J Appl Physiol 99: 1600 –1606, 2005;
doi:10.1152/japplphysiol.00501.2005.
Invited Review
HIGHLIGHTED TOPIC
Physiology and Pathophysiology of Sleep Apnea
Shared genetic risk factors for obstructive sleep apnea and obesity
Sanjay R. Patel
Division of Sleep Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
susceptibility genes; pleiotropy; gene ⫻ environment effects
(OSA), a disorder characterized by
repetitive collapse of the upper airway during sleep, is one of
the most common respiratory disorders, with an estimated
prevalence of 24% and 9% among middle-aged American men
and women, respectively (92). Obesity in modern Western
society is also extremely common. As of 2002, nearly one-third
of US adults met clinical criteria for obesity, and this prevalence appears to only be increasing (27).
That obesity and OSA often colocalize is of no surprise.
Other than perhaps male gender, obesity is the strongest risk
factor for the development of OSA. Relative to those with a
stable weight, a 10% increase in weight over 4 yr is associated
with a sixfold increase in the risk of developing moderate to
severe OSA (58). Weight loss trials have found significant
reductions in apnea severity with moderate weight loss (69,
74). However, the mechanisms by which obesity causes OSA
are not completely defined, with many potential pathways
hypothesized (93). Perhaps the most obvious is that fat deposition in the neck and airway lumen may lead to increased
collapsibility of the upper airway. In addition, adiposity in the
chest and abdomen may result in reductions in lung volumes.
Recent studies suggest reduced lung volume may independently predispose to upper airway collapse (37). Another
possible mechanism relating obesity with sleep apnea is via the
hormonal effects of adipose tissue. Leptin, a hormone produced by adipose tissue, has important effects on weight
OBSTRUCTIVE SLEEP APNEA
Address for reprint requests and other correspondence: S. R. Patel, BWH
Sleep Disorders Program at BIDMC, Brigham and Women’s Hospital, 75
Francis St., Boston, MA 02115 (e-mail: [email protected]).
1600
regulation by stimulating hypothalamic satiety centers (6, 34,
57). Human obesity is typically associated with elevated leptin
levels, suggesting a state of leptin resistance (15). Besides
regulating weight, leptin may have important effects on ventilatory drive. Leptin-deficient mice hypoventilate and have a
blunted response to hypercapnia (53, 84). Administration of
leptin corrects these abnormalities independent of changes in
weight (53). Through these effects on ventilatory control,
elevated leptin levels (or the underlying leptin-resistant state)
may play a pathogenic role in the development of OSA.
It is also possible that OSA may play a causal role in the
development of obesity. OSA patients have elevated leptin
levels compared with weight-matched controls, and OSA treatment lowers these levels (39, 53, 55). These findings suggest
OSA may be a cause of leptin resistance and thus a propensity
for further weight gain. Not only does sleep disruption, a
common result of OSA, reduce serum leptin levels, it also
increases levels of the appetite-stimulating hormone ghrelin
(76, 82). These findings were associated with increases in
hunger and appetite scores (76). Epidemiological studies
consistently implicate reduced sleep as a risk factor for the
development of obesity (36, 47, 70, 82, 87, 89). Although
overall weight does not appear to fall with treatment of
OSA, one study did find the amount of fat inside the
abdominal cavity (visceral fat) diminishes (10). This fat
compartment appears to have unique hormonal effects as the
amount of visceral adipose tissue is more strongly associated with metabolic complications of obesity such as insulin
resistance and dyslipidemia than measures of subcutaneous
fat or overall obesity (28, 29).
8750-7587/05 $8.00 Copyright © 2005 the American Physiological Society
http://www. jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on June 15, 2017
Patel, Sanjay R. Shared genetic risk factors for obstructive sleep apnea and obesity.
J Appl Physiol 99: 1600 –1606, 2005; 10.1152/japplphysiol.00501.2005.—Both obesity
and obstructive sleep apnea (OSA) are complex disorders with multiple risk factors,
which interact in a complicated fashion to determine the overall phenotype. In addition
to environmental risk factors, each disorder has a strong genetic basis that is likely due
to the summation of small to moderate effects from a large number of genetic loci.
Obesity is a strong risk factor for sleep apnea, and there are some data to suggest sleep
apnea may influence obesity. It is therefore not surprising that many susceptibility
genes for obesity and OSA should be shared. Current research suggests that approximately half of the genetic variance in the apnea hypopnea index is shared with obesity
phenotypes. Genetic polymorphisms that increase weight will also be risk factors for
apnea. In addition, given the interrelated pathways regulating both weight and other
intermediate phenotypes for sleep apnea such as ventilatory control, upper airway
muscle function, and sleep characteristics, it is likely that there are genes with
pleiotropic effects independently impacting obesity and OSA traits. Other genetic loci
likely interact with obesity to influence development of OSA in a gene-by-environment
type of effect. Conversely, environmental stressors such as intermittent hypoxia and
sleep fragmentation produced by OSA may interact with obesity susceptibility genes to
modulate the importance that these loci have on defining obesity-related traits.
Invited Review
SHARED GENETICS OF SLEEP APNEA AND OBESITY
FAMILIAL AGGREGATION OF OBESITY AND SLEEP APNEA
SHARED SUSCEPTIBILITY GENES
Given the strong genetic components to both obesity and
apnea phenotypes as well as the tight association with multiple
interweaving links between these two diseases, it would not be
surprising for there to exist common susceptibility genes for
both obesity and OSA. In fact, it has been suggested that the
familial aggregation of OSA may simply be a reflection of that
found in obesity. This is clearly not the case. Even after
controlling for BMI, significant familial aggregation for OSA
persists (32, 66). Furthermore, a study of nonobese apneic
patients also demonstrated strong heritability of OSA (49).
