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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72717
Title: | 布魯蓋達症候群—找出高危險群 Study on Brugada Syndrome—Identification of high-risk population |
Authors: | Ching-Yu Julius Chen 陳璟毓 |
Advisor: | 賴亮全(Liang-Chuan Lai) |
Co-Advisor: | 江福田(Fu-Tien Chiang) |
Keyword: | 布魯蓋達症候群,心因性猝死,危險性分級,性別差異,家族篩檢,SCN10A,SKAT-O, Brugada syndrome,sudden cardiac death,risk stratification,gender differences,family screening,SCN10A,SKAT-O, |
Publication Year : | 2019 |
Degree: | 博士 |
Abstract: | 布魯蓋達症候群 (Brugada syndrome, BrS) 是一種體顯性遺傳性疾病,病患可能會因心室顫動而猝死。據統計,在心因性猝死 (sudden cardiac death, SCD) 的病患中,約4%是由此病所致。此病好發於東南亞,盛行率約0.12%,而在台灣亦不少見,目前我們研究團隊的收案人數已達到全亞洲最多。為了避免憾事的發生,了解台灣的現況並找出高危險群是至關重要的。
布魯蓋達症候群的猝死好發於40歲前後,因此對於年輕人要積極做危險性分級 (risk stratification),在高風險的病患裝設植入性心臟整流去顫器 (implantable cardioverter-defibrillator, ICD) 可以防止猝死。然而,年長病患的風險是否仍高,是否也需要同等積極,目前相關的研究並不多。我們從5,214位健康年長者(平均69.3歲)的心電圖中發現,典型第一型Brugada心電圖的盛行率為0.077%,而無論是用HRS/EHRA/APHRS還是ISHNE的心電圖標準,有Brugada型心電圖的病患在四年的追蹤期間並沒有較高的死亡率,表示如果在無症狀的年長者身上發現Brugada型心電圖應該不用太擔心。 另外,布魯蓋達症候群好發於男性,男女比約9比1,目前認為跟性荷爾蒙對離子通道的調控有關,我們想知道會不會因此影響女性布魯蓋達症候群的危險度。因為男女人數的懸殊差異,過去的研究結果大多反映了男性布魯蓋達症候群的特徵,並不能直接套用在女性身上,於是我們嘗試比較台灣的布魯蓋達症候群中男女間的差異,發現雖然猝死或暈厥的發生率沒有差異,但女性病患會在較年輕的歲數發生暈厥,且女性較常會有猝死的家族病史和有較長的QTc,而發生猝死或暈厥的女性病患的心跳略慢於無症狀者。因此,女性的布魯蓋達症候群要更積極進行危險性分級,對於心跳慢者要提高警覺,並且要注意她們的家族中是否有潛在病患。 因為布魯蓋達症候群會遺傳,所以對家族成員進行篩檢是必要的,如此可以找出潛在的病患並預防猝死。家族篩檢的工具除了心電圖外,基因檢測也很重要,其中判斷變異 (variant) 的致病性相當關鍵。過去發現比較確定會致病的變異主要是出現在SCN5A這個基因上面,而一些疾病資料庫如ClinVar和HGMD (the Human Gene Mutation Database) 會對過去曾發表過的變異進行致病性的評比。隨著定序技術的發展和普及化,我們可以在網路上查詢到某一變異在許多地區和國家的盛行率,大家開始意識到種族之間的基因多樣性。我們發現一些過去認為罕見且會致病的變異其實在某些種族是很常見的,尤其是SCN5A以外的基因變異,必須重新檢視其致病性。此結果突顯了各種族大型生物資料庫的重要性,並且在評估一個基因變異的致病性時應多方參考其在各種族的盛行率。 雖然SCN5A是目前公認和布魯蓋達症候群最相關的基因,但根據我們的研究,台灣的布魯蓋達症候群病患中只有16.5%可以找到SCN5A的致病變異。如能找到其他與此病相關的基因將有助於家族篩檢。即使過去有許多研究認為尚有其他基因和此病有關,但它們的重要性仍存在爭議。SCN10A是近幾年認為和此病相關的重要基因,發現是透過和SCN5A的互動影響鈉電流。我們利用SKAT-O的計算發現SCN10A的罕見變異 (rare variants, allele frequencies < 1%) 在病患的盛行率明顯高於正常人,顯示其在台灣布魯蓋達症候群的重要致病角色。而我們在3.4%的病患身上找到SCN10A的致病變異,代表這樣的變異並不少見,值得篩檢。 根據上面的研究結果,我們提供在台灣的年長和女性布魯蓋達症候群病患的表現及危險性評估資料,也發現在判斷一個基因變異的致病性時應注意其在其他種族的盛行率。另外,SCN10A對於此病扮演著重要的角色,除了該列入常規篩檢的基因項目,也值得進一步探索其致病機轉。 Brugada syndrome (BrS) is an inheritable arrhythmic disease with a hereditary pattern of autosomal dominance, which could cause ventricular fibrillation and lead to sudden death. It accounts for 4% of sudden cardiac death (SCD). It has the highest prevalence in the Southeast Asia, about 0.12%, and it is also not uncommon in Taiwan. In order to prevent the tragedy, the prevalence and characteristics of the patients with BrS in Taiwan should be investigated, as well as identification of the high-risk population. The mean age of SCD attributed to BrS is around 40 years old. Thus, risk stratification in the young patients should be done aggressively, and implantable cardioverter-defibrillator (ICD) may prevent SCD in high-risk population. However, it is unclear that if the elderly patients also have the risk of SCD, and if an aggressive attitude is still necessary. In a cohort of 5,214 apparently healthy elders (mean 69.3 years old), I found 4 participants (0.077%) with typical type 1 Brugada electrocardiographic pattern (BrP), and the elders with BrP by either the criteria from HRS/EHRA/APHRS or ISHNE didn't have a higher mortality rate than those without BrP in the 4-year follow-up. It seems that BrP in the apparently healthy elders is relatively benign. Furthermore, most patients with