Kay Denise M, Factor Stewart A, Samii Ali, Higgins Donald S, Griffith Alida, Roberts John W, Leis Berta C, Nutt John G, Montimurro Jennifer S, Keefe Robert G, Atkins April J, Yearout Dora, Zabetian Cyrus P, Payami Haydeh
New York State Department of Health, Division of Genetic Disorders, Wadsworth Center, Albany, New York 12208, USA.
Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5;147B(7):1222-30. doi: 10.1002/ajmg.b.30758.
Point mutations and copy number variations in SNCA, the gene encoding alpha-synuclein, cause familial Parkinson's disease (PD). A dinucleotide polymorphism (REP1) in the SNCA promoter may be a risk factor for common forms of PD. We studied 1,802 PD patients and 2,129 controls from the NeuroGenetics Research Consortium, using uniform, standardized protocols for diagnosis, subject recruitment, data collection, genotyping, and data analysis. Three common REP1 alleles (257, 259, and 261 bp, with control frequencies of 0.28, 0.65, and 0.06) and several rare alleles (combined frequency <0.01) were detected. We confirmed association of REP1 with PD risk [odds ratio (OR) = 0.86, P = 0.006 for 257-carriers; OR = 1.25, P = 0.022 for 261-carriers]. Using a normalization procedure, we showed that the 257 and 261 alleles are both independently associated with PD risk (for 257, P = 0.002 in overall data, 0.003 in non-familial PD, 0.001 in early-onset PD; for 261, P = 0.056 in overall data, 0.024 in non-familial PD, 0.052 in early-onset PD). The 257-associated risk was consistent with a dominant model [hazard ratio (HR) = 0.99, P = 0.91 for 257/257 vs. 257/X where X denotes all other common alleles; HR = 1.16, P = 0.004 for X/X vs. 257/X]. The 261-associated risk was consistent with a recessive model (HR = 1.89, P = 0.026 for 261/261 vs. 261/X; HR = 0.95, P = 0.42 for X/X vs. 261/X). Genotype-specific mean onset ages (+/-SD) ranged from 54.8 +/- 12.1 for 261/261 to 59.4 +/- 11.5 for 257/257, displaying a trend of decreasing onset age with increasing allele size (P = 0.055). Genetic variation in SNCA and its regulatory regions play an important role in both familial and sporadic PD.
编码α-突触核蛋白的基因SNCA中的点突变和拷贝数变异会导致家族性帕金森病（PD）。SNCA启动子中的二核苷酸多态性（REP1）可能是常见形式PD的一个风险因素。我们使用统一、标准化的方案进行诊断、受试者招募、数据收集、基因分型和数据分析，对神经遗传学研究联盟的1802例PD患者和2129例对照进行了研究。检测到三个常见的REP1等位基因（257、259和261bp，对照频率分别为0.28、0.65和0.06）以及几个罕见等位基因（合并频率<0.01）。我们证实了REP1与PD风险的关联[257携带者的优势比（OR）=0.86，P=0.006；261携带者的OR=1.25，P=0.022]。通过归一化程序，我们表明257和261等位基因均独立与PD风险相关（对于257，总体数据中P=0.002，非家族性PD中P=0.003，早发性PD中P=0.001；对于261，总体数据中P=0.056，非家族性PD中P=0.024，早发性PD中P=0.052）。257相关风险与显性模型一致[257/257与257/X（其中X表示所有其他常见等位基因）的风险比（HR）=0.99，P=0.91；X/X与257/X的HR=1.16，P=0.004]。261相关风险与隐性模型一致（261/261与261/X的HR=1.89，P=0.026；X/X与261/X的HR=0.95，P=0.42）。特定基因型的平均发病年龄（±标准差）范围从261/261的54.8±12.1到257/257的59.4±11.5，显示出发病年龄随等位基因大小增加而降低的趋势（P=0.055）。SNCA及其调控区域的基因变异在家族性和散发性PD中均起重要作用。