That this should be the case should be of no surprise given that
other pathophysiological pathways to apnea development such
as craniofacial structure and ventilatory control have also been
demonstrated to have a heritable component (13, 32, 49, 63,
65). Thus the susceptibility genes for OSA are not exclusively
the same genes as those modulating obesity. That does not
mean, however, that no overlap exists.
Clearly, given the strong effect of obesity on OSA pathogenesis, any genetic variant that predisposes to obesity will
secondarily also lead to the development of OSA. Thus any
obesity gene might also be considered to be an apnea gene.
However, obesity is not a monolithic process. Clearly, there are
some forms of obesity that have a more important role in the
pathogenesis of sleep apnea. For example, fat deposition in the
neck is much more important than fat deposition in the limbs
(17). An android fat deposition pattern (excess subcutaneous
truncal-abdominal fat) and visceral adiposity have also been
found to more closely predict OSA than overall obesity (31,
72). Therefore genetic polymorphisms that influence fat deposition in these sites will be more important OSA genes. There
is a wealth of evidence that these fat distribution pattern
phenotypes are genetically driven. Large differences in the
J Appl Physiol • VOL
patterns of fat deposition exist across inbred strains of cattle,
suggesting an important role for genetics (83). Among humans,
even after correction for overall obesity, measures of fat
deposition pattern aggregate within families. The ratio of
subscapular skinfold thickness to subscapular plus suprailiac
thicknesses, a measure of the android fat pattern, has been
reported to have a heritability of 43% (71). Measures of central
obesity such as BMI-adjusted waist circumference and ratio of
trunk to extremity skinfold ratio have heritabilities of 29 – 48%
(40). These findings strongly support the hypothesis that there
are genetic polymorphisms that specifically promote fat deposition in the subcutaneous regions of the torso or around the
abdominal viscera. Through this mechanism, these variants
would promote the development of both obesity and OSA.
Another type of potential genetic interaction between obesity and OSA is one in which a particular polymorphism leads
to both obesity and OSA through independent mechanisms
(Fig. 1). For example, by impacting leptin function, a genetic
polymorphism may reduce satiety and also increase ventilatory
instability. This is what is referred to as genetic pleiotropy.
Pleiotropic genetic effects have clearly been described in other
situations. A well known example is at the APOE locus, which
codes for apolipoprotein E. The ⑀4 allele of APOE is an
important risk factor for both atherosclerotic heart disease as
well as Alzheimer’s dementia (24, 91). The circadian regulatory gene, CLOCK, also appears to influence multiple biological systems. CLOCK-knockout mice have profound disruptions in circadian rhythmicity, and so it is not surprising that
these animals would have abnormal timings for feeding and
activity (88). In addition, however, these mutant animals demonstrate an overall increase in caloric intake associated with a
phenotype of obesity and metabolic syndrome (85). Similarly,
given the large number of neurological, metabolic, and mechanical overlaps between obesity and OSA, it is likely that a
polymorphism affecting one biochemical system may affect
the risk for both disorders via multiple paths. For example,
disruptions of the orexin system could potentially result in a
common link between obesity and OSA. Orexinergic neurons
in the lateral hypothalamus play an important role in sustaining
wakefulness with projections to all of the wake-promoting
areas of the brain (21). Loss of these neurons is associated with
a narcolepsy phenotype (60). These neurons, as the name
Fig. 1. Both obesity and sleep apnea are heavily influenced by underlying
genotype. Some susceptibility genes act directly on one phenotype and through
the causal relationships between obesity and sleep apnea have indirect effects
on the other. Other loci have pleiotropic effects, impacting susceptibility to
both obesity and sleep apnea via independent mechanisms.
99 • OCTOBER 2005 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on June 15, 2017
That obesity is in large part genetically determined has been
known for almost three decades (26). A large twin study
estimated the heritability of weight to be 78% (79). That is to
say, 78% of the variability in weight across a population is
explained by shared intrafamilial factors. Subsequent studies
demonstrated that adopted children have a body size more
closely resembling their biological parents than their adopted
parents (80). Studies in Finland and the United Kingdom have
estimated the heritability of body mass index (BMI) to be
60 – 80% (42, 61). Linkage to obesity-related phenotypes has
been investigated in some 50 genomewide scans to date with
dozens of candidate loci and genes identified (3, 59).
Similarly, familial factors have been known to influence
OSA risk for nearly 25 years (77). Since then, several groups
have quantified the familial risk of OSA by studying widely
different populations. All of these studies have identified a
strong heritable component to OSA (30, 32, 49, 62, 66).
Family-based studies suggest that the risk of OSA is approximately twice as great among relatives of apneic persons (30,
66). In addition, a dose-response relationship exists such that
the risk of OSA increases with increasing number of apneic
relatives (66). Quantitative apnea-related phenotypes also demonstrate substantial heritability. A study of elderly twins found
the heritability of both the respiratory disturbance index and
the oxygen desaturation index to be nearly 40% (7).
1601
Invited Review
1602
SHARED GENETICS OF SLEEP APNEA AND OBESITY
suggesting that a susceptibility locus for both phenotypes
might exist in this region (54). However, adjustment for BMI
only dropped the LOD for AHI to 1.3, suggesting that the
obesity effect at this locus does not fully explain the apnea
effect. This may represent two independent loci, one influencing AHI and one BMI. Another possibility is that there is only
one locus at 2p regulating both AHI and BMI but via independent mechanisms. A strong candidate gene for both phenotypes
in this region is proopiomelanocortin (POMC). The POMC
locus, found at 2p23.3, encodes for a number of hormones
including melanocyte-stimulating hormone (MSH). POMC
neurons in the arcuate nucleus of the hypothalamus are important in energy homeostasis via MSH. Leptin’s anorexic activity
is mediated via depolarization of these neurons, and use of an
MSH agonist decreases both body fat and leptin levels in
humans (16, 25). Obesity phenotypes have been consistently
linked to the POMC locus (14, 33, 38, 67), haplotypes in this
gene have been associated with leptin levels (38, 50), and
severe mutations in this gene produce a severe childhood
obesity phenotype (44). Leptin’s effects on ventilatory drive in
mouse models are also mediated via MSH, suggesting that this
pathway may independently predispose to apnea as well (64).