BrS are male (male : female = 9 : 1), which is thought to be related to the impact of sexual hormones on the ion channels, and I am interested that if it may also have a prognostic effect in female BrS. Because of the male predominance, most of the past studies reflected the characteristics of male BrS, which could not apply on the female BrS. Therefore, I tried to compare the gender differences of BrS in Taiwan. Although there was no difference in the risk of SCD or syncope between genders, females suffered from syncope earlier than males and had a longer QTc, and the percentage of family history of SCD in females was slightly higher than males. Besides, the females with SCD or syncope had a slightly slower heart rate than those with no or mild symptom. As a result, female BrS deserves more medical attention, especially the female patients with low heart rate, and the potential patients among their family members should be discovered. Because of the heritability of BrS, it is necessary to do family screening in order to find out the potential patients and prevent SCD. Along with electrocardiograms, genetic screening is of class I recommendation, and the way to determine the pathogenicity of a variant is crucial. Currently, the most relevant gene is SCN5A, and several disease databases including ClinVar and HGMD (the Human Gene Mutation Database) analyzed the pathogenicity of the variants reported before. As the technique of sequencing improves and becomes available, the allele frequency of a variant among many areas and countries could be obtained via internet, and it is evident that there is the genetic diversity among ancestries. I found that several previously reported pathogenic rare variants were relative common in some ancestries, especially non-SCN5A variants, whose pathogenicity should be reassessed. This finding emphasized the importance of the large-scaled reference in every ancestry, and the allele frequencies of a variant in different ancestries should be taken into account when determining its pathogenicity. Although SCN5A is currently the most relevant gene in BrS, there were only 16.5% of Taiwanese patients with BrS having SCN5A causative variants according to my study. It is of great value in family screening if other relevant genes could be found. However, several genes reported to be associated with BrS are still controversial. SCN10A is a relevant gene appealing many attentions in these years, which could interact with SCN5A and influence the sodium current. I used the SKAT-O algorithm and found that rare variants (allele frequencies < 1%) of SCN10A were significantly enriched in the BrS patients, which implied the pathogenic role in BrS in Taiwan. Moreover, there were 3.4% of the patients having SCN10A causative variants, which was not uncommon and deserved for screening. According to the above findings, I provided the characteristics and prognosis of the elderly and female patients with BrS in Taiwan, and revealed the importance of allele frequencies of a variant among the thorought ancestries when judging its pathogenicity. Besides, SCN10A has an important role in BrS, and it should be included in the screening panel and deserves further investigation for the mechanism of pathogenesis. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72717 |
DOI: | 10.6342/NTU201902002 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 生理學科所 |
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