Identification of a risk haplotype of the alpha-synuclein gene in Japanese with sporadic Parkinson's disease.

alpha-Synuclein is one of the main components of Lewy bodies, a pathological marker of Parkinson's disease (PD). Certain missense mutations of the alpha-synuclein gene cause familial PD, but the role of the gene in sporadic PD is still controversial. We scrutinized polymorphisms of the alpha-synuclein gene in a Japanese population and investigated their associations with sporadic cases of PD. The 5' flanking region to intron 2 of the alpha-synuclein gene (3.8 kb) and two polymorphisms in intron 4 previously reported in Caucasian sporadic cases of PD were analyzed in 185 sporadic PD and 191 controls. Five novel single nucleotide polymorphisms (SNPs), 16 reported SNPs, and one reported polynucleotide polymorphism (PNP) were found. Most of the polymorphisms examined were in linkage disequilibrium. Significant associations with PD were found in 15 of 21 SNPs, especially in intron 1 (IVS1+155 TmAn PNP and the IVS1+719 C>T SNP, P < 0.0001). Haplotype analysis showed that T10A7-A-A and T11A6-G-G haplotypes at three loci (IVS1+155 - IVS1+273 - IVS1+608) were strongly negative and positive risk factors of sporadic PD, respectively (odds ratios were 0.23 [95% confidence interval, 0.16-0.32] and 1.51 [95% confidence interval, 1.29-1.75]). In conclusion, our findings indicate that genetic variations of the alpha-synuclein gene affect the development of sporadic PD.