摘要:阻塞性睡眠呼吸中止症 (obstructive sleep apnea,OSA)是一個常見疾病,其機制為睡眠時肌肉張力下降,造成上呼吸道塌陷,氣流阻滯以及血氧降低,進而引起慢性間歇性缺氧、睡眠片段及交管神經興奮。OSA 臨床表現具多樣性,從無嗜睡的單純打鼾到併發心血管疾病,神經認知異常、代謝異常,而且常合併肥胖引起的併發症。整夜睡眠多項生理檢查 (polysomnography) 為目前 OSA 診斷標準,以每小時呼吸停止次數(apnea-hypopnea index,AHI)為評量 OSA 嚴重度的指標,但其與 OSA 臨床嚴重度無法有很好的關聯。連續陽壓呼吸器(continuous positive airway pressure,CPAP)目前為 OSA首選治療,特別在改善嗜睡以及血壓上,且其效果在嗜睡明顯病人的效果更好。 現今研究顯示,OSA 是一個複雜性基因疾病且具家族遺傳性,其臨床表型(phenotyping)包括高度表型及中度表型。前者為呼吸相關的障礙如 AHI,後者則分為髗顏特徵及上呼吸道解剖位置、呼吸驅動力及上呼吸道塌陷度、醒睡週期的控制及嗜睡感受力,以及體脂肪堆積及代謝症候群。且其致病分子機制牽涉到多個基因調控的路徑,進而影響併發症的產生。許多研究嘗試釐清候選基因與 OSA 的關聯,但研究結果卻不一致。為了釐清基因型對表型的影響,我們之前研究探討台灣家族 congenital central hypoventilation syndrome (CCHS) 的多變臨床表型,從新生兒因呼吸衰竭致死,到成人從無症狀到清醒及睡眠時皆有換氣低下。存活家族成員的基因篩檢,確認在三位成人發作的 CCHS,具有 PHOX2B gene 25 repeat polyalanine expansions (20/25 genotype)。此外為釐清 ACE I/D polymorphism 跟 OSA 關聯,我們整合分析 10 個研究,結果顯示 ACE I/D polymorphism 跟罹患 OSA 風險無顯著關聯,即使去除掉種族、OSA 患者來源、及高血壓的干擾,ACE I/D genotype 和 allele frequency 與 OSA 風險仍無顯著關聯。 除了上述單一候選基因的研究外,有幾個研究以全基因的篩檢尋找跟 OSA 相關候選基因。Whole genome scan 顯示在高加索人中 chromosomes 2p 及 19p,在非裔美人中chromosomes 8q 與 AHI 的關聯不受 BMI 影響。Whole genome SNP array 顯示與 OSA 相關基因,在歐裔美人為 C-reactive protein (C-RP)與 glial cell line-derived neurotrophic factor (GDNF),在非裔美人為 serotonin receptor 2a (HTR2A)中的 rs9526240。我們之前研究以 oligomicroarray 以及 Pathway Enrichment Analysis 確認了在 CPAP 治療後基因表現改變 1.5 倍以上的 1603 基因。再從 1603 基因,確認 37 個牽涉在 6 個生物路徑的基因。此 6 個生物路徑包括氧化還原、 細胞訊息傳導、 細胞凋亡、細胞沾接及能動性、 細胞週期,及細胞激素。用此 37 基因我們建立三個模式分別來預測基準線時 OSA 相關併發症,以及對 4 星期 CPAP 及 12 星期 CPAP 治療反應。 由於 OSA 有顯著人種差異且仍有許多問題未解,包括某些分子機制、臨床多樣性及治療反應的差別等,因此建立台灣本土 OSA 患者臨床表型資料庫同時釐清與基因型關聯,是回答這些問題重要且迫切的一環。本計劃乃招募台大醫院睡眠中心診斷為中重度OSA 患者為指標病患(index proband)及其一等親及二等親家族成員,以及其二位朋友(control proband)的家族成員為控制組家庭(control family),加上利用文獻發表可能的單一候選基因以及 whole genome SNP array,來從事下三方面研究 (1) 釐清台灣 OSA 病患臨床表型及家族群聚性 (2) 釐清台灣 OSA 病患臨床表型與基因型關聯 (3) 釐清牽涉台灣 OSA 病患臨床表型的分子路徑與基因體。本研究有以下重要性 (1)透過研究台灣 OSA病患的基因表現與臨床表徵之關聯性,可將結果應用於發展臨床診斷與治療,提供個人化醫療處置參考 (2)建立台灣本土 OSA 臨床表型與基因型資料庫,為將來學術研究重要資產 (3)研究成果亦可技轉而衍生科技商機,以呼應政府近年大力推展生技經濟的政策。
Abstract: Obstructive sleep apnea (OSA) is characterized with recurrent collapse of upper airway during sleep resulting in hypoxia and sleep fragmentation. Patients of OSA might have symptoms like snoring, non-restorative sleep, witnessed apnea, and excessive daytime sleepiness. Currently, polysomnography is the gold standard for diagnosing OSA and the apnea-hypopnea index (AHI) is the parameters to indicate the severity of OSA. However, AHI poorly correlated with clinical severity of OSA, where the symptoms of patients with the identical AHI could vary from minimal to striking. The sequels of OSA include cardiovascular diseases, metabolic disorders, and neurocognitive dysfunctions. Till now, continuous positive airway pressure (CPAP) is the standard treatment for OSA where it can effectively improve daytime sleepiness, blood pressure, metabolic abnormalities, and quality of life, especially in patients with daytime sleepiness. The growing evidence