Evidence for pleiotropy also exists at chromosome 8q.
Among African-Americans in the Cleveland Family Study, the
peak LOD scores were 1.3 and 1.6 for AHI and BMI, respectively (55). Again, after controlling for BMI, the AHI LOD
only dropped to 1.1, suggesting that the obesity and apnea
promoting effects in this region were independent. A potential
candidate locus in this region is the COH1 gene at 8q22–23.
This gene encodes a transmembrane protein with a presumed
role in vesicle-mediated sorting and intracellular protein transport on the basis of its structure (43). Severe mutations in this
gene have been associated with Cohen syndrome, an autosomal
recessive condition characterized by truncal obesity (9). Other
findings include facial dysmorphism, mental retardation, and
ocular anomalies. The craniofacial abnormalities include microcephaly, facial hypotonia, and laryngomalacia, all of which
could predispose to OSA. Thus mutations in this gene that are
milder but more common may play a role, via separate pathways, in contributing to nonsyndromic forms of both obesity
and OSA.
The serotoninergic system is another common pathway that
could link obesity and OSA. Serotonin has important effects on
the stimulation of satiety centers in the arcuate nucleus (5). In
addition, serotonin potentiates hypoglossal neural output,
which increases upper airway dilator muscle activity (45, 75).
Thus reductions in serotoninergic activity, by increasing appetite, could promote obesity and, by lowering muscle tone in the
Table 1. Candidate genes that might link the genetic mechanisms of obesity with sleep apnea through
either pleiotropy or gene ⫻ environment interactions
Candidate Gene
Pleiotropy
POMC
COH1
SLC6A14
Gene ⫻ environment interaction
PPARG
UCP1, UCP2
Relationship to Obesity
Relationship to Sleep Apnea
Mediator of leptin effects on appetite
Regulation of fat deposition pattern
Serotoninergic regulation of weight
Mediator of leptin effects on ventilatory drive
Regulation of craniofacial development
Serotoninergic control of upper airway muscle activity
Regulation of adipocyte differentiation
Regulation of thermogenesis
Downregulated by hypoxia
Upregulated by sleep deprivation
POMC; proopiomelanocortin; PPARG, peroxisome proliferator-activated receptor-␥; UCP1 and UCP2, uncoupling protein-1 and -2, respectively.
J Appl Physiol • VOL
99 • OCTOBER 2005 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on June 15, 2017
orexin implies, also play an important role in stimulating
appetite, projecting on to the arcuate nucleus of the hypothalamus (68). Thus mutations affecting orexin, the orexin receptor, or proteins involved in the downstream signaling of orexin
binding might simultaneously affect metabolic and sleep-related function. Several other potential candidate genes are
listed in Table 1.
The recently reported linkage scans from the Cleveland
Family Study represent the first genomewide linkage studies of
OSA phenotypes (54, 55). The results provide insight into
possible genetic overlaps between obesity and OSA. Linkage
to the apnea-hypopnea index (AHI) as a measure of OSA and
BMI as a measure of obesity was tested across the autosomal
chromosomes in both a Caucasian and an African-American
cohort. The heritability of AHI in both groups was ⬃33%,
whereas the heritability of BMI was over 50%. After controlling for BMI, significant heritability for AHI remained, supporting the notion that the genetic susceptibility to OSA is not
completely defined by weight. In further multivariate modeling
of a larger subset of the Cleveland Family Study, obesity
measures such as BMI and serum leptin explained 50 –55% of
the genetic variance in AHI (56). This suggests that about half
of the genetic determinants of AHI are obesity related and half
are obesity independent.
Linkage findings are described by the logarithmic odds
(LOD) score, a measure of the odds ratio of linkage to no
linkage. Although none of the linkage findings in either racial
group achieved genomewide significance (LOD ⬎ 3.3) (46),
there were several regions with intermediate LOD scores,
indicative of possible linkage in the setting of complex, multifactorial diseases such as obesity and OSA (90). Furthermore,
the change in linkage evidence for AHI after adjustment for
BMI provides insight into mechanisms of action if a susceptibility locus is present. Among the Caucasians, a LOD score of
1.4 was found for AHI and 1.7 for BMI on chromosome 12p
(54). After adjustment for BMI, the maximal LOD for AHI in
this region dropped to only 0.4 whereas the LOD for BMI
adjusted for AHI fell to 0.2. These data suggest that if a
susceptibility gene for AHI exists in this region, it likely
mediates its effect on apnea via obesity. On the other hand, a
maximal LOD for AHI of 1.4 was found on 19q with no
linkage evidence for BMI in this region (54). Adjustment for
BMI had no effect on the AHI LOD, suggesting that a susceptibility gene in this region exerts its effect on AHI through
obesity-independent mechanisms.
A different pattern of linkage findings was found at the short
arm of chromosome 2. Among the Caucasians, the maximal
LOD for AHI is 1.6 and for BMI is 3.1 in this region, again
Invited Review
SHARED GENETICS OF SLEEP APNEA AND OBESITY
upper airway, could promote OSA. Both linkage and haplotype
association studies in a Finnish population suggest a serotoninrelated gene at Xq24 is associated with obesity (51, 81). The
SLC6A14 gene encodes for a sodium chloride-dependent
transporter of neutral and cationic amino acids, which appears
to play an important role in the transport of tryptophan, the
precursor of serotonin, into the central nervous system (73). A
French study has confirmed the association of this polymorphism with obesity, and an association with hunger and satiety
scores was also found (19). Whether this polymorphism is
associated with OSA (via or independent of any obesity effects) has not yet been studied, as the OSA linkage scans
reported thus far have not included the sex chromosomes.
