Introduction
Obstructive sleep apnea (OSA) is a relatively common sleep disorder characterized by recurrent episodes of partial or complete collapse of the upper airway during sleep, leading to loud snoring, sleep fragmentation, daytime sleepiness, and chronic episodes of intermittent hypoxia [
1]. It has been estimated that 34% of men and 17% of women are affected by OSA [
2,
3]. Patients with OSA are at high risk of hypertension, diabetes, cardiovascular diseases, stroke, and other disorders [
1,
4]. Previous studies have reported multiple risk factors for OSA [
5‐
9], including obesity, male sex, micrognathia, menopause, fluid retention, adenotonsillar hypertrophy, and smoking. However, the pathogenesis of OSA is not fully understood.
OSA clusters within families [
5] and having a first-degree relative with OSA increases the risk of OSA by more than 1.5-fold. The apnea–hypopnea index (AHI) is the most commonly used metric for OSA, and approximately 35% to 40% of variation in AHI can be explained by genetic factors [
6,
10‐
13]. Other than male sex, the primary risk factor for OSA is excessive weight gain and obesity is the strongest risk factor for the development of OSA, and at least 70% of OSA patients are obese [
14]. Peroxisome proliferator-activated receptor gamma (PPARG) is a member of the nuclear receptor family that includes 48 human transcription factors [
15]. PPARG has been linked to development of obesity [
15‐
17] and may play an important role in the pathophysiological mechanisms underlying OSA. PPARG expression was downregulated in the adipose tissue of OSA patients relative to control individuals, as measured using qPCR [
18].
The
PPARG rs1801282 (G/C) polymorphism was reported to be associated with OSA in obese Indian subjects [
19], whereas no association between rs1801282 (G/C) and OSA was observed in a Chinese Han population [
20]. Potential associations between other
PPARG variants and OSA have not been investigated in Chinese Han individuals.
In this study, we aimed to identify genetic variants of PPARG by targeted sequencing in unrelated Chinese Han subjects and to explore potential associations between OSA and the identified variants.
Discussion
The relationship between PPARG polymorphisms and OSA was investigated in individuals with and without OSA. Our results showed that the PPARG rs1801282 polymorphism was independently associated with OSA.
OSA is a complex disease that is influenced by a combination of genetic [
12,
30] and environmental factors. The molecular mechanisms underlying OSA are not well understood. From a pathological viewpoint, several factors can cause OSA, including sympathetic nervous system activity, obesity, upper airway dilator muscle dysfunction, craniofacial abnormalities, heightened chemosensitivity, and a low arousal threshold [
9,
31]. These pathological processes are also influenced by genes.
PPARG is known to affect obesity, adipose and muscle tissue metabolism, and craniofacial abnormalities thereby causing OSA. Obesity is the strongest risk factor for the development of OSA [
14], and PPARG plays an important role in the development of obesity [
15,
16]. PPARG regulates lipid and glucose metabolism, and downregulation of PPARG has been shown to have anti-obesity effects [
32]. PPARG activation decreased free fatty acid levels and increased lipid storage in adipose tissue [
33]. It was reported that craniofacial abnormalities and dysfunction of adipose and muscle tissue metabolism may cause upper airway obstruction, which is another risk factor for OSA. Roles of
PPARG in regulating human adipocyte differentiation and adipogenesis have been identified [
17]. Chang et al. [
34] found that the progression of myogenesis was regulated by the level of intracellular PPARG.
PPARG polymorphisms may be involved in the growth hormone/STAT5B pathway [
35], and mice that were deficient in members of this pathway developed craniofacial abnormalities [
30]. The growth hormone/STAT5B pathway also plays an important role in regulating energy metabolism in adipose and muscle tissue, suggesting that PPARG may cause craniofacial abnormalities and dysfunction of adipose and muscle tissue metabolism through this pathway [
36,
37]. In addition, the rs1801282 SNP is located in an exon and is a missense variant that affects the amino acid sequence of the PPARG protein (Pro12Ala). Together, these findings indicated that variants in
PPARG may affect the development of OSA, although the exact mechanism remains unclear.
We found that the frequency of the
PPARG G allele was significantly lower in subjects with OSA compared with subjects without OSA. This association was present both in obese and non-obese individuals with OSA. Bharat et al. previously found that the frequency
of the PPARG G allele was significantly higher in subjects with OSA when compared to obese control [
19]. It was reported that allele subtypes differed in lean, overweight, and obese subjects [
38]. However, the results of our study were inconsistent with those of Bharat et al. in obese subjects. All of the individuals included in our study were Chinese Han while the individuals studied by Bharat et al. were Asian Indians. This further illustrates the genetic differences at the
PPARG locus between different ethnic groups.
We also found that rs1801282 was associated with OSA, whereas previously, Guan et al. [
20] found no association between rs1801282 and OSA in a Chinese Han population. We found that the Guan et al.’s study was designed as a case-control and our study was a cross-sectional study, which may be the reasons that there were differences between Guan et al.’s study and our study. We hypothesized that genes linked with metabolic disorders may be relevant to the genetics of OSA because of the prominence of metabolic disorders in the syndrome’s phenotype. The
PPARG rs1801282 polymorphism has attracted much attention because of its correlation with various metabolic conditions including obesity, diabetes, and dyslipidemia. In this study, we confirmed that the
PPARG rs1801282 polymorphism was associated with OSA.
Previous studies showed that age was an independent risk factor for OSA [
9] and that most individuals with OSA were male [
9]. In our study, there were more male individuals in the OSA group than in the non-OSA group, so to avoid confounding effects, we adjusted for age and sex. Obesity plays an important role in OSA.
PPARG rs1801282 polymorphisms were associated with decreased BMI and may slightly protect against childhood obesity [
39]. BMI is associated with PPARG and adipogenesis is affected by PPARG [
19], a known regulator of lipid and glucose metabolism. We found that individuals with OSA had higher BMI and TGs but lower HDL-C than non-OSA subjects. To avoid confounding effects, we also adjusted for BMI, TGs, HDL-C, and FBG.
Care was taken to avoid bias in this study. Genomic DNA extraction and targeted sequencing were performed according to the manufacturer’s instructions by a trained experimentalist who was unaware of the subjects’ clinical status. In the statistical analysis, adjustments were made for the confounding effects of risk factors for OSA and PPARG. Finally, the cross-sectional design of the study and consecutive recruitment of subjects reduced the effects of outcome-selection bias.
Despite this, our study had some limitations. First, the sample size was small and larger studies are needed to confirm our results. Second, the participants may not be entirely representative of the general Han Chinese population. Potential false-positive results may still be possible after multiple corrections. Prospective cohort studies are needed to confirm the variants and associations identified in our study. Third, the controls of this study were also from Otolaryngological Department but not from the population. Finally, the exact mechanisms of the identified PPARG variants is not fully understood and requires further functional studies.
In conclusion, we identified a PPARG variant in patients with OSA. The variant was predicted to be associated with the occurrence of OSA in Chinese Han subjects. Individuals with the PPARG rs1801282 CG genotype were at lower risk of having OSA than individuals with the CC genotype after adjusting for confounding effects. Genetic analysis may be helpful for individualized typing of patients with OSA and could contribute to personalized diagnosis and treatment.
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