Genetic determinants of upper airway structures that predispose to obstructive sleep apnea

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Abstract

Genetic factors are thought to play an important role in human development. Recent data indicate that obstructive sleep apnea may have a genetic basis. Sleep apnea is a very common disorder with significant cardiovascular and neurophysiologic morbidity. The pathogenesis of sleep apnea is related to a reduction in the size of the upper airway. The reduction in airway size is secondary to increased adipose tissue (enlargement of the parapharyngeal fat pads), alterations in craniofacial structure (reduction in mandibular size) and enlargement of the surrounding soft tissue structures (tongue, lateral pharyngeal walls). Genetic factors are one of the factors that have been proposed to mediate the size of each of these anatomic risk factors for sleep apnea. Recent evidence is accumulating about the genetic loci for these structural risk factors that predispose to the development of obstructive sleep apnea.

Introduction

Obstructive sleep apnea is an extremely common disorder with major public health ramifications. Sleep apnea is thought to affect 20 million Americans (Young et al., 1993, Young et al., 2002). Evidence is accumulating that genetic factors are involved in the pathogenesis of sleep apnea (Buxbaum et al., 2002, Palmer and Redline, 2003, Palmer et al., 2004, Redline and Tishler, 2000, Redline, 2005). If sleep apnea has a genetic component what are the intermediate traits (or phenotypes) associated with this condition? Although there are a number of possible intermediate traits for sleep apnea including ventilatory and neurologic control those associated with upper airway anatomy (reduced upper airway size) are thought to be important for understanding the phenotype (Schwab et al., 2003). The fundamental abnormality in patients with sleep apnea is a reduction in the size of their upper airway. Therefore, it has been proposed that the intermediate traits associated with sleep apnea arise from three upper airway structural domains each of which reduces the size of the upper airway (see Fig. 1): a particular form of regional obesity (increased volume of the lateral parapharyngeal fat pads); alterations in craniofacial structure (in particular a reduction in mandibular body length); enlargement of critical upper airway soft tissues (tongue, soft palate and the lateral pharyngeal walls) (Schwab et al., 2003). Each of these structural risk factors predisposes to obstructive sleep apnea by decreasing the caliber of the upper airway. In order to understand the genetic determinants of upper airway structure it is necessary to understand the genetic determinants of each of these intermediate traits.

Section snippets

Upper airway anatomy

The pharynx is a complicated structure performing several crucial physiologic functions (breathing, swallowing, vocalization, mastication) and each of these functions can be influenced by upper airway anatomy. The upper airway has been divided into three regions: (1) the nasopharynx (the nasal turbinates to the hard palate); (2) the oropharynx, separated into retropalatal (the hard palate to the distal margin of the soft palate) and retroglossal (the distal margin of the soft palate to the base

Clinical importance and evidence of genetic determinants for obstructive sleep apnea

Obstructive sleep apnea is a serious public health disorder that affects at least 4% of middle-aged men and 2% of middle-aged women (Young et al., 1993, Young et al., 2002) and is associated with significant cardiovascular and neurophysiologic morbidity (daytime sleepiness) (Nieto et al., 2000, Peppard et al., 2000, Shahar et al., 2001). It has been shown that obstructive sleep apnea is an independent risk factor for hypertension (Nieto et al., 2000, Peppard et al., 2000, Shahar et al., 2001),

Genetics determinants of obesity and the parapharyngeal fat pads

Obesity has been shown to be the strongest risk factor for the development of obstructive sleep apnea and central body fat appears to be especially important (Palmer and Redline, 2003). Sleep apnea is thought to be a component of the metabolic syndrome (abdominal obesity, dyslipidemia, elevated blood pressure, insulin resistance, proinflammatory state, prothrombotic state) (Grundy et al., 2004, Punjabi et al., 2004). Although the environment plays a role in the development of obesity, familial

Genetics determinants of craniofacial structure

In addition to obesity or regional obesity, craniofacial structure is thought to be an important phenotype for sleep apnea since reduction in size of the craniofacial skeleton can lead to reductions in airway caliber. Several cephalometric studies have demonstrated craniofacial abnormalities in patients with obstructive sleep apnea compared to age and gender matched controls (Miles et al., 1996, Lowe et al., 1995). These studies, in general, have demonstrated that patients with sleep apnea have

Genetics determinants of upper airway soft tissue structures

The third anatomic intermediate phenotype for sleep apnea is enlargement of the upper airway soft tissue structures such as the tongue, soft palate and lateral pharyngeal walls. Enlargement of these structures can reduce airway caliber and predispose to sleep apnea. We have shown that the volume of a number of upper airway soft tissue structures, specifically the tongue, lateral pharyngeal walls and total soft tissue, are enlarged in patients with obstructive sleep apnea (see Fig. 5) (Schwab et

Conclusions

Genetic factors are thought to play an important role in the development of obstructive sleep apnea although definitive data demonstrating a robust relationship between sleep apnea and genetic factors has not yet been shown. The critical abnormality in patients with sleep apnea is narrowing of the upper airway. Multiple factors (enlargement of the upper airway soft tissue structures, increased upper airway adipose tissue and reduction in the size of the craniofacial structures) have been shown

Acknowledgements

This investigation was supported by the National Institutes of Health Grants: HL-60287, HL-57843, HL-67948.

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