GENE ⴛ ENVIRONMENT INTERACTION
Fig. 2. Sleep apnea susceptibility genes may interact with obesity through
numerous mechanisms to influence sleep apnea predisposition. Genetic polymorphisms may modulate the degree to which obesity alters ventilatory drive,
reduces lung volume, or narrows the upper airway. Other polymorphisms may
affect the degree to which these stresses result in the development of sleep
apnea. Similarly, obesity susceptibility genes may interact with sleep apnea in
its potential effect on obesity.
J Appl Physiol • VOL
implicated as risk factors for the development of obesity (4, 18,
20, 48, 86). Because hypoxia is known to suppress PPARG
gene transcription (94, 95), the importance of a mild defect in
PPARG function may become magnified in the setting of
recurrent exposure to hypoxia from OSA. Thus PPARG allelic
variants may play a much more important role in determining
obesity phenotypes in individuals with OSA, and OSA may
play a much more important role in promoting weight gain
among those with a mutation in PPARG.
Similarly, the effects of uncoupling protein-1 (UCP1) and
UCP2, two other obesity candidate genes, may be influenced
by OSA. These genes encode for uncoupling proteins, mitochondrial proton channels that divert energy from ATP synthesis to thermogenesis (2). In so doing, their activation increases energy consumption. Polymorphisms in both genes
have been associated with obesity phenotypes (8, 12, 22–23,
52). Interestingly, sleep deprivation in rodent models has been
shown to increase expression of both UCP1 and UCP2 (11,
41), suggesting the sleep disruption of OSA may influence
expression of these genes and thus the relative importance of a
variant at these loci in determining obesity risk.
FUTURE DIRECTIONS
There appear to be multiple causal pathways linking obesity
with sleep apnea. Although obesity is clearly a strong risk
factor for OSA, further research is needed to better define any
potential risk OSA carries for promoting weight gain. Both
diseases also clearly have a strong genetic basis. Although
work has begun to identify the specific genetic polymorphisms
that confer risk to the development of these disorders, clearly
much more needs to be accomplished in this arena. A recent
workshop sponsored by the American Thoracic Society laid
out recommendations for future research aimed at dissecting
the genetic bases for sleep-disordered breathing (78). A chief
objective was the development of novel phenotypes, including
biomarkers, that more closely reflect only one or a few molecular pathways rather than the overarching syndrome defined
with the AHI. These simpler phenotypes could be more amenable to genetic analysis because of the fewer sources of
variance than a global measure of apnea. The same holds true
for obesity research, where the use of more specific phenotypes
of fat deposition patterns would provide not only better insight
into the molecular mechanisms underlying obesity but also a
better understanding of how obesity and OSA interrelate.
The use of dense single nucleotide polymorphism maps will
allow for better resolution of linkage findings so as to narrow
down candidate loci. A better understanding of the neurobiology and molecular pathways underlying obesity and sleep
apnea will also allow for a more rational selection of candidate
genes to test for association with these disorders. Ultimately,
the use of gene-knockout animal models will be important to
establish causality of any identified associations. In performing
these genetic studies, it will be important to simultaneously
consider both disorders given their close relationship. Methodology for conducting bivariate linkage scans has already been
developed, and there is evidence to suggest that such a strategy
is more powerful than traditional univariate approaches (1).
Not only will many genetic variants influence the development
of OSA by causing obesity or vice versa but it is likely that
there are also variants with pleiotropic effects predisposing to
99 • OCTOBER 2005 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on June 15, 2017
Another potential method of genetic interaction between
obesity and OSA is a form of gene-by-environment effect
where the adverse effects of obesity or OSA can be thought of
as environmental stressors (Fig. 2). Each of the methods by
which obesity predisposes to OSA can be influenced by an
individual’s underlying genetic susceptibility. An increase in
fat deposition around the upper airway will be more likely to
produce apnea in individuals with a lower ability to respond to
this stressor due to reduced upper airway dilator muscle tone.
Conversely, obesogenic effects of OSA may be influenced by
the underlying genetic milieu. Genetic polymorphisms may
modulate the effect that exposure to sleep fragmentation from
OSA has on leptin and ghrelin dynamics. Other polymorphisms might influence the effect that these hormonal perturbations have on producing further weight gain.
The peroxisome proliferator-activated receptor-␥ (PPARG)
gene located on chromosome 3p25 encodes a protein that is a
key component of a nuclear transcription factor important in
adipocyte differentiation (4). Variants in this gene have been
1603
Invited Review
1604
SHARED GENETICS OF SLEEP APNEA AND OBESITY
obesity and OSA via independent mechanisms. Identifying
such genes and understanding their function will provide novel
insights into the shared pathogenesis of these diseases. Finally,
the possibility that genetic polymorphisms may affect the
susceptibility that each disease confers toward the other should
not be ignored. Incorporating such a model of gene ⫻ environment interaction into future study designs along with an
understanding of the effects of obesity on OSA can allow for
a better delineation of OSA susceptibility genes and vice versa.
Similarly, use of such a model along with information about
the genetics of obesity would allow for a more complete
understanding of how OSA may impact obesity.
17.
18.
19.
20.
GRANTS
Research support was provided by an American Heart Association Scientist
Development Grant and by National Heart, Lung, and Blood Institute Grant
HL-60292.
21.
REFERENCES
22.
J Appl Physiol • VOL
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
99 • OCTOBER 2005 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on June 15, 2017
1. Almasy L, Dyer TD, and Blangero J. Bivariate quantitative trait linkage
analysis: pleiotropy versus co-incident linkages. Genet Epidemiol 14:
953–958, 1997.
