additional confounders.

Nature versus nurture

OSA has a hereditary component and is more prevalent in those with family members who have SDB [8]. Hereditary factors invoke 40% of the variance in the occurrence of OSA in the population; the rest is apparently attributable to environmental factors [9]. Environmental factors predisposing to the development and clinical expression of OSAS include alcohol ingestion, sedative use, sleep deprivation, tobacco use and sleeping in the supine posture [10, 11]. Reduced nasal patency can also significantly contribute to OSA [12].

Children
Paediatric SDB may affect up to 3% of school-aged children (although more recent studies suggest this may be an underestimate [13]) with consequences very similar to those of adults [1417]. The most common cause of OSA in children is related to enlargement of the tonsillar and adenoidal tissue. The role of obesity is more controversial in childhood OSA [18]. Additionally, congenital craniofacial abnormalities as well as abnormalities of brainstem control of breathing, such as the PHOXB mutations, will result in problems with breathing during sleep [19]. Sleepiness is not necessarily a correlate of SDB in childhood and various manifestations including hyperactive behaviour and failure to thrive can be important indicators for problems with the upper airway during sleep [20]. Recent attempts to phenotype childhood OSA have been undertaken [21]. The major differences between adult and paediatric OSA are summarised in table 1.

Natural history of OSA

Long-term cohort studies of OSA patients commencing either in childhood of adulthood are not available. The dominant paradigm suggests that the snoring individual will progress to developing increased resistance of the upper airways culminating in SDB and finally OSA. However, there is no evidence to support this apart from a few small studies which have demonstrated a worsening of SDB over variable periods of time [22, 23]. There have also been a small number of studies

Table 1. Differences and similarities in the clinical presentation of adult and paediatric obstructive sleep
apnoea

Children Subjective and objective sleepiness less apparent Behavioural difficulties in up to 25% of children Concentration affected Academic progress affected Enuresis Failure to thrive: increased sleep energy expenditure and decreased growth hormone secretion Increased inflammatory markers: independently of adenotonsillar hypertrophy Hypertension Increased insulin resistance

Adults Subjective and objective sleepiness Concentration and memory affected, personality changes Driving impairment Intellectual impairment Nocturia Mood disturbances Reduced libido/impotence Marital disharmony Reduced quality of life Increased inflammatory markers Hypertension Increased insulin resistance Increased risk of cardiovascular/ cerebrovascular morbidity

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investigating the cardiovascular consequences of untreated OSA in adults which have shown increased mortality from cardiovascular and cerebrovascular disease in those with more severe SDB [24, 25]. However, these studies are not controlled for possible confounders such as noncompliance with other treatment and baseline cardiovascular disease severity; patients were not studied again to assess whether oxygen desaturation and SDB had worsened over time. More recently, results from the Wisconsin Sleep Cohort Study reporting results over 16 yrs of follow-up have shown sleep apnoea (defined as an apnoea/hypopnoea index (AHI) .5 or .15 events?h-1) prevalence fluctuates according to the populations weight. The prevalence of a high AHI increases contingent with greater obesity. Using controlled regression models, untreated SDB predicts increased depression, stroke, mortality and hypertension [5]. There have been no studies which have followed up paediatric patients into adulthood to see whether SDB improves, worsens or recurs after treatment. There is currently no published evidence to suggest that the majority of adult snorers snored in childhood or adolescence. Furthermore, the development and characteristics of OSA in adults may vary as a function of the normal ageing process [26]. The aetiology of the disease may change with increasing age due to changes in parapharyngeal fat pad deposition [27], serotonergic dysregulation of brainstem respiratory control (due to wear and tear) [28], and age-related changes in bony structures such as edentulism [29]. Variations in neuromuscular control of the upper airway become more important in the elderly [30], and increased background prevalence of cardiac and cerebrovascular disease increase the likelihood of periodic breathing. The clinical phenotype of OSA also changes with older subjects reporting less daytime sleepiness for a given level of OSA [31]. Hypotheses have been postulated suggesting that the development of SDB with intermittent hypoxia may lead to ischaemic preconditioning which may act as a protective mechanism in the older subject [32]. Thus, SDB and OSA in the elderly are unlikely to be equivalent to the same disorders that develop in childhood, youth or middle age.

