A sleep apneic’s gene: perspectives for development of diabetes

Obstructive sleep apnea (OSA) is a prevalent sleep breathing disorder with major cardiometabolic sequelae.¹ Several longitudinal studies have demonstrated an association between OSA and incident type 2 diabetes.^{2, 3} In a recent population based longitudinal study of more than 36,000 individuals and up to 25 years of follow-up, Strausz et al showed that OSA is an independent risk factor for diabetes and diabetic kidney disease.⁴ OSA increased the risk for development of diabetes by 48% and the risk for development of diabetic kidney disease in the diabetic population by 75%. Importantly, the presence of co-morbidities such as diabetes increases the mortality risk for OSA patients.^{5, 6} All-cause mortality was increased by OSA in diabetic individuals by 35%.⁴ Together, these studies suggest that diabetes prevention in OSA population would have profound clinical implications. Towards this goal, it would be important to risk stratify OSA patients such that individuals in whom development of diabetes is more likely may be readily identified.

OSA is a complex heterogeneous disorder resulting from culmination of various anatomical, neuromuscular, and environmental factors. In recent years, emerging evidence from familial aggregation of OSA along with genetic linkage and genetic association studies have suggested a strong genetic predisposition to develop OSA.⁷ Notably, obesity is a common underlying denominator for both OSA and diabetes which has a strong underlying genetic component as well. Since not all sleep apneic patients develop diabetes, it is likely that OSA provides a unique environment (intermittent hypoxic conditions and sleep fragmentation) preluding development of diabetes in only some genetically predisposed individuals. In this issue of the journal, Bielicki et al. present their findings from targeted association-based approach to identify genetic risk for diabetes in OSA subjects.⁸ This study is the first to examine genetic basis for diabetes in well-defined OSA population. Five candidate genes were selected based on prior evidence linking to the development of diabetes and obesity. Single nucleotide polymorphism in these genes was determined by specific TaqMan genotyping assays using DNA samples obtained from 600 OSA patients. Importantly, in this cross-sectional study, the diagnosis of OSA was based on polysomnographic evidence and presence/absence of diabetes was confirmed by HbA1C, fasting glucose or oral glucose tolerance test. In spite of the small population and limited gene polymorphisms being investigated, the Authors identified APOA5 rs3135506 GG homozygotes as associated with lower incidence of type 2 diabetes in OSA subjects. In other words, presence of APOA5 rs3135506 CG heterozygotes was associated with increased the risk for diabetes by more than 2.5 fold. Importantly, polymorphism in APOA5 has been previously demonstrated to associate with circulating triglyceride levels, body mass index, diabetes, hypertension and ischemic stroke.^{9, 10} Of note, APOA5 polymorphisms include several variants which were not included in the above study such as rs662799.⁹ Moreover, ethnic and gender differences in APOA5 gene polymorphisms have been shown which suggests that additional studies need to be undertaken in more diverse population to understand the importance of this gene to OSA pathology.⁹ Interestingly, in the study population, OSA patients with diabetes showed higher levels of triglycerides even in presence of lower level of total cholesterol. These findings suggest an important role for lipid metabolism in development of diabetes in OSA patients. If confirmed, this may be exploited to improve long-term clinical outcomes in OSA populations.

An important limitation related to gene association studies in human populations is that they cannot demonstrate causality. Therefore, animal studies examining the importance of genetic variations of APOA5 in conditions of intermittent hypoxia and/or sleep fragmentation need to be undertaken to demonstrate direct effects on glucose homeostasis. These studies would also be important to identify drugs which may be more useful in mitigating the risk associated with specific gene variations. Lastly, the study population was limited by the sample size which prevented the examination of the differential effects of the gene polymorphisms in males versus females. Global combined efforts should be engineered to undertake study of APOA5 gene polymorphism in large diverse well-defined OSA populations.

Nevertheless, the findings provide a strong basis for future studies examining genetic predisposition to development of diabetes and other comorbidities in OSA subjects. Designing studies using unbiased approaches to identify gene polymorphisms which may predict cardiometabolic dysfunctions would be critical to prevent bias related to targeted gene approach and allow identification of novel genes/targets which may underlie OSA pathophysiology. Longitudinal prospective studies examining the ability of gene polymorphisms in predicting development of diabetes and other cardiometabolic disorders in OSA patients would be of clinical importance as well. The goal would be to identify the contribution of relevant single nucleotide polymorphism to provide an overall individualized composite score to determine diabetes, cardiovascular and mortality risk in OSA. Using genetic markers for risk stratification in OSA population would allow development of personalized interventions to prevent diabetes and other comorbidities in OSA population thereby decreasing overall cardiometabolic burden and reduce mortality risk. Indeed, studies investigating the role of genetic variations including the APOA1/C3/A4/A5 gene cluster and lipid response to lipid-lowering drugs such as fenofibrate have been undertaken.¹¹

Irrespective of OSA, diabetes is a major global health concern associated with increased morbidity, mortality as well high economic burden.¹² Furthermore, the relationship between OSA and diabetes is bidirectional.^{2, 13} Individuals with diabetes have been shown to have a higher risk for development of sleep apnea. The relationship of incident OSA in diabetic population may be more profound in diabetic patients using insulin compared to individuals without diabetes.¹³ Therefore, future studies examining the genetic factors predisposing diabetic individuals to develop OSA will be of interest so that optimal therapeutic interventions may be used to reduce the risk for OSA and associated cardiovascular diseases. To summarize, use of gene polymorphisms to identify high risk patients in OSA and diabetic populations presents as an exciting opportunity which may provide important clues to the development of individualized treatment strategies to reduce cardiovascular burden and mortality risk.