2. Argyropoulos G and Harper ME. Uncoupling proteins and thermoregulation. J Appl Physiol 92: 2187–2198, 2002.
3. Bell CG, Walley AJ, and Froguel P. The genetics of human obesity. Nat
Rev Gen 6: 221–234, 2005.
4. Berger J and Moller DE. The mechanisms of action of PPARs. Annu Rev
Med 53: 409 – 435, 2002.
5. Blundell JE, Goodson S, and Halford JC. Regulation of appetite: role of
leptin in signalling systems for drive and satiety. Int J Obes Relat Metab
Disord 25, Suppl 1: S29 –S34, 2001.
6. Campfield LA, Smith FJ, Guisez Y, Devos R, and Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity
and central neural networks. Science 269: 546 –549, 1995.
7. Carmelli D, Colrain IM, Swan GE, and Bliwise DL. Genetic and
environmental influences in sleep-disordered breathing in older male
twins. Sleep 27: 917–922, 2004.
8. Cassell PG, Neverova M, Janmohamed S, Uwakwe N, Qureshi A,
McCarthy MI, Saker PJ, Albon L, Kopelman P, Noonan K, Easlick J,
Ramachandran A, Snehalatha C, Pecqueur C, Ricquier D, Warden C,
and Hitman GA. An uncoupling protein 2 gene variant is associated with
a raised body mass index but not Type II diabetes. Diabetologia 42:
688 – 692, 1999.
9. Chandler KE, Kidd A, Al-Gazali L, Kolehmainen J, Lehesjoki AE,
Black GC, and Clayton-Smith J. Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome. J Med Genet 40: 233–241,
2003.
10. Chin K, Shimizu K, Nakamura T, Noboru N, Masuzaki H, Ogawa Y,
Mishima M, Nakamura T, Nakao K, and Ohi M. Changes in intraabdominal visceral fat and serum leptin levels in patients with obstructive
sleep apnea syndrome following nasal continuous positive airway pressure
therapy. Circulation 100: 706 –712, 1999.
11. Cirelli C and Tononi G. Uncoupling proteins and sleep deprivation. Arch
Ital Biol 142: 541–549, 2004.
12. Clement K, Ruiz J, Cassard-Doulcier AM, Bouillaud F, Ricquier D,
Basdevant A, Guy-Grand B, and Froguel P. Additive effect of A–⬎G
(-3826) variant of the uncoupling protein gene and the Trp64Arg mutation
of the beta 3-adrenergic receptor gene on weight gain in morbid obesity.
Int J Obes Relat Metab Disord 20: 1062–1066, 1996.
13. Collins DD, Scoggin CH, Zwillich CW, and Weil JV. Hereditary aspects
of decreased hypoxic response. J Clin Invest 62: 105–110, 1978.
14. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC,
Dyer TD, Stern MP, MacCluer JW, and Blangero J. A major quantitative trait locus determining serum leptin levels and fat mass is located on
human chromosome 2. Nat Genet 15: 273–276, 1997.
15. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW,
Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, and
Caro JF. Serum immunoreactive-leptin concentrations in normal-weight
and obese humans. N Engl J Med 334: 292–295, 1996.
16. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath
TL, Cone RD, and Low MJ. Leptin activates anorixegenic POMC
neurons through a neural network in the arcuate nucleus. Nature 411:
480 – 484, 2001.
Davies RJ, Ali NJ, and Stradling JR. Neck circumference and other
clinical features in the diagnosis of the obstructive sleep apnoea syndrome.
Thorax 47: 101–105, 1992.
Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto
J, Laakso M, Fujimoto W, and Auwerx J. A Pro12Ala substitution in
PPARgamma2 associated with decreased receptor activity, lower body
mass index and improved insulin sensitivity. Nat Genet 20: 284 –287,
1998.
Durand E, Boutin P, Meyre D, Charles MA, Clement K, Dina C, and
Froguel P. Polymorphisms in the amino acid transporter solute carrier
family 6 (neurotransmitter transporter) member 14 gene contribute to
polygenic obesity in French Caucasians. Diabetes 53: 2483–2486, 2004.
Ek J, Urhammer SA, Sorensen TI, Andersen T, Auwerx J, and
Pedersen O. Homozygosity of the Pro12Ala variant of the peroxisome
proliferation-activated receptor-gamma2 (PPAR-gamma2): divergent
modulating effects on body mass index in obese and lean Caucasian men.
Diabetologia 42: 892– 895, 1999.
Espana RA and Scammell TE. Sleep neurobiology for the clinician.
Sleep 27: 811– 820, 2004.
Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber
B, Sandhofer F, Ladurner G, Hell E, Strosberg AD, Patsch JR,
Krempler F, and Patsch W. A common polymorphism in the promoter
of UCP2 is associated with decreased risk of obesity in middle-aged
humans. Nat Genet 28: 178 – 83, 2001.
Evans D, Minouchehr S, Hagemann G, Mann WA, Wendt D, Wolf A,
and Beisiegel U. Frequency of and interaction between polymorphisms in
the beta3-adrenergic receptor and in uncoupling proteins 1 and 2 and
obesity in Germans. Int J Obes Relat Metab Disord 24: 1239 –1245, 2000.
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux
R, Myers RH, Pericak-Vance MA, Risch N, and van Duijn CM.
Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis APOE and
Alzheimer Disease Meta Analysis Consortium. JAMA 278: 1349 –1356,
1997.
Fehm HL, Smolnik R, Kern W, McGregor GP, Bickel U, and Born J.
The melanocortin melanocyte-stimulating hormone/adrenocorticotropin(4 –10) decreases body fat in humans. J Clin Endocrinol Metab 86:
1144 –1148, 2001.
Feinleib M, Garrison RJ, Fabsitz R, Christian JC, Hrubec Z, Borhani
NO, Kannel WB, Rosenman R, Schwartz JT, and Wagner JO. The
NHLBI twin study of cardiovascular disease risk factors: methodology and
summary of results. Am J Epidemiol 106: 284 –285, 1977.