GENETIC ASPECTS OF OSA

Clinico-physiological phenotypes of OSA

Phenotype is the total physical appearance and constitution of a living entity [33]. The genotype interacting with the environment creates the phenotype. Phenotyping OSA is difficult. In 1999, the American Academy of Sleep Medicine Task Force developed the most widely accepted definition of OSA syndrome for adults in present use [34]. OSA syndrome severity is based on the degree of daytime sleepiness and overnight monitoring of breathing. Both are rated separately. However, there is no accounting for age- or sex-related changes. Paediatric OSA has an unclear definition with an AHI o1 event?h-1 generally considered to be sufficient to confirm SDB, although some studies have used an AHI o5 events?h-1 [20]. Whether this definition is equally relevant to a newborn as to a 13-yr-old has not been formally incorporated into guidelines. Furthermore, symptomatology is more difficult to define. An additional factor which should be borne in mind is that the AHI as measured objectively using physiological monitoring is unrelated to measures of sleepiness across any given population, so that two concepts which may be completely unrelated to each other are used to establish the definition of OSA [3537]. Within the population as a whole, there are few normative data regarding SDB without symptoms or minimally symptomatic. Additionally, SDB severity is highly dependent on the technology used to measure it overnight. Due to this, many researchers in the area have conceived OSA as a sum total of a number of intermediate phenotypes, which include craniofacial morphology, obesity, susceptibility to sleepiness, and ventilatory and upper airway control. Observational and epidemiological studies have shown that various components will have greater influence in some individuals with OSA compared to others.

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Craniofacial morphology
In both adults and children, craniofacial features associated with SDB include more obtuse cranial base dimensions, inferior displacement of the hyoid bone, macroglossia, adenotonsillar hypertrophy, increase in lower facial height, a retroposed maxilla and a short mandible [7, 29]. Craniofacial growth occurs in specific stages throughout embryogenesis, into childhood and adulthood [38]. Craniofacial skeletal growth continues throughout adulthood, into old age accompanied by significant sexual dimorphism. For instance, females experience growth of the craniofacial skeleton with pregnancy and other hormonal changes; mandibular orientation and occlusal relations also change throughout the life cycle [38]. Environmental mechanisms play a strong role; these include habits such as thumb sucking, abnormal tongue posturing, nasopharyngeal disease, disturbed respiratory function (e.g. mouth breathing), tumours, loss of teeth, malnutrition and endocrinopathy [39]. Thus, environmental influences can significantly alter the skeleton and affect phenotypic expression, with mandibular position and size playing the greatest role in determining facial alignment and predisposition to SDB. The number of studies examining this intermediate phenotype in children and adults is limited. Genes involved in the embryogenesis, growth, development and expression of the craniofacial complex are subject to very complex gene-gene and gene-environmental effects and their pathways are yet to be fully elucidated [40]. Adenotonsillar hypertrophy (AT) is one of the most common causes of SDB and OSA in children and removal of the tonsils can be effective in both thin and obese children [20, 41]. Genetic predisposition to AT hypertrophy has recently been shown [42] to be an important factor in children, with other research groups neatly demonstrating environmental factors such as respiratory syncytial virus infection in early life playing a possible role [43]. Furthermore, tonsillar tissue from children with SDB has shown greater upregulation of inflammatory cytokine pathways compared to children with recurrent tonsillitis alone [44]. The prevalence of AT hypertrophy in adults with OSA is unknown.

Obesity
As stated previously, obesity is the most commonly identified risk factor for OSA in adults and is increasingly becoming a factor contributing to childhood OSA. Fat deposition results in a reduction in nasopharyngeal calibre and, if severe enough, can lead to hypoventilation due to reduced chest wall compliance [45]. There is increasing evidence that adipokines, such as leptin, may affect regulation of the respiratory centre [46]. The heritability in BMI is said to range between 25% and 40%, thus suggestive of a strong environmental influence [47]. Susceptibility to obesity is largely genetic but a favourable environment must exist for its phenotypic expression. Regulation of appetite and energy expenditure is complex and redundant pathways are biased towards weight gain. Information on obesity susceptibility genes is updated regularly through the human obesity gene map (http://obesitygene.pbrc.edu). To date, over 300 markers, genes and chromosomal regions have been associated or linked with human obesity phenotypes. Only a few single gene mutations causal of obesity have been found in rare cases. Supporting cellular work is lacking at the present time.

