α-突觸核蛋白(SNCA)基因被認(rèn)為是帕金森病最可能的易感基因,但目前證據(jù)還不確鑿,。日前,美國梅奧臨床醫(yī)學(xué)院Maraganore等的一項大規(guī)模協(xié)作分析證實,SNCA基因啟動子區(qū)二核苷酸重復(fù)序列(REP1)等位基因長度變異與帕金森病發(fā)病危險增加相關(guān),。
Maraganore等成立了一個全球性遺傳學(xué)協(xié)會——帕金森病遺傳流行病學(xué)協(xié)會,從該協(xié)會的18個分會收集資料進(jìn)行分析。結(jié)果11個分會提供了符合納入標(biāo)準(zhǔn)的總共2692例帕金森病患者和2652名對照者的資料,Maraganore等對其進(jìn)行了匯總分析,。
結(jié)果顯示,帕金森病組與對照組的SNCA REP1各等位基因頻率存在顯著性差異(P<0.001),其中最長的變異——長度為263 bp的等位基因與帕金森病發(fā)病危險增高顯著相關(guān)(OR=1.43,P<0.001);兩組患者的多位點單體型(multilocus haplotypes)頻率存在顯著性差異(P<0.001),而僅有包含REP1位點的雙位點單體型(two-loci haplotypes)與帕金森病發(fā)病危險相關(guān),。
研究提示:據(jù)估計,普通人群中約3%的帕金森病由SNCA REP1位點變異所致。由于上述變異最終導(dǎo)致SNCA過表達(dá),因此阻斷其表達(dá)可能對帕金森病具有治療作用。
部分英文原文：
The potential role of the SNCA gene has been "one of the most promising leads" in the genetics of PD, the authors write, following the "landmark" discovery in 1997 of several families with a rare mutation in the alpha-synuclein gene that was a direct cause of PD. Shortly thereafter, it was observed that a primary constituent of Lewy bodies, a pathological hallmark of all PD patients, is alpha-synuclein protein.
Previous sequencing of the SNCA gene has shown some common variants, including a dinucleotide repeat sequence (REP1) within the promoter, Dr. Maraganore and colleagues point out. SNCA gene expression has a 3-fold variance range across different REP1 alleles, they note, suggesting that the association seen for specific genotypes with increased PD risk may stem from an increase in SNCA transcription.
"There have been a few studies that suggested common variations in the SNCA gene, including this REP1 variation that we focused on, might be associated with an increased risk of PD, but the findings were inconsistent," Dr. Maraganore said. "So we decided that it would be an important task to determine whether in fact common variations in this gene increased risk for PD and whether that in turn could be one of the mechanisms by which alpha-synuclein could be contributing to PD across populations."
To study the gene further, they established a global genetics consortium funded primarily under a grant from the Michael J. Fox Foundation for Parkinson's Research, called the Genetic Epidemiology of Parkinson Disease Consortium, with several objectives: to determine whether variability in the SNCA REP1 allele length is in fact associated with PD susceptibility; whether SNCA promoter haplotypes are associated with PD; and whether REP1 variability modifies the age at disease onset.