Flegal KM, Carroll MD, Ogden CL, and Johnson CL. Prevalence and
trends in obesity among US adults, 1999 –2000. JAMA 288: 1723–1727,
2002.
Fujioka S, Matsuzawa Y, Tokunaga K, Kawamoto T, Kobatake T,
Keno Y, Kotani K, Yoshida S, and Tarui S. Improvement of glucose and
lipid metabolism associated with selective reduction of intra-abdominal
visceral fat in premenopausal women with visceral fat obesity. Int J Obes
15: 853– 859, 1991.
Fujioka S, Matsuzawa Y, Tokunaga K, and Tarui S. Contribution of
intra-abdominal fat accumulation to the impairment of glucose and lipid
metabolism in human obesity. Metabolism 36: 54 –59, 1987.
Gislason T, Johannsson JH, Haraldsson A, Olafsdottir BR, Jonsdottir
H, Kong A, Frigge ML, Jonsdottir GM, Hakonarson H, Gulcher J,
and Stefansson K. Familial predisposition and cosegregation analysis of
adult obstructive sleep apnea and the sudden infant death syndrome. Am J
Respir Crit Care Med 166: 833– 838, 2002.
Grunstein R, Wilcox I, Yang TS, Gould Y, and Hedner J. Snoring and
sleep apnoea in men: association with central obesity and hypertension. Int
J Obes Relat Metab Disord 17: 533–540, 1993.
Guilleminault C, Partinen M, Hollman K, Powell N, and Stoohs R.
Familial aggregates in obstructive sleep apnea syndrome. Chest 107:
1545–1551, 1995.
Hager J, Dina C, Francke S, Dubois S, Houari M, Vatin V, Vaillant E,
Lorentz N, Basdevant A, Clement K, Guy-Grand B, and Froguel P. A
genome-wide scan for human obesity genes reveals a major susceptibility
locus on chromosome 10. Nat Genet 20: 304 –308, 1998.
Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz
D, Lallone RL, Burley SK, and Friedman JM. Weight-reducing effects
of the plasma protein encoded by the obese gene. Science 269: 543–546,
1995.
Invited Review
SHARED GENETICS OF SLEEP APNEA AND OBESITY
J Appl Physiol • VOL
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
obesity in African-American families. Am J Respir Crit Care Med 169:
1314 –1321, 2004.
Patel SR, Larkin EK, Palmer LJ, Tishler PV, Elston RC, White DP,
and Redline S. Shared genetic variance of sleep apnea and related
metabolic traits [Abstract]. Am J Respir Crit Care Med 169: A759, 2004.
Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D,
Boone T, and Collins F. Effects of the obese gene product on body weight
regulation in ob/ob mice. Science 269: 540 –543, 1995.
Peppard PE, Young T, Palta M, Dempsey J, and Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing.
JAMA 284: 3015–3021, 2000.
Perusse L, Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ,
Argyropoulos G, Walts B, Snyder EE, and Bouchard C. The human
obesity gene map: the 2004 update. Obes Res 13: 381– 490, 2005.
Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y,
Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M,
Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers
GJ, Bouras C, Kucherlapati R, Nishino S, and Mignot E. A mutation
in a case of early onset narcolepsy and a generalized absence of hypocretin
peptides in human narcoleptic brains. Nat Med 6: 991–997, 2000.
Pietilainen KH, Kaprio J, Rissanen A, Winter T, Rimpela A, Viken
RJ, and Rose RJ. Distribution and heritability of BMI in Finnish
adolescents aged 16y and 17y: a study of 4884 twins and 2509 singletons.
Int J Obes Relat Metab Disord 23: 107–115, 1999.
Pillar G and Lavie P. Assessment of the role of inheritance in sleep apnea
syndrome. Am J Respir Crit Care Med 151: 688 – 691, 1995.
Pillar G, Schnall RP, Peled N, Oliven A, and Lavie P. Impaired
respiratory response to resistive loading during sleep in healthy offspring
of patients with obstructive sleep apnea. Am J Respir Crit Care Med 155:
1602–1608, 1997.
Polotsky VY, Smaldone MC, Scharf MT, Li J, Tankersley CG, Smith
PL, Schwartz AR, and O’Donnell CP. Impact of interrupted leptin
pathways on ventilatory control. J Appl Physiol 96: 991–998, 2004.
Redline S, Leitner J, Arnold J, Tishler PV, and Altose MD. Ventilatory-control abnormalities in familial sleep apnea. Am J Respir Crit Care
Med 156: 155–160, 1997.
Redline S, Tishler PV, Tosteson TD, Williamson J, Kump K, Browner
I, Ferrette V, and Krejci P. The familial aggregation of obstructive sleep
apnea. Am J Respir Crit Care Med 151: 682– 687, 1995.
Rotimi CN, Comuzzie AG, Lowe WL, Luke A, Blangero J, and
Cooper RS. The quantitative trait locus on chromosome 2 for serum leptin
levels is confirmed in African-Americans. Diabetes 48: 643– 644, 1999.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka
H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR,
Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu
WS, Terrett JA, Elshourbagy NA, Bergsma DJ, and Yanagisawa M.
Orexins and orexin receptors: a family of hypothalamic neuropeptides and
G protein-coupled receptors that regulate feeding behavior. Cell 92:
573–585, 1998.
Schwartz AR, Gold AR, Schubert N, Stryzak A, Wise RA, Permutt S,
and Smith PL. Effect of weight loss on upper airway collapsibility in
obstructive sleep apnea. Am Rev Respir Dis 144: 494 – 498, 1991.
Sekine M, Yamagami T, Handa K, Saito T, Nanri S, Kawaminami K,
Tokui N, Yoshida K, and Kagamimori S. A dose-response relationship
between short sleeping hours and childhood obesity: results of the Toyama
Birth Cohort Study. Child Care Health Dev 28: 163–170, 2002.