Sleepiness
In adults, sleepiness, as a direct consequence of nocturnal SDB, is required for the definition of OSA. However, there are many instances of individuals who may have an AHI of 100 but deny sleepiness or impairment during the day. Observations like this support an inherent differential susceptibility to somnolence among individuals. A network of neuronal and humoral mechanisms regulates sleep [48], with the cytokines, interleukin (IL)-1 and tumour necrosis factor-a central to sleep activation pathways. Other sleep inducing cytokines include IL10, IL6, interferon, IL2, IL4, colony stimulating factor and fibroblast growth factor [49]. Many of these cytokines are pleiotropic and implicated in initiating or propagating the sequelae of OSA, particularly

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inflammation [50]. In children, sleepiness is not always manifest as a symptom of fragmented nocturnal sleep due to SDB. Behavioural disorders are more common [20].

Upper airway control

Neural pathways central to maintaining upper airway muscle tone during sleep are thought to be largely serotonin dependent [51]. Thus, selective serotonin reuptake inhibitors have been trialled as a pharmacological therapy for increasing upper airway tone with mixed results [52]. At present, further characterisation of upper airway neurophysiology is necessary in order to make genetic studies more meaningful.

Ventilatory control
Ventilatory responses to hypoxia and hypercapnia vary widely in the normal population [53]. A high degree of heritability of peripheral chemoreceptor responses to hypoxia and hyperoxia has been evidenced through studies in monozygotic twins [54] and three-generation family studies [55]. The genetic basis for arousal thresholds from sleep to hypercapnoea or hypoxia has never been studied. A number of studies have been conducted in children and adults with OSA and their family members examining their hypercapnic and hypoxia ventilatory responses, but numbers have been small (nf50 in each study) and have shown either no or only small differences across groups [5663]. Several studies have shown abnormalities of respiratory control in patients with OSA that have been reversed by the use of continuous positive airways pressure, therefore, the changes may be a secondary and not a primary manifestation of the OSA genotype.

Sequelae of OSA
GENETIC ASPECTS OF OSA

In OSA, repetitive upper airway obstruction with attendant hypoxaemia and increased arousals contribute to the disruption of cardiovascular, metabolic and endocrine function [64, 65]. OSA is an independent risk factor for diurnal hypertension and has been implicated as a risk factor in stroke [66]. Repetitive hypoxaemia contributes to systemic inflammation and may enhance the development of atherosclerosis [67]. Cell and molecular mechanisms involving inflammatory mediators are upregulated in patients with OSA [68]. Genetic predisposition to pro-inflammatory cytokine production may exacerbate these effects [69]. The presence of hypercytokinaemia, hyperleptinaemia, insulin resistance, hypertension and visceral obesity occur in disproportionate measure in the population with OSA, even when obesity is controlled for [70, 71]. Similar effects of OSA have been identified in children, specifically regarding hypertension [72], inflammation [73] and metabolic syndrome [74].

Genetic and genomic approaches in OSA

Two general approaches in study design have been used to explore the genetics of human disease: linkage studies and casecontrol association studies which incorporate candidate gene association and genome-wide association.

Linkage studies
Linkage studies are mainly utilised in the study of single-gene disorders. Genetic markers throughout the genome are identified, which are not necessarily functionally significant in terms of phenotypic effect. Generally these studies use extended families. Complex statistical techniques are deployed to assess the strength of association of a genetic locus with a phenotypic marker. This is reported as a LOD score (logarithm of the odds). In linkage analyses, a LOD score .3 indicates

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significant linkage (the phenotypic locus and putative genetic marker have a chance of ,1/1000 of not being linked). A score between 2 and 3 is suggestive of linkage and a score ,2 is not suggestive of linkage [75]. To date, three genome-wide scans have been undertaken in adults with SDB [7678]. All three studies utilised a 9cM genome scan. OSA was phenotyped on the basis of AHI alone using overnight, in-home measurement of breathing using a portable monitor. DNA was pooled and multipoint, variance-component linkage analysis was performed for the OSA-associated quantitative phenotypes of AHI and BMI. The first study was in European-American pedigrees comprising 66 families and 349 subjects [76]. The second study involved 59 African-American pedigrees [77]. The third study extended the first two by including more pedigrees in both ethnic groups and increasing the data set to 634 individuals from 128 African-American families and 641 individuals from 109 European-American families [78]. Results of the studies are summarised in table 2. In all studies, adjustment of AHI to BMI and statistical modelling reduced the LOD scores, making linkage of OSA to AHI insignificant or questionable.

