The association of HLA-DQB 1 * 0602 but not HLA-DRB 1 * 15 with obstructive sleep apnea

Purpose: Obstructive sleep apnea (OSA) is a sleep breathing disorder with unclear multifactorial pathogenesis. This study aimed to investigate the association between OSA and two human leukocyte antigens (HLA) alleles; DQB1*0602 and DRB1*15. Methods: Forty patients with OSA and 40 control subjects were enrolled in the study. OSA diagnosis was made utilizing the Apnea-Hypopnea Index (AHI)≥5 in overnight polysomnography (PSG). AHI was also used to determine OSA severity. Controls were randomly selected from healthy volunteers who had a low risk for OSA, utilizing the Berlin Questionnaire. Polymerase chain reaction (PCR) using Sequence Specific Primers (PCR-SSPs) was used to determine the association between HLA (HLA-DQB1*0602 and HLA-DRB1*15) and OSA, then statistical analyses of the results were performed. Results: HLA-DQB1*0602 allele was found in 85% of all OSA patients and 50% of controls (P< 0.001). In patients with severe OSA, HLA-DQB1*0602 was present in the 92.9% compared with 66.7% in non-severe OSA (P=0.05). HLA-DRB1*15 allele was found in 15% of OSA patients and 20% of controls, with no difference between the two groups (P=0.556). No statistical difference was found in HLA-DRB1*15 between severe and non-severe OSA (P=0.499). After adjusting for gender, HLA-DQB1*0602 allele was associated with increased odds of OSA (OR = 6.17, 95% CI 1.87-20.3, p = 0.003), but HLA-DRB1*15 allele was not associated with OSA (OR 0.45, 95% CI 0.12-1.73, p = 0.242). Conclusions: The presence of HLA-DQB1*0602 allele, but not HLA-DRB1*15 allele, was significantly associated with OSA. ORIGINAL RESEARCH © 2017 CIM Clin Invest Med • Vol 40, no 4, August 2017 E167 Correspondence to: Suleiman M. Momany, MBBS, FCCP, Assistant Professor, Chief, Division of Pulmonary, Critical Care, and Sleep Medicine Department of Internal Medicine Jordan University of Science and Technology King Abdullah University Hospital Irbid 22110 – Jordan E-mail: smomani@hotmail.com Manuscript submitted 31st January 2017 Manuscript accepted 14th May, 2017 Clin Invest Med 2017; 40 (4): E167-E175. Many medical conditions are increasingly recognized a having a genetic contribution to their susceptibility, pathogenesis, phenotypes, natural history and/or prognosis. Expanding knowledge of these genetic associations provides a better understanding of disorders, which may improve screening and diagnostic tools, impact preventive measures and therapeutic options [1,2]. A number of genetic factors partly control or influence several sleep traits, including circadian rhythm and sleep wake cycles, EEG patterns and response to sleep deprivation [2]. The impact of genes on many sleep disorders has also been identified [1,3-5]. Family clustering was observed in narcolepsy [6], which is a sleep disorder that is characterized by excessive daytime somnolence, sleep paralysis, hypnagogic hallucinations and cataplexy [7]. Narcolepsy has been reported to be associated with human leukocyte antigens (HLA) [5,8-11]. HLA are complex genetic regions on chromosome 6 that encode cell surface proteins. They are objective genetic markers that may be implicated directly in the pathogenesis of disease or associate disease susceptibility through genes within the major histocompatibility complex (MHC) [12]. Variations in the HLA regions are associated with variety of diseases and disorders that are related to the immune system [13]. Complex disorders that have polygenic or multifactorial pathogenesis are more difficult to study than disorders influenced by a single factor or gene [13]. Obstructive sleep apnea (OSA) is an example of a complex multifactorial disorder. It is a sleep breathing disorder that results from repetitive partial or complete cessation of airflow due to upper airway collapse during sleep, despite breathing effort. OSA is a major health problem, contributing to significant morbidity and mortality related to heightened risk of cardiovascular events and motor vehicle accidents [14-16]. The pathogenesis of OSA remains unclear and heritable components are among multiple diverse contributing mechanisms including immune system and inflammatory pathways [17-19]. Growing evidence suggests that genetic factors and their interaction with non-genetic factors influence the development of OSA [20,21]. The estimated genetic contribution to OSA pathogenesis is about 40%, while the rest is blamed on nongenetic factors [22]. Many interacting risk factors for OSA exist and are thought to be affected by genetic factors; including family history, gender, race, obesity and upper airway morphology [18,19,23,24,25]. Genetic factors were found to have a role in OSA development via pathways involved with ventilatory control, craniofacial anatomy, inflammation and immunity [26]. Several non-HLA genetic associations were identified in the pathogenesis of OSA [21, 22,26] and numerous candidate genes have been reported in different populations [20,22,27-30]. The association of HLA with increased susceptibility to diverse respiratory disorders has been described [31-38]. There is strong evidence suggesting that (HLA-DQB1*0602 allele) is r e l a t e d t o n a r c o l e p s y [ 5 , 8 1 1 ] . H y p o c r e t i n i s a neurotransmitter that plays a role in the regulation of wakefulness and sleep [39]. It has been suggested that the autoimmune attack of DQ0602 (DQB1*0602 and DQA1*0102) on hypocretin-secreting neurons is responsible for narcolepsy [40]. Narcolepsy and OSA share the major symptom of excessive sleepiness and may, therefore, share genetic causative factors. Rheumatoid arthritis is an inflammatory disorder that has been found to have high association with sleep disturbances and sleep apneas [41-43]. Some HLA types that are associated with rheumatoid arthrit is (HLA-DRB1 al le les / HLA-DRB1*15 allele) may also play a role in OSA development [44]. The relation between HLA system and OSA is still a field for research. The current study aimed to investigate the association of two alleles with OSA in Northern Jordan: HLA-DQB1*0602, which is associated with narcolepsy; and HLA-DRB1*15, which is associated with rheumatoid arthritis.