Selby JV, Newman B, Quesenberry CP Jr, Fabsitz RR, King MC, and
Meaney FJ. Evidence of genetic influence on central body fat in middleaged twins. Hum Biol 61: 179 –194, 1989.
Sharma SK, Kurian S, Malik V, Mohan A, Banga A, Pandey RM,
Handa KK, and Mukhopadhyay S. A stepped approach for prediction of
obstructive sleep apnea in overtly asymptomatic obese subjects: a hospital
based study. Sleep Med 5: 351–357, 2004.
Sloan JL and Mager S. Cloning and functional expression of a human
Na⫹ and Cl⫺-dependent neutral and cationic amino acid transporter B0⫹.
J Biol Chem 274: 23740 –23745, 1999.
Smith PL, Gold AR, Meyers DA, Haponik EF, and Bleecker ER.
Weight loss in mildly to moderately obese patients with obstructive sleep
apnea. Ann Intern Med 103: 850 – 855, 1985.
Sood S, Liu X, Liu H, Nolan P, and Horner RL. 5-HT at hypoglossal
motor nucleus and respiratory control of genioglossus muscle in anesthetized rats. Respir Physiol Neurobiol 138: 205–221, 2003.
Spiegel K, Tasali E, Penev P, and Van Cauter E. Sleep curtailment in
healthy young men is associated with decreased leptin levels, elevated
99 • OCTOBER 2005 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on June 15, 2017
35. Harsch IA, Konturek PC, Koebnick C, Kuehnlein PP, Fuchs FS, Pour
Schahin S, Wiest GH, Hahn EG, Lohmann T, and Ficker JH. Leptin
and ghrelin levels in patients with obstructive sleep apnoea: effect of
CPAP treatment. Eur Respir J 22: 251–257, 2003.
36. Hasler G, Buysse DJ, Klaghofer R, Gamma A, Ajdacic V, Eich D,
Rossler W, and Angst J. The association between sleep duration and
obesity in young adults: a 13-year prospective study. Sleep 27: 661– 666,
2004.
37. Heinzer RC, Stanchina ML, Malhotra A, Fogel RB, Patel SR, Jordan
AS, Schory K, and White DP. Lung volume and continuous positive
airway pressure requirements in obstructive sleep apnea. Am J Respir Crit
Care Med 172: 114 –117, 2005.
38. Hixson JE, Almasy L, Cole S, Birnbaum S, Mitchell BD, Mahaney
MC, Stern MP, MacCluer JW, Blangero J, and Comuzzie AG. Normal
variation in leptin levels is associated with polymorphisms in the proopiomelanocortin gene POMC. J Clin Endocrinol Metab 84: 3187–3191, 1999.
39. Ip MSM, Lam KSL, Ho CM, Tsang KWT, and Lam WK. Serum leptin
and vascular risk factors in obstructive sleep apnea. Chest 118: 580 –586,
2000.
40. Katzmarzyk PT, Malina RM, Perusse L, Rice T, Province MA, Rao
DC, and Bouchard C. Familial resemblance in fatness and fat distribution. Am J Hum Biol 12: 395– 404, 2000.
41. Koban M and Swinson KL. Chronic REM-sleep deprivation of rats
elevates metabolic rate and increases uncoupling protein-1 gene expression in brown adipose tissue. Am J Physiol Endocrinol Metab 289:
E68 –E74, 2005.
42. Koeppen-Schomerus G, Wardle J, and Plomin R. A genetic analysis of
weight and overweight in 4-year-old twin pairs. Int J Obes Relat Metab
Disord 25: 838 – 844, 2001.
43. Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J,
Traskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M,
Fryns JP, de la Chapelle A, and Lehesjoki AE. Cohen syndrome is
caused by mutations in a novel gene, COH1, encoding a transmembrane
protein with a presumed role in vesicle-mediated sorting and intracellular
protein transport. Am J Hum Genet 72: 1359 –1369, 2003.
44. Krude H, Biebermann H, Luck W, Horn R, Brabant G, and Gruters
A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19: 155–157,
1998.
45. Kubin L, Tojima H, Davies RO, and Pack AI. Serotonergic excitatory
drive to hypoglossal motoneurons in the decerebrate cat. Neurosci Lett
139: 243–248, 1992.
46. Lander E and Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11: 241–247,
1995.
47. Locard E, Mamelle N, Billette A, Miginiac M, Munoz F, and Rey S.
Risk factors of obesity in a five year old population. Parental versus
environmental factor. Int J Obes Relat Metab Disord 16: 721–729, 1992.
48. Masud S and Ye S. Effect of the peroxisome proliferator activated
receptor-gamma gene Pro12Ala variant on body mass index: a metaanalysis. J Med Genet 40: 773–780, 2003.
49. Mathur R and Douglas NJ. Family studies in patients with the sleep
apnea-hypopnea syndrome. Ann Intern Med 122: 174 –178, 1995.
50. Miraglia del Giudice E, Cirillo G, Santoro N, D’Urso L, Carbone MT,
Di Toro R, and Perrone L. Molecular screening of the proopiomelanocortin (POMC) gene in Italian obese children: report of three new
mutations. Int J Obes Relat Metab Disord 25: 61– 67, 2001.
51. Ohman M, Oksanen L, Kaprio J, Koskenvuo M, Mustajoki P, Rissanen A, Salmi J, Kontula K, and Peltonen L. Genome-wide linkage
scan of obesity in Finnish sibpairs reveals linkage to chromosome Xq24.
J Clin Endocrinol Metab 85: 3183–3190, 2000.
52. Oppert JM, Vohl MC, Chagnon M, Dionne FT, Cassard-Doulcier
AM, Ricquier D, Perusse L, and Bouchard C. DNA polymorphism in
the uncoupling protein (UCP) gene and human body fat. Int J Obes Relat
Metab Disord 18: 526 –531, 1994.