Candidate gene-association studies

A gene of interest is chosen as the result of a biological hypothesis for the disease and is then sequenced in cases with the disease and unrelated, disease-free controls. Both common and rare variants of the gene can be detected. There are two main classes of variation at the molecular level: copy number variants (deletions or duplications of DNA segments) and single nucleotide polymorphisms (SNP; single-base positions with sequence variation). However, the association of the genetic variant with disease is a statistical finding not necessarily reflecting genetic association [79]. A pathological effect should only be inferred if there is both a lower frequency of the variant
Table 2. Genome-wide scans of obstructive sleep apnoea in two populations living in the USA Study Linkage to AHI unadjusted P ALMER [76] 66 European-American pedigrees Candidate region on chromosome Unadjusted LOD score
R.L. RIHA

1p 2p 12p 19p 8q 1 46cM 6 162cM 10 122cM 19 35cM 8 45cM/100cM/140cM 13 49cM 20 p

1.39 1.64 1.43 1.4 1.29 2.0 4.7 2.7 1.9 1.32.0 2.0 3.9

P ALMER [77] 59 African-American pedigrees L ARKIN [78] 109 European-American pedigrees

128 African-American pedigrees

Linkage to AHI adjusted L ARKIN [78] 109 European-American pedigrees 128 African-American pedigrees

6 80.4cM 11 38cM 8 43cM 18 126cM 22 52cM

3.3 2.1 2.3 3.5 2.2

LOD: logarithm of the odds; AHI: apnoea/hypopnoea index; cM: centi-Morgans.

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SNP in the control population and further studies reveal alteration in gene product. A number of candidate gene studies have been performed in adult and paediatric OSA. To date, there has been no consistent replication of the findings of any of the studies and most are underpowered, poorly controlled and variably phenotyped. Adult studies, which have been replicated, are summarised in table 3. Only five casecontrol studies have been published in the paediatric literature examining the following candidate genes in relation to OSA: apolipoprotein E (APOE) epsilon 4 [98, 99], SNPs in cysteinyl leukotriene receptors in tonsils [100], insulin gene variable number of tandem repeats [101], and angiotensin converting enzyme SNPs [102]. Meta-analyses are a useful method for pooling the results of a number of genetic studies and examining a true effect in a larger population. A recent meta-analysis of eight studies examining the APOE epsilon 4 allele and its association with the risk for OSA found an odds ratio (OR) of 1.13 (95% CI 0.861.47) [103]. There was statistically significant heterogeneity (I2572%, P50.001). The authors concluded that there was currently no evidence to support a causal relationship between this gene and OSA.

Genome-wide association studies

Candidate-gene studies may be refined by using the common patterns of DNA sequence variation (HapMap Project: www.hapmap.org), thus making the indirect association approach readily applicable and more cost-effective. In this approach, tag SNPs are used to identify unique haplotypes. The Human Genome Project has made possible an SNP map, which is a high-density map of 200,000600,000 SNPs and a database that contains 1.8 million SNPs (http://snp.cshl.org/). Advances in SNP mapping and high-throughput SNP genotyping platforms are making it increasingly feasible to conduct genome-wide association studies (GWAS). GWAS can be used to survey the entire genome at once and are hypothesis free. Common, rather than rare, variants are more likely to be detected and SNP associations are generally of modest effect. Association with disease is more difficult to establish in comparison to the techniques discussed previously. This method has been instrumental in the discovery of several possible candidate genes in type I diabetes mellitus [104], obesity [105] and hypertension [106]. Most recently, the results of a large candidate gene study of OSA in pedigrees involving 729 AfricanAmericans and 694 European-Americans revealed differential associations of various SNPs associated with AHI or OSA (defined as a dichotomous trait using AHI .15 events?h-1) [107]. 505 SNPs in European-Americans and 1,080 SNPs in African-Americans were genotyped with results being adjusted variably for BMI, age, age-squared and sex. In European-Americans, AHI was significantly associated with allelic variants within C-reactive protein and glial cell line-derived neurotrophic factor; in African-Americans, only serotonin receptor 2a was significantly associated with AHI. The results await replication, although with improved approaches to phenotyping this may not be readily achievable.
GENETIC ASPECTS OF OSA