showed that the OSA is a heritable complex genetic disease where the genetic basis contributed the development of OSA and its sequel. The phenotyping of OSA include high level and intermediate level. The former indicates the AHI, and later includes craniofacial morphology, ventilator control, obesity, and sleepiness vulnerability. Many studies tried to determine the association of candidate genes with OSA through association studies. However, the results were conflicting. To clarify the influence of genotyping on phenotyping, we reported a Chinese family with congenital central hypoventilation syndrome (CCHS) that had a clinical spectrum ranging from newborn fatality to adulthood. Genetic analysis was used to confirm the presence of the PHOX2B expansion mutation. Moreover, to clarify the association between ACE I/D polymorphisms and OSA, we undertook a meta-analysis on all studies published in this area. It has not demonstrated an association between the ACE I/D polymorphism and OSA susceptibility irrespective of ethnicity, population sample or the presence/absence of co-morbid hypertension. Nowadays, a couple of studies tried to genome-wide profiled the candidate genes involved in the biologic pathway of OSA. The whole genome scan identified chromosomes 2p 及 19p and chromosomes 8q was associated with AHI in Caucasian and African American, respectively, which is independent of BMI. Also, the whole genome SNP array identified candidate genes associated with OSA as C-reactive protein (C-RP) and glial cell line-derived neurotrophic factor (GDNF) in European Americans and rs9526240 within serotonin receptor 2a (HTR2A) in African Americans. We identified 37 candidate genes involved in six biologic pathways of OSA including oxidative phosphorylation, cell signaling, apoptosis, cellular adhesion and motility, cell cycle, and cytokine/chemokine. Furthermore, three models were constructed to predict the sequel and response to 4-week and 12-week CPAP treatment, respectively. Since the presentations of OSA are different among races, hence database of Taiwanese patients with OSA is urgently needed to clarify molecular mechanisms. Through recruiting the patients of moderate-severe OSA (index proband) and their first and second-degree family members, and friends and their family members (control family) and via candidate genes reported in the literature and whole genome SNP array, this project aims to achieves following goals (1) Investigating the phenotyping and familial aggregation of OSA (2) Investigating the association of genotyping on phenotyping of OSA (3) Investigating the candidate genes and the involved biologic pathways of OSA. The anticipated contributions of the results include (1) Highlighting the promise of patient-tailored management (2) Establishing an invaluable database of phenotyping and genotyping of OSA for future research (3) Promoting production of biotechnology patent and business.