53. O’Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley
CG, Schwartz AR, and Smith PL. Leptin prevents respiratory depression
in obesity. Am J Respir Crit Care Med 159: 1477–1484, 1999.
54. Palmer LJ, Buxbaum SG, Larkin E, Patel SR, Elston RC, Tishler PV,
and Redline S. A whole-genome scan for obstructive sleep apnea and
obesity. Am J Hum Genet 72: 340 –350, 2003.
55. Palmer LJ, Buxbaum SG, Larkin EK, Patel SR, Elston RC, Tishler
PV, and Redline S. Whole genome scan for obstructive sleep apnea and
1605
Invited Review
1606
77.
78.
79.
80.
81.
82.
84.
85.
ghrelin levels, and increased hunger and appetite. Ann Intern Med 141:
846 – 850, 2004.
Strohl KP, Saunders NA, Feldman NT, and Hallett M. Obstructive
sleep apnea in family members. N Engl J Med 299: 969 –973, 1978.
Strohl KP, Tankersley C, Cohen MM, Elston RC, Gozal D, Haddad G,
Jacob H, Kiley J, Kinane B, Lifton RP, Mignot E, Mockrin S,
Neubauer J, and Redline S. Finding genetic mechanisms in syndromes of
sleep disordered breathing (ATS Statement). New York: American Thoracic Society, 1999; http://www.thoracic.org/statements/sleepdisorder/sleep.asp.
Stunkard AJ, Foch TT, and Hrubec Z. A twin study of human obesity.
JAMA 256: 51–54, 1986.
Stunkard AJ, Sorenson TI, Hanis C, Teasdale TW, Chakraborty R,
Schull WJ, and Schulsinger F. An adoption study of human obesity.
N Engl J Med 314: 193–198, 1986.
Suviolahti E, Oksanen LJ, Ohman M, Cantor RM, Ridderstrale M,
Tuomi T, Kaprio J, Rissanen A, Mustajoki P, Jousilahti P, Vartiainen
E, Silander K, Kilpikari R, Salomaa V, Groop L, Kontula K, Peltonen
L, and Pajukanta P. The SLC6A14 gene shows evidence of association
with obesity. J Clin Invest 112: 1762–1772, 2003.
Taheri S, Lin L, Austin D, Young T, and Mignot E. Short sleep duration
is associated with reduced leptin, elevated ghrelin, and increased body
mass index. PLoS Med 1: 210 –217, 2004.
Talamantes MA, Long CR, Smith GC, Jenkins TG, Ellis WC, and
Cartwright TC. Characterization of cattle of a five-breed diallel: VI. Fat
deposition patterns of serially slaughtered bulls. J Anim Sci 62: 1259 –
1266, 1986.
Tankersley CG, O’Donnell C, Daood MJ, Watchko JF, Mitzner W,
Schwartz A, and Smith P. Leptin attenuates respiratory complications
associated with the obese phenotype. J Appl Physiol 85: 2261–2269, 1998.
Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E,
Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, and Bass J. Obesity and metabolic syndrome in circadian Clock
mutant mice. Science 308, 1043–1045, 2005.
J Appl Physiol • VOL
86. Valve R, Sivenius K, Miettinen R, Pihlajamaki J, Rissanen A, Deeb
SS, Auwerx J, Uusitupa M, and Laakso M. Two polymorphisms in the
peroxisome proliferator-activated receptor-gamma gene are associated
with severe overweight among obese women. J Clin Endocrinol Metab 84:
3708 –3712, 1999.
87. Vioque J, Torres A, and Quiles J. Time spent watching television, sleep
duration and obesity in adults living in Valencia, Spain. Int J Obes Relat
Metab Disord 24: 1683–1688, 2000.
88. Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL,
McDonald JD, Dove WF, Pinto LH, Turek FW, and Takahashi JS.
Mutagenesis and mapping of a mouse gene, Clock, essential for circadian
behavior. Science 264: 719 –725, 1994.
89. Von Kries R, Toschke AM, Wurmser H, Sauerwald T, and Koletzko
B. Reduced risk for overweight and obesity in 5- and 6-year old children
by duration of sleep: a cross-sectional study. Int J Obes Relat Metab
Disord 26: 710 –716, 2002.
90. Weeks DE, Conley YP, Mah TS, Paul TO, Morse L, Ngo-Chang J,
Dailey JP, Ferrell RE, and Gorin MB. A full genome scan for agerelated maculopathy. Hum Mol Genet 9: 1329 –1349, 2000.
91. Wilson PW, Schaefer EJ, Larson MG, and Ordovas JM. Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler
Thromb Vasc Biol 16: 1250 –1255, 1996.
92. Young T, Palta M, Dempsey J, Skatrud J, Weber S, and Badr S. The
occurrence of sleep-disordered breathing among middle-aged adults.
N Engl J Med 328: 1230 –1235, 1993.
93. Young T, Peppard PE, and Gottlieb DJ. Epidemiology of obstructive
sleep apnea. Am J Respir Crit Care Med 165: 1217–1239, 2002.
94. Yun Z, Maecker HL, Johnson RS, and Giaccia AJ. Inhibition of PPAR
gamma 2 gene expression by the HIF-1 regulated gene DEC1/Stra13: a
mechanism for regulation of adipogenesis by hypoxia. Dev Cell 2: 331–
341, 2002.
95. Zhou S, Lechpammer S, Greenberger J, and Glowacki J. Hypoxia
inhibition of adipocytogenesis in human bone marrow stromal cells
requires TGFbeta/Smad3 signaling. J Biol Chem 280: 22688 –22696, 2005.
99 • OCTOBER 2005 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on June 15, 2017
83.
SHARED GENETICS OF SLEEP APNEA AND OBESITY