Genomic approaches to OSA

The total sum of an individual organisms genes is known as the genome and, thus, genomics is the study of all the genes of a cell or tissue at the DNA (genotype), mRNA (transcriptome) or protein (proteome) levels. For instance, gene expression studies can be used to identify associations between genes and OSA. Analysis of mRNA levels expressed by proband genes in comparison to levels expressed by normal controls can identify genetic factors underlying the disease and the secondary molecular factors that are consequential to it [108]. Such an approach may also lead to the recognition of previously unknown pathophysiological pathways. High-throughput technologies have been developed to principally address gene expression and products of gene expression, such as RNA, protein and metabolites and can be used to provide a snapshot of gene function in the cell at a given time-point. These techniques are summarised in table 4 [109] and include: genomics, proteomics (identification of proteins in the body and the

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Table 3. Candidate gene studies for causes and consequences of obstructive sleep apnoea (OSA) in adults# Population AHI Phenotype Association Ref. [80]

Gene

Allele

Hypothesis

ACE

I/D

ACE SNPs associated with development of OSA AHI

ACE

I/D

Han Chinese with differing degrees of sleep apnoea and hypertension: n5174 ACE SNPs associated with Wisconsin Sleep Cohort: development of hypertension n51100 in OSA Cleveland Family Study: n5972 AHI

[81]

ACE

I/D

ACE SNPs associated with development of hypertension in OSA

[82]

ACE

I/D

ACE SNPs associated with development of OSA

AHI .10

[83]

ACE

I/D

AHI and blood pressure

[84]

ACE

I/D

Patients with hypertension: n5157 Population controls: n5181 ACE SNPs associated with 30 Han Chinese with: development of hypertension OSA and hypertension, n530 in OSA OSA normotensive, n530 Controls, n530 ACE SNPs associated with OSA Turkish patients: n564 OSA presence Controls: n537 AHI German patients with moderate-to-severe OSA: n5429 AHI

[85]

ADRB2

Cys47-Arg Gly16Arg ADRB2 SNPs influence Gln27Glu cardiovascular morbidity in OSA

[86]

ADRB3

Trp64 Arg

OSA associated with obesity and insulin resistance and hypertension

Patients with OSA: n5387 Controls: n5137

AHI

Central obesity associated with D allele, OSA, hypertension D allele associated with hypertension at mild/moderate levels of OSA only Hypertension risk reduced in subjects with D allele; one or two D alleles protective against hypertension in severe apnoea Significant interaction between OSA and ACE I/D polymorphism I/I genotype and I allele more common in hypertensive patients with OSA No difference in allele distribution among cases and controls Higher risk of abnormal CVS profile with deleterious SNPs; higher risk of mortality post-MI with deleterious SNPs No association of ADRB3 SNP with OSA; BMI higher in subjects with -64Arg
R.L. RIHA

[87]

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GENETIC ASPECTS OF OSA

Table 3. Continued Population Male Han Chinese with: OSA, n5165 Controls, n5153 AHI Phenotype Association Ref. [88]

Gene

Allele

Hypothesis

ADRB2 ADRB3

Cys47-Arg Gly16Arg Gln27Glu Trp64 Arg

Central obesity is more common in OSA

TNF-a

-308 A/G

TNF-a associated with OSA

[69]

TNF-a

-308 A/G

TNF-a associated with OSA

[89]

HTR2A

-1438G/A T102C

Upper airway control dependent on the serotonergic system

[90]

5HTR2A 5HTR2C

T102C 796G/C

Upper airway control dependent on the serotonergic system

[91]

LEPR

Gln223Arg (A/G)

Leptin levels raised in OSA

[92]

LEP LEPR

Tetranucleotide repeat in 39-flank region leptin gene; Lys109Arg (A/G); Gln223Arg (A/G); Lys656Asn (G/C)

