α-突触核蛋白(SNCA)基因被认为是帕金森病最可能的易感基因,但目前证据还不确凿。日前,美国梅奥临床医学院Maraganore等的一项大规模协作分析证实,SNCA基因启动子区二核苷酸重复序列(REP1)等位基因长度变异与帕金森病发病危险增加相关。
Maraganore等成立了一个全球性遗传学协会——帕金森病遗传流行病学协会,从该协会的18个分会收集资料进行分析。结果11个分会提供了符合纳入标准的总共2692例帕金森病患者和2652名对照者的资料,Maraganore等对其进行了汇总分析。
结果显示,帕金森病组与对照组的SNCA REP1各等位基因频率存在显著性差异(P<0.001),其中最长的变异——长度为263 bp的等位基因与帕金森病发病危险增高显著相关(OR=1.43,P<0.001);两组患者的多位点单体型(multilocus haplotypes)频率存在显著性差异(P<0.001),而仅有包含REP1位点的双位点单体型(two-loci haplotypes)与帕金森病发病危险相关。
研究提示:据估计,普通人群中约3%的帕金森病由SNCA REP1位点变异所致。由于上述变异最终导致SNCA过表达,因此阻断其表达可能对帕金森病具有治疗作用。
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.