Leptin regulation altered in OSA

-64Arg SNP of ADBR3 more common in OSA and possible association with obesity; no association of ADBR2 SNPs with OSA Scottish patients with OSA: AHI, ESS, history of -308A SNP associated n5103 sleepiness, age and with OSA Controls: n5190 sex-related cut-offs for AHI developed AHI -308A SNP associated Indian OSA patients with OSA (n5104) versus 103 controls (n5103); all were obese Turkish OSA patients: n555 AHI T102C SNP not Controls: n5102 associated with OSA; -1438A SNP more common in OSA Male Japanese OSA patients: AHI .5 and HTR2C SNP of too n5177 daytime low a frequency; no Male controls: n5100 somnolence association of 5-HT2A receptor SNP with OSA OSA patients: n5102 AHI .5 -223 Arg carriage more Controls: n577 frequent in the more obese especially females Subjects with Arg/Arg genotype had higher triglyceride and cholesterol levels Japanese OSA patients: AHI .5 No association of any SNPs n5130 with OSA Controls: n550

[93]

ACE: angiotensin converting enzyme; ADRB2: b2-adrenoreceptor; ADRB3: b3-adrenoreceptor; TNF- a: tumour necrosis factor-a; HTR2A: 5-hydroxytryptamine receptor 2A; HTR2C: 5-hydroxytryptamine receptor 2C; LEPR: leptin receptor; LEP: leptin; APOE: apolipoprotein E gene; SNP: single nucleotide polymorphism; ApoE: apolipoprotein E; AHI: apnoea/hypopnoea index; ESS: Epworth Sleepiness Scale; OSAS; obstructive sleep apnoea syndrome; CVS: cardiovascular; post-MI: post-myocardial infarction; BMI: body mass index; I: insertion; D: deletion; +ve: positive; -ve: negative. #: studies replicated in different populations.

Diagnosis of OSA No difference in allelic variants of APOE AHI .5 No association of ApoE E4 with AHI Stratification of Higher AHI in E4 +ve OSAS group with group AHI .5 according to APOE genotype AHI .5 Normal distribution of E4/E4

determination of their role in physiological and pathophysiological functions); transcriptomics (the study of messenger RNA molecules produced in an individual or population of a particular cell type); epigenomics (the expression of epigenetic mechanisms such as DNA methylation and modifications to histone proteins which regulate high-order DNA structure and gene expression); and metabolomics (the study of the metabolites in a biological cell, tissue, organ or organism, which are the end products of cellular processes). Results from these studies should be interpreted as preliminary, and await replication in other and larger populations. Limitations of the techniques are currently significant and substantial work needs to be undertaken in order to identify body tissues and fluids which provide the most meaningful information about the consequences of OSA. The reader is referred to two recent, exhaustive reviews of this area in the context of OSA [116, 117].
R.L. RIHA

Ref.

[94]

[95]

[96]

Phenotype

Association

Finnish patients: n5291 Random controls: n5728 Japanese-American males aged 7997 yrs: n5718 ApoE E4 +ve (n5222) versus ApoE E4 -ve (n5569)

Sleep Heart Health Study community recruits: n51775

Population

[97]

Unresolved questions and future research

In spite of tremendous technological advances in the fields of molecular biology and genomics, a number of issues remain regarding OSA as a disorder. First, OSA defies an unequivocal phenotypic definition. If there is to be any progress, it is essential to address the complexity of the disease fully using a standardised approach. This has major implications for assessing disease prevalence, causal effects on cardiovascular and metabolic status and the long-term effectiveness of treatment. A variety of approaches could be trialled, including the use of cluster analysis [108, 118] and mathematical modelling incorporating non-linear approaches and chaos theory. The paradigm that OSA and SDB are inextricably linked on the same disease spectrum has remained unchallenged for over 30 yrs. There is no evidence that snoring will develop into SDB and then develop into OSA. Secondly, longitudinal studies of populations with OSA (both paediatric and adult) should be established in order to address change in phenotype over time.

APOE4 precursor of atherosclerosis APOE4 precursor of atherosclerosis APOE4 precursor of atherosclerosis

APOE4

APOE4

APOE4

Table 3. Continued

APOE

APOE

APOE

APOE

Gene

APOE4

Allele

APOE4 precursor of atherosclerosis

Hypothesis

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Table 4. High-throughput technologies utilised in human populations with obstructive sleep apnoea (OSA) Technology Analyte Abnormality detected Use in human populations with OSA No studies published

Genomics Global genome sequencing CGH arrays SNP arrays

Genomic DNA Sequences of genomic DNA Oligonucleotides

Mutations

Alterations in copy No studies published number Polymorphisms, No studies published alteration in copy number, loss of heterozygosity DNA hyper- or hypomethylation Modification of gene expression levels No studies published

Epigenomics DNA methylation arrays Transcriptomics Gene expression arrays

Oligonucleotides over whole genome Oligonucleotides or cDNA

GENETIC ASPECTS OF OSA

miRNA expression arrays Proteomics 2D-gel electrophoresis

Oligonucleotides

Modification of miRNA levels Modification of relative abundance and activity of proteins

4 adult OSA patients and 4 controls [110] 20 non-obese OSA children and 20 controls [111] Adenotonsillar hypertrophy in paediatric OSA [112] No studies published

Proteins, peptides

11 OSA children and 11 controls [113] 60 OSA children; 30 snoring children; 30 controls [114] 20 OSA children and 20 controls [115] 11 OSA children and 11 controls [113] No studies published No studies published No studies published

MALDI-TOF MS; SELDI-TOF MS

Proteins, peptides

Tandem MS Protein arrays Tissue microarrays Metabolomics Separation by GC, HPLC or CE

Peptide sequences Lysates, proteins, peptides Tissue biopsies Molecules ,1 kDa in size and certain macromolecules such as albumin; protein Detection of products resulting from cell metabolism

No studies published

Detection by MS or NMR
CGH: comparative genomic hybridisation; SNP: single nucleotide polymorphism; MALDI-TOF MS: matrixassisted laser desorption ionisation time-of-flight mass spectrometry (MS); SELDI-TOF MS: surface-enhanced laser desorption/ionisation time-of-flight MS; GC: gas chromatography; HPLC: high-performance liquid chromatography; CE: capillary electrophoresis; NMR: nuclear magnetic resonance spectroscopy. Data taken from [109].

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Thirdly, better characterisation of clinico-physiological phenotypes should be undertaken. Innovative approaches have been developed to assess the craniofacial dimensions most pertinent to the development of OSA using simple photographic techniques combined with digital technology [119, 120]. Finally, why conduct genetic studies in OSA? A single genetic basis to the disorder is unlikely. OSA appears to be a polygenic disorder, both in children and adults; the result of breakdown in many quantitatively varying physiological systems, heavily influenced by the environment. Potentially, the most meaningful studies are those addressing the sequelae of OSA where recognition of genetic predisposition to their development could lead to more targeted treatments in the future. The speed with which the field of genetics is evolving lends hope that those who work in the field of OSA learn from the studies conducted in other polygenic disorders, their pitfalls and successes and, in due course, move further and faster.

Conclusion
OSA is a highly prevalent condition throughout most countries. With obesity being one of the strongest risk factors for its development it will become increasingly common as our populations gain weight. Untreated, OSA carries a significant economic burden to society in the form of public-health risk (e.g. sleepiness whilst driving) and the risk of cardiovascular morbidity and mortality as its most important sequelae. OSA is known to be hereditary but a number of environmental and developmental factors can affect the degree of its expression, e.g. obesity, hormonal changes, nasal occlusion and lymphoid tissue growth.
R.L. RIHA

The definition of OSA in adults and children, as well as the limited knowledge regarding its evolution and natural history, makes phenotyping of the condition difficult. For this reason OSA is generally considered to be a sum of its component parts with relative contributions in each individual from craniofacial morphology, susceptibility to sleepiness, ventilatory control, obesity, upper airway control and lymphoid tissue overgrowth. Because OSA is phenotypically heterogeneous, this complexity makes establishment of a single genetic basis elusive. Furthermore, unlike other polygenic disease models, such as chronic obstructive pulmonary disease, asthma and hypertension, funding for studies in OSA has been limited. A number of genetic approaches have been utilised, including genome-wide studies, case control studies and GWAS. The results of these demonstrate our first tentative, but hopeful, steps of uncovering some of the markers of disease expression as well as disease progression and its sequelae, such as hypertension and increased metabolic abnormalities. Rapid technological advances in the field of genomics may lead to the discovery of important markers of dysfunctional metabolic pathways worsened or precipitated by the presence of OSA. However, at present, only a few studies have been undertaken and numbers are small. Future efforts aimed at exploring the sequelae of OSA and possible genetic modulators of these are more likely to yield clinically useful data, which will ultimately result in improved patient care.

Statement of Interest
None declared.

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